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Modern science versus the stigma of obesity
Abstract
Obese people, who are already subject to adverse health effects, are additionally victimized by a social stigma predicated on the Hippocratic nostrum that weight can be controlled by 'deciding' to eat less and exercise more. This simplistic notion is at odds with substantial scientific evidence illuminating a precise and powerful biologic system that maintains body weight within a relatively narrow range. Voluntary efforts to reduce weight are resisted by potent compensatory biologic responses. This article will review some of this evidence, together with promising avenues of research. Further progress in understanding and treating obesity will come not from repetition of anachronistic preconceptions but rather from the rigorous scientific approach that has driven advances in so many other areas of medicine.
... The CNS elicits these functions through three mechanism: (a) controlling foodrelated behaviors, including food intake (b) controlling the autonomic nervous system, which regulate the energy expenditure and other metabolic processes; and (c) controlling the neuroendocrine system by modulating hormone secretion. The modulation and coordination of this complex systems occurs in different brain areas [10,11]. However, it is well known that the hypothalamic neuronal networks integrate peripheral information (i.e., nutrients and hormones) to modulate energy balance [12,13]. ...
... Both neuron types regulate food intake, energy expenditure and nutrient partitioning. When energy intake exceeds expenditure, the expression of orexigenic neuropeptides, such as AgRP and NPY decreases, whereas the expression of anorexigenic neuropeptides, such as CART and POMC increases [3,10]. Opposite changes occur when energy expenditure exceeds intake. ...
Sirtuins are NAD+ dependent deacetylases that regulate a large number of physiological processes. These enzymes are highly conserved and act as energy sensors to coordinate different metabolic responses in a controlled manner. At present, seven mammalian sirtuins (SIRT 1-7) have been identified, with SIRT1 and SIRT6 shown to exert their metabolic actions in the hypothalamus, both with crucial roles in eliciting responses to dampen metabolic complications associated with obesity. Therefore, our aim is to compile the current understanding on the role of SIRT1 and SIRT6 in the hypothalamus, especially highlighting their actions on the control of energy balance.
... This condition is attributed to unhealthy diets (i.e., excessive consumption of high fat, high sugar, and high salt foods and beverages) and physical inactivity (Nguyen et al., 2014). Moreover, different studies in humans and murine models in recent decades have revealed that the interaction between genes and environmental factors also impacts food intake and energy homeostasis favoring the development of obesity (Friedman et al., 2004). ...
... In these models, body fat accumulates over a relatively long period, although the harmful metabolic consequences are evident in a few days. Comparing to the models of gene manipulation, the gradual increase of weight over time in the models of diet-induced obesity is better represented, as it happens in the human population as a consequence of an energy imbalance over several years (Friedman et al., 2004;Guillemot-Legris & Muccioli, 2017). ...
Animal models of experimentation have been an alternative for the study and analysis of the central nervous system (CNS). A strict design can help us understand functions as complex as memory and learning, inform us of the ability of the CNS to respond to external stimuli, to understand what is wrong in cases of illness and even try substances that can alleviate this. In this chapter we will briefly review the phenomenon of epilepsy, in which the neuronal excitation without the fine control of inhibition, can end in the death of neurons of brain regions related to memory and learning such as the hippocampus, or the cerebellum, responsible for movement. We will also review the use of antiepileptics to alleviate this pathology. We will refer to the experimental animal model in which using kainic acid can produce status
epilepticus in rats, characterized by prolonged seizures. Finally, we will present results of experiments using this animal model; performed with the aim of know if the use of antiepileptics not only decreases the frequency and intensity of the seizures, but also if they are able to prevent neuronal damage from increasing, an aspect that in our opinion it has not been completely elucidated.
... This condition is attributed to unhealthy diets (i.e., excessive consumption of high fat, high sugar, and high salt foods and beverages) and physical inactivity (Nguyen et al., 2014). Moreover, different studies in humans and murine models in recent decades have revealed that the interaction between genes and environmental factors also impacts food intake and energy homeostasis favoring the development of obesity (Friedman et al., 2004). ...
... In these models, body fat accumulates over a relatively long period, although the harmful metabolic consequences are evident in a few days. Comparing to the models of gene manipulation, the gradual increase of weight over time in the models of diet-induced obesity is better represented, as it happens in the human population as a consequence of an energy imbalance over several years (Friedman et al., 2004;Guillemot-Legris & Muccioli, 2017). ...
Introduction. Epilepsy affects approximately 1% of the world population and it involves changes at various physiological levels. Carbamazepine (CBZ) is a well-known and commonly prescribed anticonvulsant with the ability to decrease the epileptic effects of Pentylenetetrazole (PTZ). Objective. Evaluate the regulator effect of CBZ on blood electrolyte levels in an animal model of epilepsy induced by PTZ, and the histological changes present in the brain. Method. Ten male Wistar rats were divided into two groups: G1 (n = 5) was administered PTZ (70 mg/kg i.p.) and G2 a dose of CBZ (50 mg/kg i.p.) prior to the dose of PTZ. The parameters evaluated were pH, serum electrolytes (Na+, K+, Ca++), glucose, lactate, hematocrit, and total hemoglobin. Results. The administration of PTZ produced electrolyte imbalance and caused dilatation of vascular capillaries and vessels, and in some cases, a break in the endothelium. A darkening and condensation of neuronal perikarya was observed. Frontal cortex, hippocampus, and cerebellum were deeply affected. Conclusion. The treatment with CBZ contributes to the equilibrium of electrolyte and avoids the neuronal death.
... Contemporary investigations have shown that T2D emerges from a complex interplay between genetic predispositions and environmental influences [21,22]. The rising incidence of diabetes over the last several decades has been linked to socioeconomic changes and lifestyle factors, such as decreased physical activity and a diet high in calories [23]. Emerging studies indicate that compositional changes (dysbiosis) within the human gut microbiota, leading to an imbalance in the production of metabolites, may be a contributing factor in the pathogenesis of T2D. ...
Purpose
Evidence suggests that changes in the composition of gut microbiota may be linked to metabolic disorders including type 2 diabetes (T2D). The present study aims to evaluate the compositional changes of the intestinal microbiota in patients with T2D as compared to healthy individuals.
Methods
In this case-control study, there were 18 T2D patients and 18 healthy individuals who served as controls. To profile the gut microbiota in both groups, bacterial DNA was extracted from fecal samples and analyzed using quantitative real-time polymerase chain reaction (qPCR).
Results
The study discovered that diabetics had significantly greater frequencies of the genus Bacteroides and the phylum Bacteroidetes than did controls (P = 0.03 and P < 0.001, respectively). Conversely, the Actinobacteria and Firmicutes phyla were significantly more abundant in the controls (P=0.01 for both). No significant differences were observed in the fecal populations of the genus Enterococcus, Clostridium clusters IV and XIVa, phylum Proteobacteria, and all bacteria between the studied groups (P=0.88, P=0.56, P=0.8, P=0.99, and P=0.7, respectively).
Conclusions
Our findings confirm that T2D may be associated with the gut microbiota fluctuations. These findings may be valuable for developing strategies to control or treatment T2D by restoring the intestinal microbiota through the strategic administration of specific probiotics/prebiotics and lifestyle and dietary modifications.
... In 2021, 529 million people suffered from diabetes. It is predicted that this number will reach 1.3 billion by 2050 [1]. Prescription drugs and insulin supplementation represent the current primary treatment of T2DM; however, some adverse effects have been noted, including liver difficulties and lactic acidosis [2]. ...
Berberine (BBR) is an isoquinoline alkaloid that can be extracted from herbs such as Coptis, Phellodendron, and Berberis. BBR has been widely used as a folk medicine to treat various disorders. It is a multi-target drug with multiple mechanisms. Studies have shown that it has antioxidant and anti-inflammatory properties and can also adjust intestinal microbial flora. This review focused on the promising antidiabetic effects of BBR in several cellular, animal, and clinical studies. Based on previous research, BBR significantly reduced levels of fasting blood glucose, hemoglobin A1C, inflammatory cytokines, and oxidative stress markers. Furthermore, BBR stimulated insulin secretion and improved insulin resistance through different pathways, including up-regulation of protein expression of proliferator-activated receptor (PPAR)-γ, glucose transporter (GLUT) 4, PI3K/AKT, and AMP-activated protein kinase (AMPK) activation. Interestingly, it was demonstrated that BBR has protective effects against diabetes complications, such as diabetic-induced hepatic damage, cardiovascular disorders, nephropathy, and neuropathy. Furthermore, multiple clinical trial studies have emphasized the ameliorative effects of BBR in type 2 diabetic patients.
... Although more information is still needed about potential causal relationships between weight-related humor and anti-fat attitudes, the fact that the two are associated could inform some media practices. A growing body of scientific literature suggests that negative depictions of people with obesity can affect viewers' anti-fat attitudes (Pearl, Puhl, & Brownell, 2012;Puhl, Luedicke, & Heuer, 2013) and even 1 In fact it may be that some people believe stigma is beneficial and assists in motivating others to exert more control over their weight (Friedman, 2004;Puhl & Brownell, 2003). However additional research has shown experiences of stigma may actually be harmful to weight loss efforts (Vartanian & Shaprow, 2008;Wott & Carels, 2009). ...
One of the few stigmatized conditions still considered “fair game” for public joking and ridicule is obesity. The standard for TV and film comedies is to show overweight characters in a stereotypical and disparaging manner. The body of research on disparaging humor has not yet sought to determine viewers’ attitudes toward weight-related humor. Of primary interest in the present study was whether reactions to humor vary systematically with viewers’ preexisting attitudes toward obesity. Participants (N = 501) viewed 7 video clips from popular film and TV programs featuring weight-related humor. Participants then rated each clip on a number of dimensions (e.g., funniness, offensiveness). Additionally they completed measures of attitudes and beliefs toward obesity including dislike for obese persons, belief in the controllability of body weight, and a belief in stereotypes about obese persons. As predicted, participants’ dislike for obese persons and their belief in disparaging stereotypes about obesity are associated with higher levels of weight-related humor appreciation. Additionally, a stronger belief in disparaging stereotypes about obesity and a belief in the controllability of obesity are negatively related to individuals’ level of distaste for weight-related humor. These findings support the empirical basis of disparagement humor theory and the disposition theory of humor appreciation. They can also inform research on the stigma of obesity and representations of stigmatized groups in the media.
... In the patients with ALI/ARDS, the level of BALF leptin in non-obese patients was 6-fold higher than obese patients [102], suggesting that the inhibited expression of pulmonary leptin by obesity could be a contributor to the obesity paradox in ALI/ARDS. Furthermore, obese individuals with type II diabetes are less likely to develop ALI/ARDS and have a reduced mortality after ALI/ARDS [33, 104,105], which could be resulting from leptin resistance, a common feature of obese patients with type II diabetes [106,107]. Compared with WT mice of ALI/ARDS, the db/db mice (leptin resistance) with ALI/ARDS manifested reduced pulmonary damage and improved survival [103], which could be due to the up-regulated level of peroxisome proliferator-activated receptor (PPAR)-γ, an inhibitor of the TGF-β1 [108] and pulmonary fibrosis [109]. Jain et al. [102] found that db/db mice show resistance to the increase of TGF-β1 and pulmonary fibrosis caused by intratracheal instillation of bleomycin. ...
Background:
Obesity is a globally increasing health problem that impacts multiple organ systems and a potentially modifiable risk factor for many diseases. Obesity has a significant impact on lung function and is strongly linked to the pathophysiology that contributes to lung diseases. On the other hand, reports have emerged that obesity is associated with a better prognosis than for normal weight individuals in some lung diseases, including pneumonia, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and lung cancer. The lesser mortality and better prognosis in patients with obesity is known as obesity paradox. Whilst obesity paradox is both recognized and disputed in epidemiological studies, recent research has suggested possible mechanisms.
Summary:
In this review, we attempts to explain and summarize these factors and mechanisms, including immune response, pulmonary fibrosis, lung function, microbiota, fat and muscle reserves, which are significantly altered by obesity and may contribute to the obesity paradox in lung diseases. We also discuss contrary literature that attributes the "obesity paradox" to confounding.
Key messages:
The review will illustrate the possible role of obesity in the prognosis or course of lung diseases, leading to a better understand of the obesity paradox and provide hints for further basic and clinical research in lung diseases.
... Cellular lipid deposition is reduced, and gene expression linked to lipid accumulation is downregulated when HSCs are activated. Leptin controls the activation of HSCs during fibrogenesis, which optimizes lipid metabolism and energy restoration [160][161][162]. According to research, curcumin inhibits the activation of leptin by decreasing the leptin receptor phosphorylation while enhancing PPAR-γ activity, which disrupts leptin signaling [163]. ...
The liver is a vital organ that plays a crucial role in the physiological operation of human 25 body. The liver controls the body's detoxification processes as well as the storage and breakdown 26 of red blood cells, plasma protein and hormone production, and red blood cell destruction; therefore 27 it is vulnerable to their harmful effects, making it more prone to illness. The most frequent compli-28 cations of chronic liver conditions include cirrhosis, fatty liver, liver fibrosis, hepatitis, and illnesses 29 brought on by alcohol and drugs. Hepatic fibrosis involves activation of hepatic stellate cells to cause 30 persistent liver damage through accumulation of cytosolic matrix proteins. The purpose of this re-31 view is to educate concise discussion of the epidemiology of chronic liver disease, the pathogenesis 32 and pathophysiology of liver fibrosis, the symptoms of liver fibrosis progression and regression, 33 the clinical evaluation of liver fibrosis and the research into nanotechnology based synthetic and 34 herbal treatments for the liver fibrosis is summarized in this article. The herbal remedies summa-35 rized in this review article includes epigallocathechin-3-gallate, silymarin, oxymatrine, curcumin, 36 tetrandrine, glycyrrhetinic acid, salvianolic acid, plumbagin, Scutellaria baicalnsis Georgi, astragalo-37 sides, hawthorn extract and andrographolides. 38
... The central signalling of leptin has a role in regulating metabolic activity in the peripheral tissues (Ahima and Osei, 2004;Richard et al., 2010). Increasing human obesity and type 2 diabetes have focused attention on the role that leptin that plays in food intake regulation and energy balance (Friedman, 2004;Myers et al., 2010). However, leptin is a pleiotropic molecule that also plays a role in development and physiology. ...
Leptin is a 16 kDa protein hormone thought to provide a metabolic link between nutritional status and reproduction in mammals. Since leptin's discover in 1994. Leptin is a polypeptide hormone, which is primarily produced by white adipose tissue and has a role for regulating food intake and energy metabolism. Leptin is mainly made by adipose tissue, but there are another organs can produce leptin, such as, placenta, liver, skeletal muscle and stomach. Research laboratories have attempted to discover this hormone's effects on reproduction, many data have been published in both humans and animals. Most studies show that the exogenous treatment of leptin to ob/ob mutant male and female mice restores their fertility, whereas the high levels of leptin in male or female subjects exhibits an inhibitory reproductive effects, whereas lower leptin levels are stimulatory. Therefore this study was conducted to illustrate the effects of leptin on the reproductive function in mammals
... The interaction between genes and diets is fundamental in human evolution. Studying the interactions between nutrition and genetic provides a better insight into the variability in biological response to nutrients, but still, this explains around 40-70% variability (Friedman 2004). Nutrigenomics, also known as nutritional genomics, is broadly defined as the relationship between nutrients, diet, and gene expression (Chadwick 2004). ...
Among the main challenges in nutrition research are development of strategies for providing dietary solutions that help people adjust their dietary needs and behavior at every stage of their life. An appropriate diet will maintain the body in good health and therefore prevent chronic diseases associated with dietary excess. Personalized nutrition is a novel approach that recommends food choices and eating patterns that meet individual needs and follow personal preferences. Over the last century, nutrition research has progressively incorporated small bodies of knowledge into the puzzle of personalization, including considering diet as a treatment for different diseases, biochemical markers, anthropometric markers, food frequency questionnaires, nutrigenetic and nutrigenomic information, and incipient nutritional genetic risk scores. Other factors will also need consideration, such as food sustainability, environmental protection, food security, cultural variations, allergies and intolerances, among others. This greatly complicates the matter of promoting personalized nutrition. Recent research aimed at predicting individual response to a nutrient includes use of deep phenotyping (i.e., through continuous postprandial monitoring), microbiota, and epigenetic data that will shape future precision nutrition approaches. Despite advances in personalized nutrition, many obstacles and challenges remain before its full benefits can transition from bench side to bedside. For instance, it requires specialized healthcare professionals, competitive costing, and potential customers ready to understand and accept new nutritional approaches. This chapter is an overview of how individualization has been shaping approaches to personalized nutrition including its social impact, business and value creation, social concerns, ethical and legal concerns, communication, and consumer attitudes toward personalized nutrition. Overall, developing precision nutrition must integrate biology, environment, and lifestyle. Although biology may remain fairly constant throughout life, both environment and lifestyle change constantly through epigenetic mechanisms. Moreover, integrating these data for every period of life will require new resources for large-scale data analysis, such as artificial intelligence and machine learning algorithms.
... The articles referenced in this mini-review focused on general aspects of obesity [1][2][3][4]6,9,10,13,14,21], neuroendocrine control of metabolism [5,7,8,[15][16][17][18][19][20][22][23][24][25], non-alcoholic fatty liver disease [11,12], unimolecular polypharmacy [108], and the experimental articles referred to FGF21 expression or referred to the metabolic actions elicited by FGFRs mimetics or activators 107,108]. ...
Fibroblast growth factor 21 is a pleiotropic hormone secreted mainly by the liver in response to metabolic and nutritional challenges. Physiologically, fibroblast growth factor 21 plays a key role in mediating the metabolic responses to fasting or starvation and acts as an important regulator of energy homeostasis, glucose and lipid metabolism, and insulin sensitivity, in part by its direct action on the central nervous system. Accordingly, pharmacological recombinant fibroblast growth factor 21 therapies have been shown to counteract obesity and its related metabolic disorders in both rodents and nonhuman primates. In this systematic review, we discuss how fibroblast growth factor 21 regulates metabolism and its interactions with the central nervous system. In addition, we also state our vision for possible therapeutic uses of this hepatic-brain axis.
... The secretion of leptin is diminished all along with fasting and increased after feeding. The level of leptin is changed by several metabolic and hormonal factors [98]. ...
The maintaining body weight is momentous in quality life. Appetite takes an important role in establishing the balance of daily food absorption and spent energy and, accordingly, controlling body weight. There is a complex physiological control regulation in the maintenance of energy balance. The regulation of appetite is carried out by central and peripheral signals. The hypothalamus, brainstem, and reward centers, which are involved in central regulation, provide manage of food absorption by integrating signals from the peripheral. Gastrointestinal hormones in the peripheral system regulate the digestion and absorption of nutrients. In the central nervous system, these hormones act as neurotransmitters. The ability to adjust food absorption in response to changes in energy status is an essential component of maintaining energy homeostasis. In cases where energy homeostasis cannot be balanced, it risks human life and causes a decrease in their quality of life. Diseases such as anorexia, which is characterized by low body weight, or obesity, which is characterized by increased body weight, may be occur. A full understanding of the mechanism of appetite may offer new treatment opportunities in the elimination of diseases and complications that may develop due to these diseases. In this context, central and peripheral processes in the adjustment of food intake were reviewed in our study.
... Childhood obesity remains a major global health challenge that continues to place a significant health and financial burden on populations worldwide [1,2]. Because obesity is preventable, a multifactorial approach is needed with global and local strategies to alleviate the associated health burden on societies and financial burden on the health system [3]. ...
Objective:
To determine the impact of a family-based assessment-and-intervention healthy lifestyle programme on health knowledge and beliefs of children and families affected by obesity. Second, to compare the health knowledge of the programme cohort to those of a national cohort in Aotearoa/New Zealand (NZ).
Design:
This mixed-methods study collected health knowledge and health belief data in a questionnaire at baseline and 12-, 24-, and 60-month follow-up assessments. Health knowledge over time was compared with baseline knowledge and with data from a nationally representative survey. A data-driven subsumption approach was used to analyse open-text responses to health belief questions across the study period.
Setting:
Taranaki region, a mixed urban-rural setting in NZ.
Participants:
Participants (caregiver/child dyads) from the Whānau Pakari randomised trial.
Results:
A greater proportion of the cohort correctly categorised foods and drinks as healthy or unhealthy at 12 months compared to baseline for most questionnaire items. Retention of this health knowledge was evident at 24- and 60-month follow-ups. More than twice as many participants correctly reported physical activity recommendations at follow-up compared to baseline (p < 0.001). Health knowledge of participants was similar to the national survey cohort at baseline, but surpassed it at 12 and 24 months. Participant beliefs around healthy lifestyles related to physical functioning, mental and emotional wellbeing, and enhancement of appearance, and gained greater depth and detail over time.
Conclusions:
This study demonstrates the important role that community-level healthy lifestyle programmes can have in knowledge-sharing and health promotion.
... 7) Obesity is a worldwide epidemic and is associated with the development of lifestyle-related diseases such as cardio-vascular disease, type 2 diabetes mellitus, hypertension, and cancer. [8][9][10][11] Obesity is a complex medical condition characterized by the accumulation of abnormal fat, in most cases as a result of increased food intake and/or decreased exercise. 12) Accumulation of excessive adipose tissue is attributed to both an increased number (hyperplasia) and enlarged size (hypertrophy) of adipose cells. ...
Prostaglandins (PGs) are lipid-derived autacoids that are synthesized from arachidonic acid by the action of cyclooxygenases and PG terminal synthases. PGs consist of PGD2, PGE2, PGF2α, prostacyclin (PGI2), and thromboxane A2, which act through G protein-coupled receptors. PGs sustain homeostatic functions and exert a variety of pathophysiological roles to regulate the development of various diseases such as obesity and dyslipidemia. Adipocytes (fat cells) have the unique capacity to accumulate large amounts of lipids as energy source in lipid droplets. Adipogenesis is the process of differentiation from preadipocytes to mature adipocytes, which is regulated by various adipogenic transcription factors. Obesity is defined as an abnormal increase in adipose tissue mass and is considered to be a risk factor for the development of lifestyle-related diseases including cardiovascular disease, hyperlipidemia, and type 2 diabetes mellitus. This review summarizes insights into the roles of PGD2, PGF2α, and their synthases in the regulation of adipogenesis and obesity.
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... O besity is a medical symptom in which the body fat accumulates excessively to the extent that it is harmful to health. 1 It increases the risk of cardiopathy, type 2 diabetes, dyslipidemia, hypertension, infections, cancer, osteoarthritis, respiratory and gynecological problems, as well as being a social stigma. 2 It is caused by an imbalance between energy intake and expenditure, subsequently resulting in excess adipose accumulation. 3 In addition, increasing evidence suggests that obesity is related to a chronic inflammation based on the abnormal cytokines such as IL-6 and TNF-a, along with the activation of pro-inflammatory signaling pathways. ...
Walnut kernel is a traditional Chinese herb recorded in the Chinese Pharmacopoeia with the efficacies of invigorating kidney, tonifying lung, and relaxing bowel. However, the potential mechanisms were unclear. This article aims to uncover the interdict mechanisms of walnut meal extracts (WMP) on high-fat diet (HFD) induced metabolic disorders in rats and reveal how the WMP benefits are associated with changes in the intestinal flora. Sprague-Dawley (SD) rats were fed a standard chow diet or an HFD for 18 weeks. After 6 weeks, the HFD rats were supplemented with 750 mg WMP/kg body weight or the vehicle for 12 weeks. The structure of gut microbiota was assessed by analyzing 16S rDNA sequences. WMP suppressed the weight gain and visceral obesity. WMP treatment also improved lipid profiles and increased antioxidative activities. WMP fully reversed hepatic steatosis with the upregulation of adipocytokines involved in lipid catabolism (e.g., adiponectin, PPAR-γ, visfatin, CEBPα) and the increased activities of lipoprotein lipase and hormone-sensitive lipase, which were associated with glucose tolerance improvement and insulin resistance (IR) mitigation. As revealed by 16S rDNA sequencing, WMP restored the diversity of intestinal flora reduced by HFD. WMP dramatically reduced the abundance of Gram-negative bacteria, especially Fusobacterium varium and Bacteroides vulgatus, and sharply increased the abundance of Lactobacillus animalis decreased by HFD. Our findings demonstrated that WMP suppressed the weight gain and adiposity in HFD-fed rats and fully reversed HFD induced IR and hepatic steatosis while dramatically reducing the abundance of Fusobacteriaceae and Enterobacteriaceae, underscoring the gut-liver axis as a primary target of walnut polyphenols.
... Therefore, the management objective for individuals with inherited subtypes should be along the continuum of 'fit but fat'. The refusal to appreciate this reality has led to unrealistic expectations, management 'failure', and the stigmatization of individuals with an inherited obese phenotype [71,72]. ...
The etiology of obesity is complex and idiosyncratic—with inherited, behavioral, and environmental factors determining the age and rate at which excessive adiposity develops. Moreover, the etiologic status of an obese phenotype (how and when it developed initially) strongly influences both the short-term response to intervention and long-term health trajectories. Nevertheless, current management strategies tend to be ‘one-size-fits-all’ protocols that fail to anticipate the heterogeneity of response generated by the etiologic status of each individual’s phenotype. As a result, the efficacy of current lifestyle approaches varies from ineffective and potentially detrimental, to clinically successful; therefore, we posit that effective management strategies necessitate a personalized approach that incorporates the subtyping of obese phenotypes. Research shows that there are two broad etiologic subtypes: ‘acquired’ and ‘inherited’. Acquired obesity denotes the development of excessive adiposity after puberty—and because the genesis of this subtype is behavioral, it is amenable to interventions based on diet and exercise. Conversely, inherited obesity subsumes all forms of excessive adiposity that are present at birth and develop prior to pubescence (pediatric and childhood). As the inherited phenotype is engendered in utero, this subtype has irreversible structural (anatomic) and physiologic (metabolic) perturbations that are not susceptible to intervention. As such, the most realizable outcome for many individuals with an inherited subtype will be a ‘fit but fat’ phenotype. Given that etiologic subtype strongly influences the effects of intervention and successful health management, the purpose of this ‘perspective’ article is to provide a concise overview of the differential development of acquired versus inherited obesity and offer insight into subtype-specific management.
... Various peripherally derived endocrine factors regulate food intake by jointly acting on defined neurocircuits in the hypothalamus and other brain regions [103][104][105][106] (Box 1; Fig. 2). Although this tightly controlled system is pivotal for survival, it has emerged as a major obstacle to achieving sizeable body weight reduction, as it progressively defends against negative energy balance and undernutrition [107][108][109][110] . ...
Enormous progress has been made in the last half-century in the management of diseases closely integrated with excess body weight, such as hypertension, adult-onset diabetes and elevated cholesterol. However, the treatment of obesity itself has proven largely resistant to therapy, with anti-obesity medications (AOMs) often delivering insufficient efficacy and dubious safety. Here, we provide an overview of the history of AOM development, focusing on lessons learned and ongoing obstacles. Recent advances, including increased understanding of the molecular gut–brain communication, are inspiring the pursuit of next-generation AOMs that appear capable of safely achieving sizeable and sustained body weight loss.
... by activation of the JNK2-PI3K cascade in response to leptin in POMC neurons. Although leptin has many functions, including effects on control of hormone release, immune system, vasculature, development, somatosensory thalamic activity and higher-level cognitive functions (Haynes et al., 1999;Kim and Moustaid-Moussa, 2000;Friedman, 2004;Myers et al., 2008;Domingos et al., 2011;Farr et al., 2014;Perissinotti et al., 2018); one of its prominent roles is as effector of the negative feedback loop, supporting homeostatic control of energy and food intake, and adipose tissue mass (Ahima et al., 1996). The majority of neurons in our hypothalamic cultures were leptin-activated, in line with a higher abundance of POMC positive neurons detected by ICC. ...
Leptin regulates hypothalamic POMC⁺ (pro-opiomelanocortin) neurons by inducing TRPC (Transient Receptor Potential Cation) channel-mediate membrane depolarization. The role of TRPC channels in POMC neuron excitability is clearly established; however, it remains unknown whether their activity alone is sufficient to trigger excitability. Here we show that the right-shift voltage induced by the leptin-induced TRPC channel-mediated depolarization of the resting membrane potential brings T-type channels into the active window current range, resulting in an increase of the steady state T-type calcium current from 40 to 70% resulting in increased intrinsic excitability of POMC neurons. We assessed the role and timing of T-type channels on excitability and leptin-induced depolarization in vitro in cultured mouse POMC neurons. The involvement of TRPC channels in the leptin-induced excitability of POMC neurons was corroborated by using the TRPC channel inhibitor 2APB, which precluded the effect of leptin. We demonstrate T-type currents are indispensable for both processes, as treatment with NNC-55-0396 prevented the membrane depolarization and rheobase changes induced by leptin. Furthermore, co-immunoprecipitation experiments suggest that TRPC1/5 channels and CaV3.1 and CaV3.2 channels co-exist in complex. The functional relevance of this complex was corroborated using intracellular Ca²⁺ chelators; intracellular BAPTA (but not EGTA) application was sufficient to preclude POMC neuron excitability. However, leptin-induced depolarization still occurred in the presence of either BAPTA or EGTA suggesting that the calcium entry necessary to self-activate the TRPC1/5 complex is not blocked by the presence of BAPTA in hypothalamic neurons. Our study establishes T-type channels as integral part of the signaling cascade induced by leptin, modulating POMC neuron excitability. Leptin activation of TRPC channels existing in a macromolecular complex with T-type channels recruits the latter by locally induced membrane depolarization, further depolarizing POMC neurons, triggering action potentials and excitability.
... Type 2 diabetes mellitus (T2DM) is a metabolic disease that is characterized by hyperglycemia and results from insulin resistance and insufficient insulin secretion [1]. e incidence of T2DM is rapidly increasing due to changes in lifestyle and habits, including increased calorie intake and decreased physical exercise, accompanied by increasing burdens on medical services [2,3]. Currently, the main treatment for T2DM is oral medications and insulin supplements. ...
The Ge-Gen-Jiao-Tai-Wan (GGJTW) formula has been used to treat type 2 diabetes mellitus (T2DM) in China for a long time. Our previous study has proved that GGJTW could alleviate the type 2 diabetic symptoms, but the underlying mechanisms are still unclear. This study aimed to investigate the changes in gut microbiota and primary bile acids (PBAs) to determine the potential mechanisms of GGJTW in treating T2DM.The fecal transplant method and pseudogerm-free rats were used in our study.The16S rRNA gene sequencing method was used to analyze the changes in the intestinal flora, and PBAs in the colon contents were detected. Finally, the expression of farnesoid X receptor (FXR), G protein-coupled membrane receptor 5 (TGR5), and glucagon-like peptide-1 (GLP-1) was assessed. Following GGJTW treatment, we observed a decrease in blood glucose levels and improvements in glucose tolerance and serum lipid levels. Furthermore, we found that GGJTW could regulate the composition of the gut microbiota and upregulate the diabetic beneficial phylum Firmicutes and bile-acid-related genus Lactobacillus. PBAs in the colon contents were increased in the GGJTW-treated group, accompanied by upregulated expression of the bile acid receptors FXR and TGR5 and increased concentrations of GLP-1. These results indicated that GGJTW could alleviate symptoms of type 2 diabetic rats by regulating the gut microbiota, promoting the production of PBAs, and upregulating the PBA-FXR/TGR5-GLP-1 pathway.
... Obesity is a medical symptom in which excess body fat accumulates to the extent that it may have an adverse effect on health [1]. It increases the risk of cardiopathy, type 2 diabetes, dyslipidemia, hypertension, infections or cancer, osteoarthritis, respiratory or gynecological problems [2]. It occurs owing to an imbalance between energy intake and expenditure, resulting in subsequent excess adipose accumulation [3]. ...
Background: This paper aims to investigate the metabolic impact of walnut meal extracts rich in polyphenols (WMP) on high fat diet (HFD)-fed rats and to determine whether the lipid-lowering effects are related to modulations of the gut microbiota. SD rats were fed a standard chow diet or an HFD for 18 weeks. After 6 weeks, the HFD rats were supplemented with 750mg WMP/kg body weight and the vehicle for 12 weeks. The structure of gut microbiota was assessed by analyzing 16S rDNA sequences.
Results: WMP suppressed the weight gain and visceral obesity. WMP treatment also improved lipid profiles and increased antioxidative activities. WMP fully reversed hepatic steatosis with upregulation of adipocytokines involved in lipid catabolism (e.g. adiponectin, PPAR-γ, visfatin, CEBPα), and increased the activity of lipoprotein lipase, hormone-sensitive lipase, in which were associated with glucose tolerance improved and insulin resistance mitigated. As revealed by 16S rDNA sequencing, WMP restored the diversity of intestinal flora reduced by HFD, dramatically reduced the abundance of Fusobacterium varium and Enterobacteriaceae, reversed and sharply raised the abundance of Lachnospiraceae UCG005 and Akkermansia decreased by HFD.
Conclusion: Our findings demonstrated that WMP suppressed the weight gain and adiposity in HFD-fed rats, and fully reversed HFD diet-induced insulin resistance and hepatic steatosis while dramatically reduced the abundance of Fusobacteriaceae and Enterobacteriaceae, underscoring the gut-liver axis as a primary target of walnut polyphenols.
... Aujourd'hui, la société est obsédée par la maigreur, qui est mise en évidence par les concours de beauté, la mode et une culture qui façonne la perception de la société concernant l'idéal féminin de la beauté, entre autres le corps, le poids et la forme des femmes. Par conséquent, cet idéal féminin de beauté s'accompagne de nouveaux problèmes tels que le manque de satisfaction de l'image corporelle et l'anorexie (Bonafini & Pozzilli, 2011 (Friedman, 2004). En outre, Shakespeare, comme beaucoup d'autres auparavant, ont souvent perçu ou considéré l'obésité comme hilarante, un phénotype physique dont on peut facilement se moquer (Buchwald & Knatterud, 2000). ...
Texte intégral accessible uniquement aux membres de l'Université de Lorraine jusqu'en février 2021.
... [1] Data have shown that the world population is facing a surge in T2DM and prediabetes due to rapid changes in lifestyle, including a growing availability of food high in calories and a decline in physical activity. [2] Approximately 5% of the population worldwide has been diagnosed as suffering from T2DM, and this level is projected to increase to 9.9% by 2030. [3] For patients whose diabetic duration is less than 5 years, DR morbidity is approximately 38% to 39%, and for those whose duration is 5 to 10 years, the morbidity is approximately 50% to 56.7%, whereas for patients whose diabetic duration is more than 10 years, the morbidity is approximately 69% to 90%. ...
Background:
Diabetes is a chronic metabolic disease characterized by elevated blood glucose levels due to insulin resistance and β-cell dysfunction. In China, Huangyusang decoction (HYS) has been widely used to treat Type 2 diabetes. However, there is no systematic review found. In order to evaluate the efficacy and safety of HYS in the treatment of Type 2 diabetes, we need to conduct a meta-analysis and systematic evaluation.
Methods:
We will enroll the randomized controlled trials (RCTs) evaluating the effectiveness and safety of HYS in the treatment of Type 2 diabetes. Data come mainly from 4 Chinese databases (CNKI, Wanfang, CBM, and VIP Database) and 4 English databases (PubMed, Embase, Cochrane Library, and Web of science). The enrollment of RCTs is from the starting date of database establishment till January 30, 2021. Fasting blood glucose is considered as the main indicator of the dyslipidemia, while the body mass index, glycated hemoglobin, fasting insulin, triglycerides, and cholesterol are regarded as the secondary indicators. There are safety indicators including liver enzyme and kidney function. The work such as selection of literature, data collection, quality evaluation of included literature, and assessment of publication bias will be conducted by 2 independent researchers. Meta-analysis will be performed by RevMan 5.0 software.
Results:
This study will provide high-quality evidence for the effectiveness and safety of HYS in the treatment of type 2 diabetes.
Conclusion:
The results of the study will help us determine whether HYS can effectively treat type 2 diabetes.
Ethics and dissemination:
This study does not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal.
Osf registration number:
DOI 10.17605/OSF.IO/AXBRV.
... Therefore, there is a critical need for efficacious therapeutic approaches for obesity. Active research continues to improve our understanding of mechanisms of energy balance, appetite, satiety, eating behavior, genetics, and environmental, and psychological aspects of obesity (Ahima & Antwi, 2008;Arora & Anubhuti, 2006;Friedman, 2004;Goodarzi, 2018;Kim et al., 2019;Maes, Neale, & Eaves, 1997;Pavlov & Tracey, 2012;Romieu, et al., 2017;Roth et al., 2016;Verdich et al., 2001). This research resulted in generating several anti-obesity drugs, including pancreatic lipase inhibitors, gamma-aminobutyric acid receptor agonists, a serotonin 2C receptor agonist, opioid antagonist, dopamine-norepinephrine reuptake inhibitor, and glucagon-like peptide-1 receptor agonists (Bessesen & Van Gaal, 2018). ...
Obesity and the metabolic syndrome (MetS), which have reached pandemic proportions significantly increase the risk for type 2 diabetes, cardiovascular disease, and other serious conditions. Recent data with COVID-19 patients indicate that obesity also is a significant risk factor for this novel viral disease and poor outcome of associated critical illness. These findings considerably change the view of obesity as a driver of serious, but slowly-progressing chronic diseases, and emphasize the urgency to explore new therapeutic approaches. Inflammation is a recognized driver of metabolic derangements in obesity and MetS, and a core feature of COVID-19 pathobiology. Recent advances in our understanding of inflammatory regulation have highlighted the role of the nervous system and the vagus nerve-based inflammatory reflex. Current bioelectronic and pharmacological therapeutic explorations centered on the inflammatory reflex offer new approaches for conditions characterized by immune and metabolic dysregulation and for ameliorating the escalating burden of obesity, MetS, and COVID-19.
... Leptin is an adipocyte-derived hormone that regulates food intake, energy homeostasis, and body weight (Friedman, 2004;Friedman & Halaas, 1998). Leptin exerts its function by activating the leptin receptor (Ob-R) expressed in the hypothalamus and other peripheral tissues. ...
Leptin is known to selectively suppress neural and taste cell responses to sweet compounds. The sweet suppressive effect of leptin is mediated by the leptin receptor Ob‐Rb, and the ATP‐gated K⁺ (KATP) channel expressed in some sweet‐sensitive, taste receptor family 1 member 3 (T1R3)‐positive taste cells. However, the intracellular transduction pathway connecting Ob‐Rb to KATP channel remains unknown. Here we report that phosphoinositide 3‐kinase (PI3K) mediates leptin's suppression of sweet responses in T1R3‐positive taste cells. In in situ taste cell recording, systemically administrated leptin suppressed taste cell responses to sucrose in T1R3‐positive taste cells. Such leptin's suppression of sucrose responses was impaired by co‐administration of PI3K inhibitors (wortmannin or LY294002). In contrast, co‐administration of signal transducer and activator of transcription 3 inhibitor (Stattic) or Src homology region 2 domain‐containing phosphatase‐2 inhibitor (SHP099) had no effect on leptin's suppression of sucrose responses, although signal transducer and activator of transcription 3 and Src homology region 2 domain‐containing phosphatase‐2 were expressed in T1R3‐positive taste cells. In peeled tongue epithelium, phosphatidylinositol (3,4,5)‐trisphosphate production and phosphorylation of AKT by leptin were immunohistochemically detected in some T1R3‐positive taste cells but not in glutamate decarboxylase 67‐positive taste cells. Leptin‐induced phosphatidylinositol (3,4,5)‐trisphosphate production was suppressed by LY294002. Thus, leptin suppresses sweet responses of T1R3‐positive taste cells by activation of Ob‐Rb–PI3K–KATP channel pathway.
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... Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia, which is one of the most common chronic diseases. Its incidence rate increases steadily together with the improvement of living level and population aging, which represents an increasing burden to medical services [1]. Oral drugs and insulin supplement are the current main treatment of T2DM, but some side effects, such as liver problems, and lactic acidosis, are noted [2]. ...
Objective:
Berberine (BBR), which is extracted from traditional Chinese herb, is abundant in Coptis chinensis and Berberis vulgaris, with a treatment on type 2 diabetes mellitus (T2DM). However, its oral bioavailability is poor. Therefore, the ability of BBR to regulate gut microbiota and intestinal metabolites might exist. This study aimed to investigate changes in gut microbiota and intestinal metabolites, and to reveal the potential mechanism of BBR.
Methods:
To observe the role of gut microbiota in the treatment of T2DM by BBR, antibiotics intervened gut microbiota was used in this study, and the therapeutic effects of BBR were evaluated. A 16S rRNA gene sequencing approach was utilized to analyze gut microbiota alterations, and UHPLC-QTOF/MS-based untargeted metabolomics analysis of colon contents was used to identity differential intestinal metabolites. Finally, serum aromatic amino acids (AAAs) were absolutely quantified using LC/MS.
Results:
Inhibition of the blood glucose levels, and improvements in glucose tolerance and serum lipid parameters were observed in the BBR treated group. Type 2 diabetic symptoms in rats in the BA group (treated with antibotics and BBR) were alleviated. However, the therapeutical effects are weaker in the BA group compared with the BBR group, indicating that BBR can be used to treat type 2 diabetic rats immediately, and modulation of gut microbiota is related to the mechanism of BBR in the treatment of T2DM. The community richness and diversity of the gut microbiota were significantly increased by BBR, and the relative abundance of Bacteroidetes was increased in the BBR group, which was accompanied by a decreased relative abundance of Proteobacteria and Verrucomicrobia at the phylum level. At the family level, a probiotic Lactobacillaceae was significantly upregulated not only in the BBR group but also in the BA group and was negatively associated with the risk of T2DM. Metabolomic analysis of colon contents identified 55 differential intestinal metabolites between the BBR group and the model group. AAAs, including tyrosine, tryptophan and phenylalanine, were obviously decreased in the BBR group not only in the colon contents but also in the serum.
Conclusions:
These results demonstrated that BBR could alleviate symptoms in type 2 diabetic rats by affecting gut microbiota composition and reducing the concentration of AAAs.
... The worldwide increasing prevalence of obesity and associated metabolic disorders such as type 2 diabetes mellitus (T2DM) and cardiovascular disease are of growing concern [1]. Weight loss strategies based on lifestyle interventions have little long-term success [2]. Because regulation of feeding behavior and energy metabolism is partly orchestrated in the brain, the brain's role in obesity and metabolic disturbances has been a topic of research for the past two decades. ...
Objectives:
There is increasing evidence that intestinal microbiota play a role in diverse metabolic processes via intestinal butyrate production. Based on bariatric surgery data in humans it has been suggested that the gut-brain axis is also involved in this process, however the underlying mechanisms are still unknown.
Design:
We therefore compared the effect of fecal microbiota transfer (FMT) from post-Roux-en-Y gastric bypass (RYGB) donors versus oral butyrate supplementation on (123I-FP-CIT determined) brain dopamine transporter (DAT) and serotonin transporter (SERT) binding as well as stable isotope determined insulin sensitivity at baseline and after 4 weeks in 24 male and female treatment-naïve metabolic syndrome subjects. Also, plasma metabolites and fecal microbiota were determined at these timepoints.
Results:
We observed an increase in brain DAT upon donor FMT compared to oral butyrate that reduced this binding. However, no effect on body weight and insulin sensitivity was seen upon post-RYGB donor feces transfer in either humans with metabolic syndrome. In line, increases in fecal levels of Bacteroides uniformis were significantly associated with an increase in DAT whereas increases in Prevotella spp. showed an inverse association. Furthermore, changes in the plasma metabolites glycine, betaine, methionine and lysine (associated with the S-adenosylmethionine cycle) were also associated with altered striatal DAT expression.
Conclusion:
Although more and larger studies are needed, our data suggest a potential gut microbiota-driven modulation of brain dopamine and serotonin transporters in human obese metabolic syndrome subjects. Moreover, these data suggest the presence of a gut-brain axis in humans,that can be modulated. NTR registration: 4488.
... Defective leptin transport across the blood-brain barrier, as well as impaired leptin receptor expression and signaling, may play a role in the onset of leptin resistance. [16][17][18] Such hyperleptinemia has been suspected to be involved in obesity-related lung complications. Independently of body weight, leptin seems to play important respiratory physiological roles. ...
Leptin is a pleotropic hormone known to regulate a wide range of systemic functions, from satiety to inflammation. Increasing evidence has shown that leptin and its receptor, ObR, are not only expressed in adipose tissue but also in several organs, including the lungs. Leptin levels were first believed to only be elevated in the lungs of obese patients and it was suspected to be responsible for obesity-related lung complications. Aside from obesity, leptin displays many faces in the respiratory system, independently of body weight, as this cytokine-like hormone plays important physiological roles, from the embryogenic state to maturation of the lungs and the control of ventilation. The leptin signaling pathway is also involved in immune modulation and cell proliferation and its dysregulation can lead to the onset of lung diseases. This review article aims to address the thousand faces of leptin and its signaling in the lungs under physiological conditions and in disease.
... Obesity arises from a chronic energy imbalance and one of its characteristic features is a state of leptin resistance marked by persistent hyperleptinemia. The effects of leptin on metabolic complications in obesity are numerous [63][64][65][66][67]. Similarly, elevated leptin levels are present in diabetes [68,69]. In patients with diabetes and ARDS, elevated leptin levels in bronchoalveolar fluid are associated with increased mortality [70]. ...
Overweight and obesity are major risk factors for diabetes, cardiovascular disease, and lung disease. These diseases are the most commonly reported health conditions that predispose individuals with SARS-CoV-2 infection to require hospitalization including intensive care unit admissions. The innate immune response is the host’s first line of defense against a human coronavirus infection. However, most coronaviruses are armed with one strategy or another to overcome host antiviral defense, and the pathogenicity of the virus is related to its capacity to suppress host immunity. The multifaceted nature of obesity including its effects on immunity can fundamentally alter the pathogenesis of acute respiratory distress syndrome and pneumonia, which are the major causes of death due to SARS-CoV-2 infection. Elevated circulating leptin concentrations are a hallmark of obesity, which is associated with a leptin-resistant state. Leptin is secreted by adipocytes in proportion to body fat and regulates appetite and metabolism through signaling in the hypothalamus. However, leptin also signals through the Jak/STAT and Akt pathways, among others, to modulate T cell number and function. Thus, leptin connects metabolism with the immune response. Therefore, it seems appropriate that its dysregulation would have serious consequences during an infection. We propose that leptin may be the link between obesity and its high prevalence as a comorbidity of the SARS-CoV-2 infection. In this article, we present a synthesis of the mechanisms underpinning susceptibility to respiratory viral infections and the contribution of the immunomodulatory effects of obesity to the outcome.
... Obesity is a chronic, multifactorial, and largely preventable disease that affects all kind of socioeconomic groups; it is caused by an imbalance between dietary energy consumption relative to energy expenditure. According to latest WHO estimates, in 2016, more than 1.9 billion of people aged 18 years and older were overweight worldwide; and of these over 650 million adults were obese [1,2]. Globally, this disease is rapidly rising, and is getting increasing attention given its strong association with cardiovascular diseases (CVDs). ...
PurposeObesity is associated with systemic insulin resistance and cardiac hypertrophy with fibrosis. Peroxisome proliferator-activated receptors (PPARs) regulate carbohydrate and lipid metabolism, improving insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. We previously demonstrated that prolonged-release pirfenidone (PR-PFD) is an agonistic ligand for Pparα with anti-inflammatory and anti-fibrotic effects, and might be a promising drug for cardiac diseases-treatment. Here, we investigated the effects of PR-PFD in ventricular tissue of mice with nonalcoholic steatohepatitis (NASH) and obesity induced by high-fat/high-carbohydrate (HFHC) diet.Methods
Five male C57BL/6 J mice were fed with normal diet (ND) and ten with HFHC diet for 16 weeks; at 8 weeks of feeding, five mice with HFHC diet were administered PR-PFD (350 mg/kg/day) mixed with HFHC diet.ResultSystemic insulin resistance, heart weight/body weight ratio, myocardial steatosis with inflammatory foci, hypertrophy, and fibrosis were prevented by PR-PFD. In addition, HFHC mice showed significantly increased desmin, Tgfβ1, Timp1, collagen I (Col I), collagen III (Col III), TNF-α, and Nrf2 mRNA levels, including α-SMA, NF-kB, Nrf2, troponin I, Acox1, Cpt1A, and Lxrα protein levels compared with the ND ventricular tissues. Mechanistically, HFHC mice with PR-PFD treatment significantly decreased these genes overexpressed by HFHC diet. Furthermore, PR-PFD overexpressed the Pgc1a mRNA levels and Pparα, Pparγ, Acox1, and Cpt1A protein levels.Conclusions
The results suggest that PR-PFD could be a promising drug for the prevention and treatment of cardiac steatosis and fibrosis induced by obesity.
... During HSC activation, the cellular lipid storage is depleted, and lipid accumulation related gene expressions are downregulated. Leptin as a hormone in regulating lipid metabolism and energy balance (Friedman, 2004) was shown to stimulate HSC activation during fibrogenesis (Aleffi et al., 2005;Cayon et al., 2006). However, it is suggested that curcumin could revert this stimulation action by leptin on HSCs. ...
Liver fibrosis is a progressive liver damage condition that is worth studying widely. It is important to target and alleviate the disease at an early stage before turning into later cirrhosis or liver cancer. There are currently no direct medicines targeting the attenuation or reversal of liver fibrosis, and so there is an urgent need to look into this area. Traditional Chinese Medicine has a long history in using herbal medicines to treat liver diseases including fibrosis. It is time to integrate the ancient wisdom with modern science and technology to look for the best solution to the disease. In this review, the principal concept of the pathology of liver fibrosis will be described, and then some of the single compounds isolated from herbal medicines, including salvianolic acids, oxymatrine, curcumin, tetrandrine, etc. will be discussed from their effects to the molecular mechanism behind. Molecular targets of the compounds are analyzed by network pharmacology approach, and TGFβ/SMAD was identified as the most common pathway. This review serves to summarize the current findings of herbal medicines combining with modern medicines in the area of fibrosis. It hopefully provides insights in further pharmaceutical research directions.
... It is also becoming increasingly clear that obesity is not a wilful choice, but a disease whereby there is a dysfunction to the biological system regulating body weight. 7 With new analytic methods such as high-throughput metagenomics sequencing, we now know that this complex system involves the gut microbiota, which has a wide range of functions in human hosts, including energy production, biosynthesis of vitamins and neurotransmitters, regulation of immune and endocrine functions, protection against pathogenic bacteria overgrowth, modification of drugs, and elimination of toxins. 8 However, the exact mechanisms through which the gut microbiome exerts its effects are not yet fully understood. ...
Gut microbiome transfer (GMT; also referred to as faecal microbiota transplantation or FMT) has been propelled from fringe therapy to mainstream science as a highly effective treatment for recurrent Clostridioides difficile infection. As a result, there has been great interest in the potential efficacy and safety of GMT in treating other medical conditions, for example, inflammatory bowel disease, and more recently as a novel therapy for obesity and metabolic diseases. For these chronic conditions, the results from clinical trials have been mixed. Further, specifically in obesity and metabolic diseases, there are limited available data, with only a few published studies with a small number of participants and short duration of follow‐up. Therefore, this review aims to explore the human, microbial, and formulation factors that may affect the success of GMT. This includes various aspects in the preparation and administration of GMT, such as stool processing, modes of delivery, pre‐treatment with antibiotics and/or bowel lavage, frequency of GMT, and possible use of precision bacteriotherapy. In addition, we examine the potential use of GMT in obesity, type 2 diabetes, and metabolic diseases based on current available literature, highlighting some recent advances in GMT research in this area, as well as potential adverse effects after GMT therapy.
Background:
Obesity and type 2 diabetes are strongly associated pathologies, currently considered as a worldwide epidemic problem. Understanding the mechanisms that drive the development of these diseases would enable to develop new therapeutic strategies for their prevention and treatment. Particularly, the role of the brain in energy and glucose homeostasis has been studied for 2 decades. In specific, the hypothalamus contains well-identified neural networks that regulate appetite and potentially also glucose homeostasis. A new concept has thus emerged, suggesting that obesity and diabetes could be due to a dysfunction of the same, still poorly understood, neural networks.
Summary:
The neuropeptide 26RFa (also termed QRFP) belongs to the family of RFamide regulatory peptides and has been identified as the endogenous ligand of the human G protein-coupled receptor GPR103 (QRFPR). The primary structure of 26RFa is strongly conserved during vertebrate evolution, suggesting its crucial roles in the control of vital functions. Indeed, the 26RFa/GPR103 peptidergic system is reported to be involved in the control of various neuroendocrine functions, notably the control of energy metabolism in which it plays an important role, both centrally and peripherally, since 26RFa regulates feeding behavior, thermogenesis and lipogenesis. Moreover, 26RFa is reported to control glucose homeostasis both peripherally, where it acts as an incretin, and centrally, where the 26RFa/GPR103 system relays insulin signaling in the brain to control glucose metabolism.
Key messages:
This review gives a comprehensive overview of the role of the 26RFa/GPR103 system as a key player in the control of energy and glucose metabolism. In a pathophysiological context, this neuropeptidergic system represents a prime therapeutic target whose mechanisms are highly relevant to decipher.
Remedies for the treatment of obesity date to Hippocrates, when patients with obesity were directed to “reduce food and avoid drinking to fullness” and begin “running during the night.” Similar recommendations have been repeated ever since, despite the fact that they are largely ineffective. Recently, highly effective therapeutics were developed that may soon enable physicians to manage body weight in patients with obesity in a manner similar to the way that blood pressure is controlled in patients with hypertension. These medicines have grown out of a revolution in our understanding of the molecular and neural control of appetite and body weight, reviewed here.
In the advanced stages of type 2 diabetes mellitus (T2DM), diabetic liver damage is a common complication that can devastate a patient’s quality of life. The present study investigated the ability of liposomal berberine (Lip-BBR) to aid in ameliorating hepatic damage and steatosis, insulin homeostasis, and regulating lipid metabolism in type 2 diabetes (T2DM) and the possible pathways by which it does so. Liver tissue microarchitectures and immunohistochemical staining were applied during the study. The rats were divided into a control non-diabetic group and four diabetic groups, which are the T2DM, T2DM-Lip-BBR (10 mg/kg b.wt), T2DM-Vildagliptin (Vild) (10 mg/kg b.wt), and T2DM-BBR-Vild (10 mg/kg b.wt + Vild (5 mg/kg b.wt) groups. The findings demonstrated that Lip-BBR treatment could restore liver tissue microarchitectures, reduce steatosis and liver function, and regulate lipid metabolism. Moreover, Lip-BBR treatment promoted autophagy via the activation of LC3-II and Bclin-1 proteins and activated the AMPK/mTOR pathway in the liver tissue of T2DM rats. Lip-BBR also activated the GLP-1 expression, which stimulated insulin biosynthesis. It decreased the endoplasmic reticulum stress by limiting the CHOP, JNK expression, oxidative stress, and inflammation. Collectively, Lip-BBR ameliorated diabetic liver injury in a T2DM rat model with its promotion activity of AMPK/mTOR-mediated autophagy and limiting ER stress.
The obesity and toxic behaviors in health like sedentary life style, high ingest of carbs, low exercise, high levels of stress, inadequate use of electronical devices as smart telephones, tablets,… among others, it’s causing directly and indirectly since a several years obesity and its impact and health disorders related.Obesity and overweight according to the who is defined as the abnormal or excessive accumulation of fat that can be harmful to health.The body mass index (BMI) is defined as the result of weight divided by height squared, calculating the number of kilos of weight per body surface squared, obtaining an estimate that defines normal weight, overweight and obesity being 25 upper limits for normal weight and overweight up to 30 and above 30 obesity.In 2016, more than 3.19 billion adults were overweight and more than 650 million obese and 41 million children under the age of 5 years were overweight worldwide.Overweight and obesity are the sixth risk factor for death in the world. 3.4 million die from related causes, 44% burden from type 2 diabetes, 23% from ischemic heart disease as well as another percentage from cancer is attributed to obesity.Traditional therapeutic options such as diet, exercise, and changes of habits are a cornerstone in control and management in all cases but it has been shown that current surgical management with adequate multidisciplinary preparation offers better results in the short and medium terms, with subsequent weight loss and metabolic control of related diseases such as type 2 diabetes.The surgical procedures options are several. Patient must be chosen very well, and we have to look for the most appropriate surgical procedure to their condition degree of obesity social economic environment, within these we have: the sleeve gastrectomy, Roux-en-Y gastric bypass, One-anastomosis gastric bypass, Sadi-s and the duodenal switch, among others.KeywordsObesitySedentary LifestyleComorbidities Bariatric surgeryBehaviorPhysical activity
Lung transplantation is the treatment of choice for patients with end-stage lung disease. Currently, just under 5000 lung transplants are performed worldwide annually. However, a major scourge leading to 90-d and 1-year mortality remains primary graft dysfunction. It is a spectrum of lung injury ranging from mild to severe depending on the level of hypoxaemia and lung injury post-transplant. This review aims to provide an in-depth analysis of the epidemiology, patho physiology, risk factors, outcomes, and future frontiers involved in mitigating primary graft dysfunction. The current diagnostic criteria are examined alongside changes from the previous definition. We also highlight the issues surrounding chronic lung allograft dysfunction and identify the novel therapies available for ex-vivo lung perfusion. Although primary graft dysfunction remains a significant contributor to 90-d and 1-year mortality, ongoing research and development abreast with current technological advancements have shed some light on the issue in pursuit of future diagnostic and therapeutic tools.
Scientific progress enables the analysis of biomarkers which can enable a personal disease prevention and improved healthcare. Whereas these opportunities can improve personal health management significantly, translation of these opportunities into practice faces social, economic and ethical aspects which need to be addressed. The article discusses some of these aspects. The health system has changed dramatically over the past 100 years. Driven by the growing understanding of body functions and new technologies to measure them, a multitude of technological, clinical and biomolecular changes and related data resulted (Towse and Garrison in J Cancer Policy 11, 2017). Based on this enormous knowledge and the collected data, it is both technically feasible and economically sensible to strongly revise the “one fits all” strategy. Considering the ineffectiveness, side effects, and high cost of some standard treatments, it is now also unethical and uneconomical to offer non-personalized services (Doble and Lorgelly in Per Med 12, 2015). Not only the personalization of treatments is extremely important, but also the prevention of diseases is even more important. One of the most common preventive measures is a healthy diet that is adapted to the needs of each individual (Kirk et al. in Comput Biol Med 133, 2021). Many people deal with the topic of maintaining health in contrast to the previous strategy of disease treatment. Even if this topic was not sufficiently advertised during the corona pandemic, there has been an upturn in direct-to-consumer (B2C) and business to distributors (B2D) analysis tests. The demand for contactless test systems has risen sharply during this time. Since fitness studios and sports courses were closed, new ways of self-optimization had to be found. The possibilities range from epigenetic analyzes to determine the biological age, physical sport- or stress level, to the determination of genetic diet or sport types, to the determination of the hormone status from urine to complex microbiota analyzes out of feces samples. Also, the new hype of DIY (do it yourself) especially concerning nutrition, pushed this economic branch of individual nutrition and health advice.
Obesity is a pediatric and adult global health problem of epidemic proportions in westernized societies. It results from imbalance of energy intake and expenditure. The cause of obesity is heterogeneous with complex biological processes playing a role including control of peptides involved in regulating appetite, cellular energy and metabolism, and fat production influenced by environmental interactions. Advances in genetic technology have led to discoveries of single gene and copy number variants playing a role in early onset of severe obesity and other obesity phenotypes. Heritability studies have shown that genetic components can contribute to 40–70% of obesity with over 350 potential genes reported in the literature. Monogenic causes of obesity and dozens of syndromic examples are discussed such as Prader-Willi syndrome, in which individuals develop obesity due to hyperphagia and decreased resting energy expenditure. The current knowledge of monogenic and syndromic causes of obesity, their genotype, and clinical features are summarized with descriptions. The genetic dissection of obesity with characterization of biological pathways and gene-protein environmental interactions at the brain level will contribute to understanding disease mechanisms and outcomes. This information can be applied for early diagnosis, prevention, and treatment as well as elucidating therapeutic targets for development of personalized medicines designed for obesity in humans.
Genetic studies of obese animals and humans have led to findings of multiple genes that confer risk of developing obesity. Individuals can be classified as having genetic obesity, strong or slight genetic predisposition, or genetic resistance to obesity. The current evidence based on familial studies suggests that 40–80% of the variation between individual body mass indices has a genetic basis. The genetic reference tool ‘human obesity gene map’ provides a global encyclopaedia for identified genes, mutations, and qualitative trait loci. Studies such as genome-wide association studies have pointed researchers towards new pathways of neurohumoral mechanisms, other regulators of energy balance, and the interplay with the obesogenic environment. Gene studies have also unmasked the presence and significance of human microbiomes (particularly gut microbiomes) in the pathogenicity of obesity. The likelihood or presence of clinical obesity can be predicted in an individual through the use of genetic susceptibility with 60% accuracy. When gut microbiomes are identified, the predictive accuracy increases to 90%.
Leptin is a hormone produced by the adipose tissue, which has effects on the central nervous system. Leptin is bound to its Ob receptor on hypo-thalamic neurons to inhibit feeding behavior and to increase sympathetically-mediated thermogenesis. In addition to anorexia and thermogenesis, leptin also has direct peripheral and central nervous system-mediated effects on the endocrine, vascular, hematopoietc, immune and musculoskeletal systems. Leptin accomplishes its effects using distributed network of leptin receptors and differential molecular signaling pathways. Leptinemia is increased in obesity because of increased adipocyte mass, but obese subjects exhibit resistance to the anorexic and metabolic effects of leptin. However, multiple studies have shown that leptin can increase sympathetic nerve activity to non-thermogenic tissues in rodents causing obesity-related hypertension. One potential explanation of this paradox is selective leptin resistance. Compared with large and persuasive number of studies on the sympathetic and blood pressure effects of leptin in experimental animals, relatively little attention was given to these effects of leptin in humans. This review article presents recent findings related to leptin and its mechanism of action, and also the role of leptin in patophysiological conditions.
Background/objectives
The pathophysiology of obesity is multifactorial, including genetic and environmental factors. Previous studies had highlighted the association of the leptin gene/receptor with obesity. We aimed to study the leptin gene rs7799039 single nucleotide polymorphism (SNP) in children, and its association with the children’s characteristics.
Methods
A cross-sectional analytic study that included 143 children with obesity (cases) and a comparable group of 86 lean children as controls. The anthropometric measures, blood pressure, and biochemical testing were done for all participants. The real-time polymerase chain reaction was used to detect rs7799039 SNP variant alleles and ELISA for leptin level assessment.
Results
The distribution of rs7799039 SNPs genotypes GG/GA/AA was comparable between both groups. Testing children regardless of their body mass index showed that the abnormalities in blood pressure, lipids values, insulin resistance, and hepatic insulin sensitivity were significantly associated with increased leptin levels. Among cases, the abnormal metabolic status was associated with higher leptin levels.
Conclusions
The genotype’ distribution of leptin gene rs7799039 SNP was similar in both children with obesity and those with normal-weight. The high blood pressure, abnormal lipid profile, and metabolic disturbances, were significantly associated with higher leptin levels and not with leptin gene rs7799039 SNP.
Obesity, a condition characterized by excessive accumulation of body fat, is a metabolic disorder related to an increased risk of chronic inflammation. Obesity is mediated by signal transducer and activator of transcription (STAT) 3, which is regulated by genes associated with retinoid-interferon-induced mortality (GRIM) 19, a protein ubiquitously expressed in various human tissues. In this study, we investigated the role of GRIM19 in diet-induced obese C57BL/6 mice via intravenous or intramuscular administration of a plasmid encoding GRIM19. Splenocytes from wild-type and GRIM19-overexpressing mice were compared using enzyme-linked immunoassay, real-time polymerase chain reaction, Western blotting, flow cytometry, and histological analyses. GRIM19 attenuated the progression of obesity by regulating STAT3 activity and enhancing brown adipose tissue (BAT) differentiation. GRIM19 regulated the differentiation of mouse-derived 3T3-L1 preadipocytes into adipocytes, while modulating gene expression in white adipose tissue (WAT) and BAT. GRIM19 overexpression reduced diet-induced obesity and enhanced glucose and lipid metabolism in the liver. Moreover, GRIM19 overexpression reduced WAT differentiation and induced BAT differentiation in obese mice. GRIM19-transgenic mice exhibited reduced mitochondrial superoxide levels and a reciprocal balance between Th17 and Treg cells. These results suggest that GRIM19 attenuates the progression of obesity by controlling adipocyte differentiation.
La diffusione epidemica dell’obesità ha attirato l’attenzione dei ricercatori sul tessuto adiposo. Le scoperte più recenti hanno evidenziato come il tessuto adiposo bianco sia in grado di secernere numerose sostanze, tra cui alcuni ormoni (per esempio la leptina) in grado di agire sul sistema nervoso centrale modificando il comportamento alimentare dell’animale. Numerose altre sostanze (adipochine), inoltre, sono in grado di influenzare diverse vie metaboliche. L’incremento del tessuto adiposo che si osserva nell’obesità è quindi responsabile dell’aumento di secrezione di adipochine che a sua volta sembra essere responsabile di quell’insieme di alterazioni metaboliche che conducono alla sindrome clinica nota come sindrome metabolica. Il tessuto adiposo bruno agisce in opposizione al tessuto adiposo bianco in quanto “brucia” i lipidi per produrre calore. Quest’ultimo è attivato dal freddo, ma anche dall’assunzione del cibo. Si pensa quindi che possa avere anche una funzione di prevenzione dell’obesità. A supporto di questa ipotesi, topi transgenici privi del tessuto adiposo bruno sviluppano obesità. Entrambi i tessuti sono compresi in diversi depositi sottocutanei e viscerali che nel loro insieme costituiscono l’organo adiposo. Quest’organo, presente con le stesse caratteristiche di base anche nell’uomo, è plastico e la quantità relativa dei due tessuti è modulabile anche farmacologicamente. Sviluppando la parte bruna con farmaci specifici si cura l’obesità dei roditori. Questi dati pongono le premesse per lo studio di possibili futuri trattamenti dell’obesità e delle sue complicanze.
This study focused on the effect of short-term intake of sweeteners on feed intake, solution consumption and neurotransmitters release on mice. The results showed that the free drinking of 10 mM sucralose solution, 100 mM maltose solution, 3 mM saccharin solution and 3 g/L stevioside solution for 32 days will not affect the normal development of the body weight and feed intake of the mice. The consumption of maltose solution was significantly higher than that of the other sweeteners. The leptin and insulin levels increased significantly after the short-term intake of these four sweeteners. The dopamine (DA) content in the whole brain of the mice increased significantly only in the maltose group. These results indicate that the short-term intake of the preferred concentrations of maltose, stevioside, sucralose and saccharin will not affect the body weight and feed intake of the mice. Mice prefer maltose solution to other sweeteners solutions. The 100 mM maltose solution and 3 mM saccharin solution could result in the oxidative stress on mice after 32 days’ short-term intake. Compared with other sweeteners, only sugars that could be broken down into small molecules of glucose might have a positive effect on dopamine levels.
Purpose:
Previous studies have shown the connection between diet quality to sleep quality and weight status, although the relationship between Lifelines Diet Score (LLDS)-a fully food-based score that uses the 2015 Dutch Dietary Guidelines and underlying international literature-and sleep quality has not been evaluated in overweight and obese individuals yet. This observational study was conducted on overweight and obese adult females to assess the relationship between adherence to a LLDS pattern and sleep quality in Iran.
Methods:
A cohort of 278 overweight and obese women aged above 18 years was enrolled and their dietary intake was assessed using a 147-item, semi-quantitative, validated food frequency questionnaire. Pittsburgh Sleep Quality Index (PSQI), a self-reported questionnaire including 19-items, was applied to estimate sleep quality among the target population. Diet quality indices (LLDS) were calculated using the P.C. Vinke, et al. method, based on the 2015 Dutch Dietary Guidelines and the underlying literature.
Results:
Subjects in the highest LLDS tertile (those who had adhered closely to the food-based score) were older, compared to the lowest tertile (37.57 ± 7.77 versus 34.57 ± 9; p = 0.01). It was shown that about 25.5% of our subjects have poor quality sleep and 39% have better sleep quality which were mostly in the third tertile with greater LLDS. The parallel values in the first tertile were 29.9% and 46.8%, respectively (p = 0.02). Binary logistic regression was applied to evaluate the association between adherence of LLDS and sleep quality. The result has shown that the LLDS were correlated with lower risk poor sleep quality, wherein those who were in higher tertile (higher adherence to LLDS) had better sleep quality (odds ratio [OR]:0.586, 95% confidence interval [CI] (0.285-1.207), p = 0.009) and the result was not affected by adjusting for potential cofounders including age, education levels, and economic levels, sleep quality remained significantly associated with [OR]: 0.531, 95% confidence interval [CI] (0.248-1.138, p = 0.014).
Conclusions:
From this observational study, the higher LLDS can be related with better sleep quality in overweight and obese women.
Level of evidence:
Level IV, evidence obtained from multiple time series with or without the intervention, such as case studies.
The leptin receptor (Ob-R) is alternatively spliced into at least five different RNAs designated Ob-R(a-e). Ob-R(a-d) predict receptors with a single transmembrane domain, and Ob-Re predicts a secreted form of the receptor. The presence of an ∼120-kDa soluble leptin receptor in mouse plasma was confirmed by precipitation with leptin-Sepharose beads followed by immunobloting with anti-leptin receptor antibodies. The soluble leptin receptor is larger than that predicted by the primary sequence. Deglycosylation of the receptor with peptide N:glycosidase F results in a decrease in molecular mass to a size consistent with that of the primary sequence. The secreted receptor was present in plasma from wild type mice but was truncated in plasma fromdb 3J/db 3J and absent indb Pas/db Pas plasma. Although db 3J/db 3J mice are known to have a frameshift mutation at amino acid 625, the basis for the mutation indb Pas/db Pas mice was not known. Further studies indicated thatdb Pas/db Pas mice carry a duplication of exons 4 and 5 of Ob-R. This mutation introduces a premature stop codon into the protein at amino acid 281. The absence of Ob-R in db 3J/db 3J anddb Pas/db Pas mice confirm the identify of the 120-kDa plasma protein as Ob-Re.
Context The prevalence of obesity and overweight increased in the United States
between 1978 and 1991. More recent reports have suggested continued increases
but are based on self-reported data.Objective To examine trends and prevalences of overweight (body mass index [BMI]
≥25) and obesity (BMI ≥30), using measured height and weight data.Design, Setting, and Participants Survey of 4115 adult men and women conducted in 1999 and 2000 as part
of the National Health and Nutrition Examination Survey (NHANES), a nationally
representative sample of the US population.Main Outcome Measure Age-adjusted prevalence of overweight, obesity, and extreme obesity
compared with prior surveys, and sex-, age-, and race/ethnicity–specific
estimates.Results The age-adjusted prevalence of obesity was 30.5% in 1999-2000 compared
with 22.9% in NHANES III (1988-1994; P<.001).
The prevalence of overweight also increased during this period from 55.9%
to 64.5% (P<.001). Extreme obesity (BMI ≥40)
also increased significantly in the population, from 2.9% to 4.7% (P = .002). Although not all changes were statistically significant,
increases occurred for both men and women in all age groups and for non-Hispanic
whites, non-Hispanic blacks, and Mexican Americans. Racial/ethnic groups did
not differ significantly in the prevalence of obesity or overweight for men.
Among women, obesity and overweight prevalences were highest among non-Hispanic
black women. More than half of non-Hispanic black women aged 40 years or older
were obese and more than 80% were overweight.Conclusions The increases in the prevalences of obesity and overweight previously
observed continued in 1999-2000. The potential health benefits from reduction
in overweight and obesity are of considerable public health importance.
The adipocyte-derived hormone leptin is crucial for energy homeostasis in mammals; mice and humans without it suffer from a voracious appetite and extreme obesity. The effect on energy balance of variations in plasma leptin above a minimal threshold is uncertain, however, particularly in humans. Here we examine a group of individuals who are genetically partially deficient in leptin, and show that differences in circulating leptin levels within the range found in normal human populations can directly influence the laying down of fat tissue (adiposity).
Human obesity has an inherited component, but in contrast to rodent obesity, precise genetic defects have yet to be defined1. A mutation of carboxypeptidase E (CPE), an enzyme active in the processing and sorting of prohormones, causes obesity in the fat/fat mouse2,3. We have previously described a woman with extreme childhood obesity (Fig. 1), abnormal glucose homeostasis, hypogonadotrophic hypogonadism, hypocortisolism and elevated plasma proinsulin and pro-opiomelanocortin (POMC) concentrations but a very low insulin level, suggestive of a defective prohormone processing by the endopeptidase, prohormone convertase 1 (PC1; ref. 4). We now report this proband to be a compound heterozygote for mutations in PC1. GlyArg483 prevents processing of proPd and leads to its retention in the endoplasmic reticulum (ER). AC+4 of the intron-5 donor splice site causes skipping of exon 5 leading to loss of 26 residues, a frameshift and creation of a premature stop codon within the catalytic domain. PC1 acts proximally to CPE in the pathway of post-translational processing of prohormones and neuropeptides. In view of the similarity between the proband and the fat/fat mouse phenotype, we infer that molecular defects in prohormone conversion may represent a generic mechanism for obesity, common to humans and rodents.
Leptin, a hormone secreted by fat cells, suppresses food intake and promotes weight loss. To assess the action of this hormone
on brain reward circuitry, changes in the rewarding effect of lateral hypothalamic stimulation were measured after leptin
administration. At five stimulation sites near the fornix, the effectiveness of the rewarding electrical stimulation was enhanced
by chronic food restriction and attenuated by intracerebroventricular infusion of leptin. In contrast, the rewarding effect
of stimulating neighboring sites was insensitive to chronic food restriction and was enhanced by leptin in three of four cases.
These opposing effects of leptin may mirror complementary changes in the rewarding effects of feeding and of competing behaviors.
The prevalence of obesity increased in the United States between 1976-1980 and 1988-1994 and again between 1988-1994 and 1999-2000.
To examine trends in obesity from 1999 through 2008 and the current prevalence of obesity and overweight for 2007-2008.
Analysis of height and weight measurements from 5555 adult men and women aged 20 years or older obtained in 2007-2008 as part of the National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the US population. Data from the NHANES obtained in 2007-2008 were compared with results obtained from 1999 through 2006.
Estimates of the prevalence of overweight and obesity in adults. Overweight was defined as a body mass index (BMI) of 25.0 to 29.9. Obesity was defined as a BMI of 30.0 or higher.
In 2007-2008, the age-adjusted prevalence of obesity was 33.8% (95% confidence interval [CI], 31.6%-36.0%) overall, 32.2% (95% CI, 29.5%-35.0%) among men, and 35.5% (95% CI, 33.2%-37.7%) among women. The corresponding prevalence estimates for overweight and obesity combined (BMI > or = 25) were 68.0% (95% CI, 66.3%-69.8%), 72.3% (95% CI, 70.4%-74.1%), and 64.1% (95% CI, 61.3%-66.9%). Obesity prevalence varied by age group and by racial and ethnic group for both men and women. Over the 10-year period, obesity showed no significant trend among women (adjusted odds ratio [AOR] for 2007-2008 vs 1999-2000, 1.12 [95% CI, 0.89-1.32]). For men, there was a significant linear trend (AOR for 2007-2008 vs 1999-2000, 1.32 [95% CI, 1.12-1.58]); however, the 3 most recent data points did not differ significantly from each other.
In 2007-2008, the prevalence of obesity was 32.2% among adult men and 35.5% among adult women. The increases in the prevalence of obesity previously observed do not appear to be continuing at the same rate over the past 10 years, particularly for women and possibly for men.
No current treatment for obesity reliably sustains weight loss, perhaps because compensatory metabolic processes resist the maintenance of the altered body weight. We examined the effects of experimental perturbations of body weight on energy expenditure to determine whether they lead to metabolic changes and whether obese subjects and those who have never been obese respond similarly.
We repeatedly measured 24-hour total energy expenditure, resting and nonresting energy expenditure, and the thermic effect of feeding in 18 obese subjects and 23 subjects who had never been obese. The subjects were studied at their usual body weight and after losing 10 to 20 percent of their body weight by underfeeding or gaining 10 percent by overfeeding.
Maintenance of a body weight at a level 10 percent or more below the initial weight was associated with a mean (+/- SD) reduction in total energy expenditure of 6 +/- 3 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 5 kcal per kilogram per day in the obese subjects (P < 0.001). Resting energy expenditure and nonresting energy expenditure each decreased 3 to 4 kcal per kilogram of fat-free mass per day in both groups of subjects. Maintenance of body weight at a level 10 percent above the usual weight was associated with an increase in total energy expenditure of 9 +/- 7 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 4 kcal per kilogram per day in the obese subjects (P < 0.001). The thermic effect of feeding and nonresting energy expenditure increased by approximately 1 to 2 and 8 to 9 kcal per kilogram of fat-free mass per day, respectively, after weight gain. These changes in energy expenditure were not related to the degree of adiposity or the sex of the subjects.
Maintenance of a reduced or elevated body weight is associated with compensatory changes in energy expenditure, which oppose the maintenance of a body weight that is different from the usual weight. These compensatory changes may account for the poor long-term efficacy of treatments for obesity.
Published heritability estimates (h2) for body mass index (BMI) range from as low as 0.05 to as high as 0.90. The purpose of this paper is to introduce new data to help narrow the range of plausible estimates.
Subjects were 53 pairs (23 M; 30 F) of monozygotic twins reared apart (MZAs), whose mean BMI was 24.2 (SD = 4.7). BMI's were transformed to approximate normality via the Box-Cox transformation. Twin paris came from the Finnish Twin Cohort (17 pairs), a data base of Japanese twins (10 pairs) and published case histories of primarily American twins (26 pairs).
The h2 for MZAs is given by the correlation among the twin pairs. For the transformed data, the zero-order correlation of twins' BMIs was 0.79 for all twins, 0.63 for the Finnish twins, 0.73 for the Japanese twins and 0.85 for the 'archival' twins. When modeled with regression to control for relevant covariates, the estimate of h2 is either 0.50 or 0.70, depending on one's definition. The semipartial r was 0.50, suggesting that 50% of the total variance in BMI appears to the genetic in origin after controlling the covariates. The partial r was 0.70, suggesting that 70% of the variance in BMI that is not accounted for by the covariates can be attributed to genetic variation. Separation age had a small positive correlation with absolute intra-pair difference in BMI, suggesting that these estimates of h2 are not biased upwards due to early shared environment.
Findings are consistent with past studies of MZAs and suggest that h2 estimates between 0.50 and 0.70 are reasonable. Implications of this finding are discussed.
Leptin's effects are mediated by interactions with a receptor that is alternatively spliced, resulting in at least five different murine forms: Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, and Ob-Re. A mutation in one splice form, Ob-Rb, results in obesity in mice. Northern blots, RNase protection assays, and PCR indicate that Ob-Rb is expressed at a relatively high level in hypothalamus and low level in several other tissues. Ob-Ra is expressed ubiquitously, whereas Ob-Rc, -Rd, and -Re RNAs are only detectable using PCR. In hypothalamus, Ob-Rb is present in the arcuate, ventromedial, dorsomedial, and lateral hypothalamic nuclei but is not detectable in other brain regions. These nuclei are known to regulate food intake and body weight. The level of Ob-Rb in hypothalamus is reduced in mice rendered obese by gold thioglucose (GTG), which causes hypothalamic lesions. The obesity in GTG-treated mice is likely to be caused by ablation of Ob-Rb-expressing neurons, which results in leptin resistance.
Leptin acts on the central nervous system to cause a reduction in food
intake and body weight,. The melanocortin system in the brain is also
implicated in energy homeostasis, with agonists of the melanocortin-4
(MC4) receptor reducing food intake and targeted mutation of the MC4
receptor causing obesity. We now show that MC4 receptor signalling is an
important mediator of leptin's effects on food intake and body weight,
demonstrating a link between the two systems.
Sequential cleavage of the precursor protein pre-pro-opiomelanocortin (POMC) generates the melanocortin peptides adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) alpha, beta and gamma as well as the opioid-receptor ligand beta-endorphin. While a few cases of isolated ACTH deficiency have been reported (OMIM 201400), an inherited POMC defect has not been described so far. Recent studies in animal models elucidated a central role of alpha-MSH in the regulation of food intake by activation of the brain melanocortin-4-receptor (MC4-R; refs 3-5) and the linkage of human obesity to chromosome 2 in close proximity to the POMC locus, led to the proposal of an association of POMC with human obesity. The dual role of alpha-MSH in regulating food intake and influencing hair pigmentation predicts that the phenotype associated with a defect in POMC function would include obesity, alteration in pigmentation and ACTH deficiency. The observation of these symptoms in two probands prompted us to search for mutations within their POMC genes. Patient 1 was found to be a compound heterozygote for two mutations in exon 3 (G7013T, C7133delta) which interfere with appropriate synthesis of ACTH and alpha-MSH. Patient 2 was homozygous for a mutation in exon 2 (C3804A) which abolishes POMC translation. These findings represent the first examples of a genetic defect within the POMC gene and define a new monogenic endocrine disorder resulting in early-onset obesity, adrenal insufficiency and red hair pigmentation.
Leptin is important in regulating energy homeostasis. Severe lipodystrophy is associated with leptin deficiency and insulin resistance, hypertriglyceridemia, and hepatic steatosis. Leptin deficiency is also associated with abnormalities of the pituitary hormones in rodent models and patients with congenital absence of leptin. We inquired whether similar abnormalities are seen in patients with lipodystrophy and whether replacement of leptin will make an impact on the regulation of pituitary hormones. Seven female patients (aged 15-42 yr, all diabetic) with lipodystrophy and serum leptin levels less than 4 mg/liter were treated with recombinant methionyl-human leptin (recombinant leptin) in physiological doses in an open-labeled study. The following parameters were evaluated before and at 4 months of leptin treatment: menstrual history, pelvic ultrasonogram, LHRH, TRH, and CRH tests. While on recombinant leptin, mean serum leptin concentration increased from 1.3 +/- 0.3 mg/liter to 11.1 +/- 2.5 mg/liter. Only one of five patients who had intact reproductive systems was cycling normally before leptin therapy, and all five had normal menses by the fourth month of leptin therapy. Serum E2 concentrations increased (110 +/- 44 pmol/liter vs. 546 +/- 247 pmol/liter, P = 0.002), serum T concentrations decreased (3.5 +/- 3.0 nmol/liter vs. 1.3 +/- 0.7 nmol/liter, P = 0.055), and the attenuated LH response to LHRH was corrected with therapy. Serum T(3) and free T(4) were in the normal range before leptin therapy and did not change. However, serum TSH concentrations fell from 2.2 +/- 1.1 microU/ml to 1.2 +/- 0.7 microU/ml (P < 0.001). The percent increase in TSH following TRH administration was similar before (560%) and at 4 months (580%) of leptin therapy. The mean nonstimulated ACTH and cortisol concentrations were, respectively, 6.0 +/- 3.4 pmol/liter and 680 +/- 280 nmol/liter before leptin and did not change after 4 months of therapy (4.2 +/- 1.2 pmol/liter, P = 0.11 and 453 +/- 142 nmol/liter, P = 0.13, respectively). The ACTH and cortisol responses to CRH stimulation were normal both before and after therapy. Leptin replacement improved menstrual abnormalities and low E2 levels and corrected the attenuated LH response to LHRH in a group of young women with lipodystrophy and leptin deficiency. These results add to the growing body of evidence that metabolic signals such as leptin play a role in neuroendocrine regulation.
The effect of 7 wk consumption of a diet containing 32.6% of kilocalories as fat [condensed milk (CM) diet] on body composition and energy intake was evaluated in nine strains of inbred mice (AKR/J, C57L/J, A/J, C3H/HeJ, DBA/2J, C57BL/6J, SJL/J, I/STN, and SWR/J). Control animals were fed a high-carbohydrate diet containing 11.6% of energy as fat (Purina Rodent Chow diet). Relative to Chow diet controls, the CM diet significantly increased carcass lipid content in six strains (AKR/J, C57L/J, A/J, C3H/HeJ, DBA/2J, and C57BL/6J), but had no or a marginal effect on adiposity in three strains of mice (SJL/J, I/STN, and SWR/J). The obesity produced by the CM diet in six strains was not due to hyperphagia. Only one of six (AKR/J) of the strains that increased adiposity on the CM diet consumed more energy than controls during the 7 wk of the experiment. The identification of inbred mouse strains that are sensitive to dietary obesity, vs. others that are resistant, provides a useful tool to pursue the metabolic and genetic basis of this trait in the mouse.
Objective.
—To determine the accuracy of caloric labeling of "diet" and "health" foods and whether the accuracy differs for certain categories of food suppliers.Design.
—Survey; "diet" and "health" foods were analyzed via bomb calorimetry and categorized as regionally distributed, nationally advertised, or locally prepared.Setting.
—Foods were sampled from retail merchants throughout the borough of Manhattan, New York, NY.Sample.
—A convenience sample of 40 food items including regionally distributed (n=12), nationally advertised (n=20), and locally prepared items (n=8).Main Outcome Measures.
—Number of kilocalories per item and number of kilocalories per gram.Results.
—All locally prepared foods had more actual than labeled kilocalories. The mean percentage of actual kilocalories greater than the labeled kilocalories (mean percentage over label) per item was 85.42% (SD=77.88%; P=.01). Regionally distributed foods had significantly more kilocalories than were reported (P=.001 for kilocalories per item, P=.02 for kilocalories per gram) and mean percentage over label per item was 25.22% (SD=15.58%) and per gram was 14.97% (SD=17.95%). Nationally advertised foods did not have significantly more actual than reported kilocalories (P=.37 for per item, P=.78 for per gram). Mean percentage over label per gram was —0.01% (SD=9.13%) and per item was 2.18% (SD=13.93%).Conclusion.
—These findings suggest that food labels may be inadequate sources for caloric monitoring. Health care professionals should consider the accuracy of caloric labeling when advising patients to use food labels to help monitor their caloric intake.(JAMA. 1993;270:1454-1456)
Height, weight, and body mass index (BMI) were assessed in a sample of 1974 monozygotic and 2097 dizygotic male twin pairs. Concordance rates for different degrees of overweight were twice as high for monozygotic twins as for dizygotic twins. Classic twin methods estimated a high heritability for height, weight, and BMI, both at age 20 years (.80,.78, and.77, respectively) and at a 25-year follow-up (.80,.81, and.84, respectively). Height, weight, and BMI were highly correlated across time, and a path analysis suggested that the major part of that covariation was genetic. These results are similar to those of other twin studies of these measures and suggest that human fatness is under substantial genetic control.(JAMA 1986;256:51-54)
Recent data have identified leptin as an afferent signal in a negative-feedback loop regulating the mass of the adipose tissue.
High leptin levels are observed in obese humans and rodents, suggesting that, in some cases, obesity is the result of leptin
insensitivity. This hypothesis was tested by comparing the response to peripherally and centrally administered leptin among
lean and three obese strains of mice: diet-induced obese AKR/J, New Zealand Obese (NZO), and Ay. Subcutaneous leptin infusion to lean mice resulted in a dose-dependent loss of body weight at physiologic plasma levels.
Chronic infusions of leptin intracerebroventricularly (i.c.v.) at doses of 3 ng/hr or greater resulted in complete depletion
of visible adipose tissue, which was maintained throughout 30 days of continuous i.c.v. infusion. Direct measurement of energy
balance indicated that leptin treatment did not increase total energy expenditure but prevented the decrease that follows
reduced food intake. Diet-induced obese mice lost weight in response to peripheral leptin but were less sensitive than lean
mice. NZO mice were unresponsive to peripheral leptin but were responsive to i.c.v. leptin. Ay mice did not respond to subcutaneous leptin and were 1/100 as sensitive to i.c.v. leptin. The decreased response to leptin
in diet-induced obese, NZO, and Ay mice suggests that obesity in these strains is the result of leptin resistance. In NZO mice, leptin resistance may be the
result of decreased transport of leptin into the cerebrospinal fluid, whereas in Ay mice, leptin resistance probably results from defects downstream of the leptin receptor in the hypothalamus.
The leptin receptor (Ob-R) is alternatively spliced into at least five different RNAs designated Ob-R(a-e). Ob-R(a-d) predict receptors with a single transmembrane domain, and Ob-Re predicts a secreted form of the receptor. The presence of an approximately 120-kDa soluble leptin receptor in mouse plasma was confirmed by precipitation with leptin-Sepharose beads followed by immunobloting with anti-leptin receptor antibodies. The soluble leptin receptor is larger than that predicted by the primary sequence. Deglycosylation of the receptor with peptide N:glycosidase F results in a decrease in molecular mass to a size consistent with that of the primary sequence. The secreted receptor was present in plasma from wild type mice but was truncated in plasma from db3J/db3J and absent in dbPas/dbPas plasma. Although db3J/db3J mice are known to have a frameshift mutation at amino acid 625, the basis for the mutation in dbPas/dbPas mice was not known. Further studies indicated that dbPas/dbPas mice carry a duplication of exons 4 and 5 of Ob-R. This mutation introduces a premature stop codon into the protein at amino acid 281. The absence of Ob-R in db3J/db3J and dbPas/dbPas mice confirm the identify of the 120-kDa plasma protein as Ob-Re.
Adaptive thermogenesis is an important component of energy homeostasis and a metabolic defense against obesity. We have cloned a novel transcriptional coactivator of nuclear receptors, termed PGC-1, from a brown fat cDNA library. PGC-1 mRNA expression is dramatically elevated upon cold exposure of mice in both brown fat and skeletal muscle, key thermogenic tissues. PGC-1 greatly increases the transcriptional activity of PPARgamma and the thyroid hormone receptor on the uncoupling protein (UCP-1) promoter. Ectopic expression of PGC-1 in white adipose cells activates expression of UCP-1 and key mitochondrial enzymes of the respiratory chain, and increases the cellular content of mitochondrial DNA. These results indicate that PGC-1 plays a key role in linking nuclear receptors to the transcriptional program of adaptive thermogenesis.
To review evidence supporting the hypothesis that metabolic manifestations of lipodystrophy result from leptin deficiency and that leptin replacement may be a viable treatment for generalized lipodystrophy.
This review results from the authors' collective clinical experience and a comprehensive MEDLINE search of the English-language literature (1998 to 2009) on "leptin and lipodystrophy."
Severe lipodystrophy syndromes are characterized by loss of subcutaneous adipose tissue and thus a relative deficiency of the adipocyte-secreted hormone leptin. Several small, nonrandomized, open-label trials in a composite total of more than 100 patients with severe lipodystrophy not related to human immunodeficiency virus infection have evaluated the efficacy and safety of recombinant human methionyl leptin (metreleptin) therapy. Variables observed to improve after treatment with metreleptin include glycemic control, insulin sensitivity, plasma triglycerides, caloric intake, liver volume and lipid content, intramyocellular lipid content, and neuroendocrine and immunologic end points. In these studies, metreleptin treatment was well tolerated. Typical daily replacement doses for metreleptin were 0.06 to 0.08 mg/kg for female patients and 0.04 mg/kg for male patients, administered by subcutaneous injection twice daily. Although metreleptin is not yet approved for routine clinical use, it is available by means of expanded access provisions for patients with severe lipodystrophy and associated metabolic abnormalities.
Evidence published in the medical literature indicates that treating severe lipodystrophy as a leptin deficiency syndrome can improve the metabolic outcomes in affected patients.
The agouti (a) locus acts within the microenvironment of the hair follicle to regulate coat color pigmentation in the mouse. We have characterized a gene encoding a novel 131 amino acid protein that we propose is the one gene associated with the agouti locus. This gene is normally expressed in a manner consistent with a locus function, and, more importantly, its structure and expression are affected by a number of representative alleles in the agouti dominance hierarchy. In addition, we found that the pleiotropic effects associated with the lethal yellow (Ay) mutation, which include pronounced obesity, diabetes, and the development of neoplasms, are accompanied by deregulated overexpression of the agouti gene in numerous tissues of the adult animal.
The effect of 7 wk consumption of a diet containing 32.6% of kilocalories as fat [condensed milk (CM) diet] on body composition and energy intake was evaluated in nine strains of inbred mice (AKR/J, C57L/J, A/J, C3H/HeJ, DBA/2J, C57BL/6J, SJL/J, I/STN, and SWR/J). Control animals were fed a high-carbohydrate diet containing 11.6% of energy as fat (Purina Rodent Chow diet). Relative to Chow diet controls, the CM diet significantly increased carcass lipid content in six strains (AKR/J, C57L/J, A/J, C3H/HeJ, DBA/2J, and C57BL/6J), but had no or a marginal effect on adiposity in three strains of mice (SJL/J, I/STN, and SWR/J). The obesity produced by the CM diet in six strains was not due to hyperphagia. Only one of six (AKR/J) of the strains that increased adiposity on the CM diet consumed more energy than controls during the 7 wk of the experiment. The identification of inbred mouse strains that are sensitive to dietary obesity, vs. others that are resistant, provides a useful tool to pursue the metabolic and genetic basis of this trait in the mouse.
The concept that obesity is a risk to health was clearly identified in the works of Hippocrates and frequently over the ensuing centuries. Obesity was originally discussed as part of more general texts. Scholarly theses on this subject began to appear in the late 16th century with the first monographs published in the 18th century. The value of dietary restriction, increasing exercise and reducing the amount of sleep were identified early in medical history dating at least from the time of Hippocrates. These concepts were often framed in a manner which implied a 'moral' weakness on the part of the overweight individual. The most spectacular dietary success was published by a layman in 1863 and was the forerunner to many subsequent diet books. Cases of massive obesity were identified in stone age carvings and have been described frequently since the time of Galen and the Roman Empire. More specific types of obesity began to be identified in the 19th century. Following the identification of the cell as the basic building block of animals and plants, fat cells were described and the possibility that obesity was due to too many fat cells was suggested. After the introduction of the calorimeter by Lavoisier, the suggestion that obesity might represent a metabolic derangement has been suggested and tested. Standards for measuring body weight appeared in the 19th century. The possibility that familial factors might also be involved was clearly identified in the 18th and 19th century. In conclusion, most of the concepts which are currently the basis for research in the field of obesity had their origin in the 19th century and often earlier.
To assess the relative importance of genetic and environmental effects on the body-mass index (weight in kilograms divided by the square of the height in meters), we studied samples of identical and fraternal twins, reared apart or reared together. The samples consisted of 93 pairs of identical twins reared apart, 154 pairs of identical twins reared together, 218 pairs of fraternal twins reared apart, and 208 pairs of fraternal twins reared together. The intrapair correlation coefficients of the values for body-mass index of identical twins reared apart were 0.70 for men and 0.66 for women. These are the most direct estimates of the relative importance of genetic influences (heritability) on the body-mass index, and they were only slightly lower than those for twins reared together in this and earlier studies. Similar estimates were derived from maximum-likelihood model-fitting analyses--0.74 for men and 0.69 for women. Nonadditive genetic variance made a significant contribution to the estimates of heritability, particularly among men. Of the potential environmental influences, only those unique to the individual and not those shared by family members were important, contributing about 30 percent of the variance. Sharing the same childhood environment did not contribute to the similarity of the body-mass index of twins later in life. We conclude that genetic influences on body-mass index are substantial, whereas the childhood environment has little or no influence. These findings corroborate and extend the results of earlier studies of twins and adoptees.
We undertook this study to determine whether there are differences in the responses of different persons to long-term overfeeding and to assess the possibility that genotypes are involved in such differences. After a two-week base-line period, 12 pairs of young adult male monozygotic twins were overfed by 4.2 MJ (1000 kcal) per day, 6 days a week, for a total of 84 days during a 100-day period. The total excess amount each man consumed was 353 MJ (84,000 kcal). During overfeeding, individual changes in body composition and topography of fat deposition varied considerably. The mean weight gain was 8.1 kg, but the range was 4.3 to 13.3 kg. The similarity within each pair in the response to overfeeding was significant (P less than 0.05) with respect to body weight, percentage of fat, fat mass, and estimated subcutaneous fat, with about three times more variance among pairs than within pairs (r approximately 0.5). After adjustment for the gains in fat mass, the within-pair similarity was particularly evident with respect to the changes in regional fat distribution and amount of abdominal visceral fat (P less than 0.01), with about six times as much variance among pairs as within pairs (r approximately 0.7). We conclude that the most likely explanation for the intrapair similarity in the adaptation to long-term overfeeding and for the variations in weight gain and fat distribution among the pairs of twins is that genetic factors are involved. These may govern the tendency to store energy as either fat or lean tissue and the various determinants of the resting expenditure of energy.
The contribution of reduced energy expenditure to the development of obesity has been a point of controversy. We measured 24-hour energy expenditure (adjusted for body composition, age, and sex), in a respiratory chamber, in 95 southwestern American Indians. Energy expenditure correlated with the rate of change in body weight over a two-year follow-up period (r = -0.39, P less than 0.001). The estimated risk of gaining more than 7.5 kg in body weight was increased fourfold in persons with a low adjusted 24-hour energy expenditure (200 kcal per day below predicted values) as compared with persons with a high 24-hour energy expenditure (200 kcal per day above predicted values; P less than 0.01). In another 126 subjects, the adjusted metabolic rate at rest at the initial visit was also found to predict the gain in body weight over a four-year follow-up period. When the 15 subjects who gained more than 10 kg were compared with the remaining 111 subjects, the initial mean (+/- SD) adjusted metabolic rate at rest was lower in those who gained weight (1694 +/- 103 vs. 1764 +/- 109 kcal per day; P less than 0.02) and increased to 1813 +/- 134 kcal per day (P less than 0.01) after a mean weight gain of 15.7 +/- 5.7 kg. In a group of 94 siblings from 36 families, values for adjusted 24-hour energy expenditure aggregated in families (intraclass correlation = 0.48). We conclude that a low rate of energy expenditure may contribute to the aggregation of obesity in families.
The relationship of weight at age 65 years and subsequent mortality was examined in a population of 1723 nonsmokers who were followed up from one to 23 years (mean, 9.5 years) during the Framingham Heart Study. In sex-specific proportional hazards analyses, risks of mortality were increased for men and women at the high and low extremes of body mass index, even when accounting for potential effects of excess weight on serum cholesterol level, blood glucose level, and systolic blood pressure. For those at the lower extreme of body mass index, the relative risk of death was almost twice as high in the years immediately after age 65 years as in later follow-up, suggesting that the increased early death rate was due to disease that was already present. At the upper extreme, risk of death was twofold over the entire follow-up period for persons with body mass indexes at or above the 70th percentile at both 55 and 65 years of age. We conclude that, even when accounting for cardiovascular risk factors, being overweight is a serious health problem for older people, especially for those with long-standing weight problems.
(JAMA 1988;259:1520-1524)
Height, weight, and body mass index (BMI) were assessed in a sample of 1974 monozygotic and 2097 dizygotic male twin pairs. Concordance rates for different degrees of overweight were twice as high for monozygotic twins as for dizygotic twins. Classic twin methods estimated a high heritability for height, weight, and BMI, both at age 20 years (.80, .78, and .77, respectively) and at a 25-year follow-up (.80, .81, and .84, respectively). Height, weight, and BMI were highly correlated across time, and a path analysis suggested that the major part of that covariation was genetic. These results are similar to those of other twin studies of these measures and suggest that human fatness is under substantial genetic control.
We performed a double-blind, controlled clinical trial comparing phentermine resin (30 mg in the morning), fenfluramine hydrochloride (20 mg three times a day), and a combination of phentermine resin (15 mg in the morning) and fenfluramine hydrochloride (30 mg before the evening meal), and placebo. We combined low doses of the two drugs to maintain efficacy while diminishing adverse effects. Eighty-one people with simple obesity (130% to 180% of ideal body weight) participated. Individualized diets were prescribed and discussed again during the 24-week study period. Weight loss in those receiving the combination (8.4 +/- 1.1 kg; mean +/- SEM) was significantly greater than in those receiving placebo (4.4 +/- 0.9 kg; Scheff é's test) and equivalent to that of those receiving fenfluramine (7.5 +/- 1.2 kg) or phentermine (10.0 +/- 1.2 kg) alone. Adverse effects were less frequent with the combination regimen than with other active treatments. Thirty-seven participants dropped out of the study, 18 for reasons related to drug treatment. Combining fenfluramine and phentermine capitalized on their pharmacodynamic differences, resulting in equivalent weight loss, fewer adverse effects, and better appetite control.
Leptin, the gene product of the obese gene, may play an important role in regulating body weight by signalling the size of the adipose tissue mass. Plasma leptin was found to be highly correlated with body mass index (BMI) in rodents and in 87 lean and obese humans. In humans, there was variability in plasma leptin at each BMI suggesting that there are differences in its secretion rate from fat. Weight loss due to food restriction was associated with a decrease in plasma leptin in samples from mice and obese humans.
The gene product of the ob locus is important in the regulation of body weight. The ob product was shown to be present as a 16-kilodalton protein in mouse and human plasma but was undetectable in plasma from C57BL/6J ob/ob mice. Plasma levels of this protein were increased in diabetic (db) mice, a mutant thought to be resistant to the effects of ob. Daily intraperitoneal injections of either mouse or human recombinant OB protein reduced the body weight of ob/ob mice by 30 percent after 2 weeks of treatment with no apparent toxicity but had no effect on db/db mice. The protein reduced food intake and increased energy expenditure in ob/ob mice. Injections of wild-type mice twice daily with the mouse protein resulted in a sustained 12 percent weight loss, decreased food intake, and a reduction of body fat from 12.2 to 0.7 percent. These data suggest that the OB protein serves an endocrine function to regulate body fat stores.
Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that is believed to modulate numerous sensory, motor and behavioural processes in the mammalian nervous system. These diverse responses are elicited through the activation of a large family of receptor subtypes. The complexity of this signalling system and the paucity of selective drugs have made it difficult to define specific roles for 5-HT receptor subtypes, or to determine how serotonergic drugs modulate mood and behaviour. To address these issues, we have generated mutant mice lacking functional 5-HT2C receptors (previously termed 5-HT1C), prominent G-protein-coupled receptors that are widely expressed throughout the brain and spinal cord and which have been proposed to mediate numerous central nervous system (CNS) actions of serotonin. Here we show that 5-HT2C receptor-deficient mice are overweight as a result of abnormal control of feeding behaviour, establishing a role for this receptor in the serotonergic control of appetite. Mutant animals are also prone to spontaneous death from seizures, suggesting that 5-HT2C receptors mediate tonic inhibition of neuronal network excitability.
Stability of body composition requires that energy intake equals energy expenditure when integrated over prolonged periods. As recent human studies have failed to demonstrate active changes in energy expenditure with changes in body composition, it is likely that energy intake is continually adjusted to preserve a constant total adipose tissue mass. If adipose tissue mass is regulated directly, then there must be some input reflecting this quantity to the central nervous system for the purpose of making corrective changes in appetite when total body fat content fluctuates. The nature of this input has been examined in a variety of animal experiments involving induced weight change, lipectomy, plasma transfer from obese or satiated animals to hungry animals, and parabiosis between obese and lean animals. The bulk of evidence suggests that the plasma level of one or more currently unidentified stable circulating molecules increases in proportion to total body fat content and augments the effect of meal-related satiety signals in the central nervous system. The implications of this adipose tissue-related satiety factor for the pathogenesis of obesity, and the possible nature of the factor are discussed.
Recent studies of the treatment of obesity by moderate and severe caloric restriction show that patients treated in randomized trials using a conventional 1200 kcal/d reducing diet, combined with behavior modification, lose approximately 8.5 kg in 20 weeks. They maintain approximately two thirds of this weight loss 1 year later. Patients treated under medical supervision using a very-low-calorie diet (400 to 800 kcal/d) lose approximately 20 kg in 12 to 16 weeks and maintain one half to two thirds of this loss in the following year. Both dietary interventions are associated with increasing weight regain over time, although regain can be minimized with the recognition that obesity, in many cases, is a chronic condition that requires continuing care. Patients who participate in a formal weight-loss maintenance program, exercise regularly, or both are likely to achieve the best long-term results.
To determine the accuracy of caloric labeling of "diet" and "health" foods and whether the accuracy differs for certain categories of food suppliers.
Survey; "diet" and "health" foods were analyzed via bomb calorimetry and categorized as regionally distributed, nationally advertised, or locally prepared.
Foods were sampled from retail merchants throughout the borough of Manhattan, New York, NY.
A convenience sample of 40 food items including regionally distributed (n = 12), nationally advertised (n = 20), and locally prepared items (n = 8).
Number of kilocalories per item and number of kilocalories per gram.
All locally prepared foods had more actual than labeled kilocalories. The mean percentage of actual kilocalories greater than the labeled kilocalories (mean percentage over label) per item was 85.42% (SD = 77.88%; P = .01). Regionally distributed foods had significantly more kilocalories than were reported (P = .001 for kilocalories per item, P = .02 for kilocalories per gram) and mean percentage over label per item was 25.22% (SD = 15.58%) and per gram was 14.97% (SD = 17.95%). Nationally advertised foods did not have significantly more actual than reported kilocalories (P = .37 for per item, P = .78 for per gram). Mean percentage over label per gram was -0.01% (SD = 9.13%) and per item was 2.18% (SD = 13.93%).
These findings suggest that food labels may be inadequate sources for caloric monitoring. Health care professionals should consider the accuracy of caloric labeling when advising patients to use food labels to help monitor their caloric intake.