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Visualization of STAT3 Phosphorylation in the Hypothalamus of LF mice (A-C) A representative example of pSTAT3 (brown) and hematoxylin (blue) staining in the hypothalamus is presented; ARH and VMH are indicated by green and yellow outlines, respectively. pSTAT3 staining intensity analyses are indicated as an overlay for positive (yellow) and negative (blue) pSTAT3 staining for the ARH (B) and VMH (C). (D-G) Increased magnification of a 100 micron section of ARH (D-E) or VMH (F-G) are presented, with analysis overlay in panels E and G, respectively.
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Diet-induced obesity (DIO) resulting from consumption of a high fat diet (HFD) attenuates normal neuronal responses to leptin and may contribute to the metabolic defense of an acquired higher body weight in humans; the molecular bases for the persistence of this defense are unknown. We measured the responses of 23 brain regions to exogenous leptin...
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In this study, we present the potential application of deuterium-depleted water (DDW) for the prevention and adjuvant treatment of obesity in rats. We tested the hypothesis that DDW can alleviate diet-induced obesity (DIO) and its associated metabolic impairments. Rats fed a high-fat diet had an increased body weight index (BWI), glucose concentrat...
Citations
... Insulin sensitivity improves when BMI drops below 25 kg/m 2 , and fasting leptin levels decrease by 15 ng/dL; the mechanisms involve better delivery of leptin to the CNS and its access to specific neuronal groups [51,90]. As a result, a person's usual weight and any past or present negative energy balance affect the transduction of the leptin signal [91]. Low blood levels of leptin and sensitivity as an antisteatotic effect are linked to sports [62], bariatric surgery [92], certain foods like polyphenols [74,93], neurocognitive control [94,95], long-term weight loss, and calorie restriction [96,97]. ...
Leptin regulates lipid metabolism, maximizing insulin sensitivity; however, peripheral leptin resistance is not fully understood, and its contribution to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study evaluated the contribution of the leptin axis to MASLD in humans. Forty-three participants, mostly female (86.04%), who underwent cholecystectomy were biopsied. Of the participants, 24 were healthy controls, 8 had MASLD, and 11 had metabolic dysfunction-associated steatohepatitis (MASH). Clinical and biochemical data and the gene expression of leptin, leptin receptor (LEPR), suppressor of cytokine signaling 3 (SOCS3), sterol regulatory element-binding transcription factor 1 (SREBF1), stearoyl-CoA desaturase-1 (SCD1), and patatin-like phospholipase domain-containing protein 2 (PNPLA2), were determined from liver and adipose tissue. Higher serum leptin and LEPR levels in the omental adipose tissue (OAT) and liver with MASH were found. In the liver, LEPR was positively correlated with leptin expression in adipose tissue, and SOCS3 was correlated with SREBF1-SCD1. In OAT, SOCS3 was correlated with insulin resistance and transaminase enzymes (p < 0.05 for all. In conclusion, we evidenced the correlation between the peripheral leptin resistance axis in OAT–liver crosstalk and the complications of MASLD in humans.
... Morabito et al., in an animal model of a high-fat diet (HFD) (60%) for 30 weeks, observed that leptin activity decreased in inflamed areas of the brain; despite the administration of exogenous leptin, these animal's weights did not decrease. However, caloric restriction caused the animals to reduce their weight and visceral fat, restore leptin and insulin levels, and decrease cerebral gliosis [45]. Inflammation in the hypothalamus and peripheral tissues induces the activation of stress-related kinases, such as c-Jun N-terminal kinase (JNK) and IkB-kinase (IKK), which inhibit mediators of leptin pathways and insulin. ...
Obesity remains a global health problem. Chronic low-grade inflammation in this pathology has been related to comorbidities such as cognitive alterations that, in the long term, can lead to neurodegenerative diseases. Neuroinflammation or gliosis in patients with obesity and type 2 diabetes mellitus has been related to the effect of adipokines, high lipid levels and glucose, which increase the production of free radicals. Cerebral gliosis can be a risk factor for developing neurodegenerative diseases, and antioxidants could be an alternative for the prevention and treatment of neural comorbidities in obese patients.
Aim:
Identify the immunological and oxidative stress mechanisms that produce gliosis in patients with obesity and propose antioxidants as an alternative to reducing neuroinflammation.
Method:
Advanced searches were performed in scientific databases: PubMed, ProQuest, EBSCO, and the Science Citation index for research on the physiopathology of gliosis in obese patients and for the possible role of antioxidants in its management.
Conclusion:
Patients with obesity can develop neuroinflammation, conditioned by various adipokines, excess lipids and glucose, which results in an increase in free radicals that must be neutralized with antioxidants to reduce gliosis and the risk of long-term neurodegeneration.
... What differs between individuals with and without obesity is the threshold. Therefore leptin signal transduction is dependent upon an individual's "usual weight" and any ongoing or previous negative energy balance (Morabito et al., 2017). ...
LEP is a pleiotropic gene and the actions of leptin extend well beyond simply acting as the signal of the size of adipose tissue stores originally proposed. This is a discussion of the multi-system interactions of leptin with the development of the neural systems regulating energy stores, and the subsequent maintenance of energy stores throughout the lifespan. The prenatal, perinatal, and later postnatal effects of leptin on systems regulating body energy stores and on the energy stores themselves are heavily influenced by the nutritional environment which leptin exposure occurs. This review discusses the prenatal and perinatal roles of leptin in establishing the neuronal circuitry and other systems relevant to the adiposity set-point (or “threshold”) and the role of leptin in maintaining weight homeostasis in adulthood. Therapeutic manipulation of the intrauterine environment, use of leptin sensitizing agents, and identification of specific cohorts who may be more responsive to leptin or other means of activating the leptin signaling pathway are ripe areas for future research.
... Therefore, these responses do not differ qualitatively or quantitatively among individuals with and without obesity. What differs among individuals is the threshold, and therefore leptin signal transduction is dependent upon an individual's "usual weight" and any ongoing or previous negative energy balance (78). ...
Although many persons with obesity can lose weight by lifestyle (diet and physical activity) therapy, successful long‐term weight loss is difficult to achieve, and most people who lose weight regain their lost weight over time. The neurohormonal, physiological, and behavioral factors that promote weight recidivism are unclear and complex. The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop in June 2019, titled “The Physiology of the Weight‐Reduced State,” to explore the mechanisms and integrative physiology of adaptations in appetite, energy expenditure, and thermogenesis that occur in the weight‐reduced state and that may oppose weight‐loss maintenance. The proceedings from the first session of this workshop are presented here. Drs. Michael Rosenbaum, Kevin Hall, and Rudolph Leibel discussed the physiological factors that contribute to weight regain; Dr. Michael Lowe discussed the biobehavioral issues involved in weight‐loss maintenance; Dr. John Jakicic discussed the influence of physical activity on long‐term weight‐loss maintenance; and Dr. Louis Aronne discussed the ability of drug therapy to maintain weight loss.
... Among potential factors of interest is exposure to hypernutrition in early infancy (10,11). We used transient elevation in circulating leptin as a surrogate for transient increases in adiposity, in order to avoid the confounding effects of hyperphagia (35), diet composition (34,36), and weight change (34,37). Obese or HFD-fed animals have complex metabolic phenotypes that include increased circulating free fatty acids, elevated glucose, decreased insulin sensitivity, increased circulating insulin, and fatty liver. ...
Leptin plays a role in central nervous system developmental programs and intercurrent physiological processes related to body fat regulation. The timing and neuromolecular mechanisms for these effects are relevant to the prevention and treatment of obesity. Factors implicated in a body weight “set point” including dietary fat, circulating leptin, and other adipokines tend to covary with adiposity and are difficult to disarticulate experimentally. To dissociate leptin effects from adiposity and diet, we created a transgenic mouse in which leptin expression is regulated by doxycycline exposure. Using this system, we investigated the physiological consequences of developmentally-timed transient hyperleptinemia on subsequent adiposity. We evaluated physiological effects of leptin elevation during adulthood (9 to 29 weeks old), “adolescence” (3 to 8 weeks old), and the immediate postnatal period [postnatal days 0 to 22 (P0 to P22)] on long-term adiposity and susceptibility to gain weight on high-fat diet (HFD) fed ad libitum. We found that inducing chronic hyperleptinemia in adult or “adolescent” mice did not alter body weight when excess leptin was discontinued, and upon later exposure to HFD, weight gain did not differ from controls. However, transient elevation of circulating leptin from P0 to P22 increased weight and fat gain in response to HFD, indicating greater susceptibility to obesity as adults. Thus, transient plasma leptin elevations—mimicking one aspect of transient adiposity—increased later susceptibility to diet-induced obesity, although these effects were restricted to a critical developmental (P0 to P22) time window. These findings may have clinical implications for weight management in infancy.
... Fasting-induced decrease in leptinaemia is partly regulated by sympathetic outflow to the white adipose tissue regulating leptin biosynthesis and secretion (Caron et al. 2018). Energy restriction also reduces leptinaemia and restores leptin-induced pSTAT3 response in several brain regions including VMH (Morabito et al. 2017). Additionally, diet switch from HFD to regular chow reverses leptin resistance in some DIO models. ...
... In particular, decreasing the dietary fat content in mice fed with HFD for 20 weeks reverses obesity and hypothalamic leptin sensitivity in the ARH after 7 weeks of diet switch (Enriori et al. 2007). Another study showed that 12 weeks of low-fat diet after 30 weeks of DIO not only decreases body weight and leptinaemia to values similar to lean mice but also recovers leptin-induced pSTAT3 levels in some brain regions to a greater extent than energy restriction (Morabito et al. 2017). However, ARH and DMH do not recover leptin sensitivity neither with energy restriction nor with dietary switch (Morabito et al. 2017). ...
... Another study showed that 12 weeks of low-fat diet after 30 weeks of DIO not only decreases body weight and leptinaemia to values similar to lean mice but also recovers leptin-induced pSTAT3 levels in some brain regions to a greater extent than energy restriction (Morabito et al. 2017). However, ARH and DMH do not recover leptin sensitivity neither with energy restriction nor with dietary switch (Morabito et al. 2017). Diet composition can also affect leptin resensitisation. ...
Leptin resistance refers to states in which leptin fails to promote its anticipated effects, frequently coexisting with hyperleptinaemia. It is closely associated with obesity, and also observed in physiological situations such as pregnancy and in seasonal animals. Leptin resensitization refers to the reversion of leptin resistant states and is associated with improvement in endocrine and metabolic disturbances commonly observed in obesity and a sustained decrease of plasma leptin levels, possibly below a critical threshold level. In obesity, leptin resensitization can be achieved with treatments that reduce body adiposity and leptinaemia, or with some pharmacological compounds, while physiological leptin resistance reverts spontaneously. The restoration of leptin sensitivity could be a useful strategy to treat obesity, maintain weight loss and/or reduce the recidivism rate for weight regain after dieting. This review provides an update and discussion about reversion of leptin resistant states and modulation of the molecular mechanisms involved in each situation.
... It has been observed that the serum concentrations of this hormone correlate positively with the mass of adipose tissue. Although leptin is a circulating signal that reduces appetite primarily by central action [21], obese subjects generally has unusually high levels of circulating leptin and thus, resistance to this hormone develops [22]. ...
