Carlos Dieguez

• MD,PhD
• Research Director at University of Santiago de Compostela

Objective Despite growing evidence, the mechanisms connecting adipose tissue (AT) function to type 2 diabetes (T2DM) remain incompletely understood. A detailed analysis of AT transcriptomes could offer valuable insights into this relationship. Here, we examined gene expression patterns in bulk subcutaneous AT, focusing on biological pathways and ce...

Objective AMP-activated protein kinase (AMPK) is a heterotrimer complex consisting of a catalytic α subunit (α1, α2) with a serine/threonine kinase domain, and two regulatory subunits, β (β1, β2) and γ (γ1, γ2, γ3), encoded by different genes. In the hypothalamus, AMPK plays a crucial role in regulating energy balance, including feeding, energy exp...

The use of incretin agonists for managing metabolic dysfunction-associated steatohepatitis (MASH) is currently experiencing considerable interest. However, whether these compounds have a direct action on MASH is still under debate. This study aims to investigate whether GLP-1R/GIPR agonists act directly in hepatocytes and hepatic stellate cells (HS...

Background The microbiota is emerging as a key factor in the predisposition to insulin resistance and obesity. Objective To understand the interplay among gut microbiota and insulin sensitivity in multiple tissues. Design Integrative multiomics and multitissue approach across six studies, combining euglycaemic clamp measurements (used in four of...

Objective p63 is a transcription factor involved in multiple biological functions. In the liver, the TAp63 isoform induces lipid accumulation in hepatocytes. However, the role of liver TAp63 in the progression of metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis is unknown. Methods We evaluated the hepatic p63 levels in differe...

Background and Aims Mitochondrial antiviral signaling protein (MAVS) is a critical regulator that activates the host’s innate immunity against RNA viruses, and its signaling pathway has been linked to the secretion of proinflammatory cytokines. However, the actions of MAVS on inflammatory pathways during the development of metabolic dysfunction–ass...

Background: Neurobiological characteristics have been identified regarding the severity of gambling disorder (GD). The aims of this study were: (1) to examine, through a path analysis, whether there was a relationship between neuroendocrine features, potentially mediational GD variables, and GD severity, and (2) to associate neuroendocrine variable...

Purpose Liver-expressed antimicrobial peptide 2 (LEAP-2) has been recently identified as the endogenous non-competitive allosteric antagonist of the growth hormone secretagogue receptor 1a (GHSR1a). In rodents, LEAP-2 blunts ghrelin-induced feeding and its plasma levels are modulated in response to nutritional status, being decreased upon fasting a...

The p63 protein has pleiotropic functions and, in the liver, participates in the progression of nonalcoholic fatty liver disease (NAFLD). However, its functions in hepatic stellate cells (HSCs) have not yet been explored. TAp63 is induced in HSCs from animal models and patients with liver fibrosis and its levels positively correlate with NAFLD acti...

Objective Free fatty acid receptor-1 (FFAR1) is a medium- and long-chain fatty acid sensing G protein-coupled receptor that is highly expressed in the hypothalamus. Here, we investigated the central role of FFAR1 on energy balance. Methods Central FFAR1 agonism and virogenic knockdown were performed in mice. Energy balance studies, infrared thermo...

Background Data implicate overlaps in neurobiological pathways involved in appetite regulation and addictive disorders. Despite different neuroendocrine measures having been associated with both gambling disorder (GD) and food addiction (FA), how appetite-regulating hormones may relate to the co-occurrence of both entities remain incompletely under...

Purpose: Climate change and global warming have been hypothesized to influence the increased prevalence of obesity worldwide. However, the evidence is scarce. Methods: The expression of genes involved in thermogenesis/browning and adipogenesis were evaluated (through qPCR) in the subcutaneous adipose tissue (SAT) from 1,083 subjects recruited in...

Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Here, we show that neddylation in mouse liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver reduces gluconeogenic capacity and the hyperglycemic a...

Objective: O-GlcNAcylation is a post-translational modification that directly couples the processes of nutrient sensing, metabolism, and signal transduction, affecting protein function and localization, since the O-linked N-acetylglucosamine moiety comes directly from the metabolism of glucose, lipids, and amino acids. The addition and removal of...

There are currently several pharmacological therapies available for the treatment of obesity, targeting both the central nervous system (CNS) and peripheral tissues. In recent years, small extracellular vesicles (sEVs) have been shown to be involved in many pathophysiological conditions. Because of their special nanosized structure and contents, sE...

The ratio between circulating levels of leptin and soluble leptin receptor (sOB-R), the free leptin index (FLI), is used as a marker of leptin resistance. Therefore, the aim of our study was to investigate the FLI in mild pre-eclamptic pregnancies in a nested case-control study within a prospective observational study. Circulating levels of leptin...

Objective: p63 is a transcription factor within the p53 protein family that has key roles in development, differentiation and prevention of senescence, but its metabolic actions remain largely unknown. Herein, we investigated the physiological role of p63 in glucose metabolism. Design: We used cell lines and mouse models to genetically manipulat...

Gambling disorder (GD) is a modestly prevalent and severe condition for which neurobiology is not yet fully understood. Although alterations in signals involved in energy homeostasis have been studied in substance use disorders, they have yet to be examined in detail in GD. The aims of the present study were to compare different endocrine and neuro...

Thyroid hormones (THs) play a major role regulating energy balance and brown adipose tissue (BAT) thermogenesis, as well as body temperature, as shown in hyperthyroid patients. However, the current landscape of preclinical thyroid hormone models is complex. For example, while rats become catabolic after TH administration, mice gain weight; so, thes...

Background and aims Leptin receptor (LEPR) deficiency promotes severe obesity and metabolic disorder. However, the current therapeutic options against this syndrome are scarce. Methods db/db mice and their wildtypes were systemically treated with neuronal-targeted small extracellular vesicles (sEVs) harboring a plasmid encoding a dominant negative...

Introduction Food Addiction (FA) has been related with eating disorders (ED), especially Bulimia Nervosa (BN). BN + FA may have different physical characteristics than patients with BN without the comorbidity, such as body mass index (BMI) or body composition, and psychological as emotion regulation. However, the relationship between psychological...

Introduction COVID19 lockdown is having a significant impact on mental health, patients with eating disorders (ED) are particularly vulnerable. Objectives 1) To explore changes in eating and other psychological features due to confinement in patients with ED from various European and Asian countries; and 2) to assess differences related to diagnos...

The Liver-Expressed Antimicrobial Peptide 2 (LEAP-2) has emerged as an endogenous GHS-R antagonist and blunts the orexigenic action of ghrelin. This study aimed to determine the Ghrelin/LEAP-2 ratio in humans and rats during pregnancy. In humans, we conducted a nested case-control study within an observational prospective cohort. Healthy and mild p...

(1) Background: Fibroblast growth factor 21 (FGF-21) is an endocrine factor involved in glucose and lipid metabolism that exerts pleiotropic effects. The aim of this study was to investigate the serum FGF-21 profile in healthy and mild preeclamptic pregnant women at each trimester of pregnancy; (2) Methods: Serum FGF-21 levels were determined by EL...

Ultraviolet radiation exerts differential effects in men and women. Parikh et al. reveal that solar exposure on the skin triggers food-seeking behaviour in males, but not females, through a mechanism dependent on ghrelin secretion from skin adipocytes.

Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown. Here we show that delayed weaning in rat pups prote...

O-GlcNAcylation is a posttranslational modification ruled by the activity of a single pair of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). These two enzymes carry out the dynamic cycling of O-GlcNAcylation on a wide range of cytosolic, nuclear, and mitochondrial proteins in a nutrient- and stress-responsive manner. To maintain proper...

Objective: Food addiction (FA) construct was introduced to reflect abnormal eating patterns that resemble behavioural ones found in substance use disorders. FA has been barely explored in anorexia nervosa (AN). This study evaluated FA occurrence and associated factors in a sample of patients with AN, distinguishing between restrictive and binge-pu...

Weight gain is a hallmark of decreased estradiol (E2) levels because of menopause or following surgical ovariectomy (OVX) at younger ages. Of note, this weight gain tends to be around the abdomen, which is frequently associated with impaired metabolic homeostasis and greater cardiovascular risk in both rodents and humans. However, the molecular und...

Background: A first approach of a phenotypic characterization of food addiction (FA) found three clusters (dysfunctional, moderate and functional). Based on this previous classification, the aim of the present study is to explore treatment responses in the sample diagnosed with Eating Disorder(ED) of different FA profiles. Methods: The sample wa...

The maintenance and regulation of body temperature in neonates is critical for survival. However, the mechanisms by which human neonates achieve body temperature control are unclear. Current evidence has demonstrated that infrared thermography is a suitable non-invasive technique that can be safely applied to human babies to investigate brown adipo...

Background & Aims The pathogenesis of liver fibrosis requires activation of hepatic stellate cells (HSCs); once activated, HSCs lose intracellular fatty acids but the role of fatty acid oxidation and carnitine palmitoyltransferase 1A (CPT1A) in this process remains largely unexplored. Methods CPT1A was found in HSCs of patients with fibrosis. Phar...

Data gleaned recently shows that ghrelin, a stomach derived peptide, and liver-expressed-antimicrobial peptide 2 (LEAP-2) play opposite roles on food intake. However, the data available with LEAP-2 in relation to in vivo studies are still very scanty and some key questions regarding the interplay among ghrelin and LEAP-2 remain to be answered. In t...

Background and aims: Food addiction (FA) and substance use (SU) have frequently been reported in patients with eating disorders (EDs). Our study aimed to assess the prevalence rates of FA and/or lifetime problematic alcohol and illicit drug use among patients with specific ED, such as: bulimia nervosa (BN), binge eating disorder (BED), and other s...

Background and aims Olfactomedin 2 (OLFM2; also known as noelin 2) is a pleiotropic protein that plays a major role in olfaction and Olfm2 null mice exhibit reduced olfactory sensitivity, as well as abnormal motor coordination and anxiety-related behavior. Here, we investigated the possible metabolic role of OLFM2. Methods Olfm2 null mice were met...

Objective To investigate whether thermogenesis and the hypothalamus may be involved in the physiopathology of experimental arthritis (EA). Methods EA was induced in male Lewis rats by intradermal injection of Freund's complete adjuvant (CFA). Food intake, body weight, plasma cytokines, thermographic analysis, gene and protein expression of thermog...

Background: The COVID-19 lockdown has had a significant impact on mental health. Patients with eating disorders (ED) have been particularly vulnerable. Aims: (1) To explore changes in eating-related symptoms and general psychopathology during lockdown in patients with an ED from various European and Asian countries; and (2) to assess differences...

Citation: Capelli, V.; Grijota-Martínez, C.; Dragano, N.R.V.; Rial-Pensado, E.; Fernø, J.; Nogueiras, R.; Mittag, J.; Diéguez, C.; López, M. Orally Induced Hyperthyroidism Regulates Hypothalamic AMP-Activated Protein Kinase. Nutrients 2021, 13, 4204. https:// Abstract: Besides their direct effects on peripheral metabolic tissues, thyroid hormones (...

Melanin-concentrating hormone (MCH) is a small cyclic peptide expressed in all mammals, mainly in the hypothalamus. MCH acts as a robust integrator of several physiological functions and has crucial roles in the regulation of sleep–wake rhythms, feeding behaviour and metabolism. MCH signalling has a very broad endocrine context and is involved in p...

Current pharmacological therapies for treating obesity are of limited efficacy. Genetic ablation or loss of function of AMP-activated protein kinase alpha 1 (AMPKα1) in steroidogenic factor 1 (SF1) neurons of the ventromedial nucleus of the hypothalamus (VMH) induces feeding-independent resistance to obesity due to sympathetic activation of brown a...

It is unclear how loss-of-function germline mutations in the widely-expressed co-chaperone AIP, result in young-onset growth hormone secreting pituitary tumours. The RET receptor, uniquely co-expressed in somatotrophs with PIT1, induces apoptosis when unliganded, while RET supports cell survival when it is bound to its ligand. We demonstrate that a...

The classical dogma states that brown adipose tissue (BAT) plays a major role in the regulation of temperature in neonates. However, although BAT has been studied in infants for more than a century, the knowledge about its physiological features at this stage of life is rather limited. This has been mainly due to the lack of appropriate investigati...

In the field of thyroid hormone (TH) action on energy balance, huge advances have been achieved in the past decade, from human, animal, and in vitro studies. A key achievement was the demonstration of the TH ‘central’ metabolic action, which was recently discovered in rodent models and challenged the previous ‘peripheral’ paradigm. In this opinion,...

Background & aims: Autophagy-related gene 3 (ATG3) is an enzyme mainly known for its actions in the LC3 lipidation process, which is essential for autophagy. Whether ATG3 plays a role in lipid metabolism or contributes to nonalcoholic fatty liver disease (NAFLD) remains unknown. Methods: By performing a liver proteomic analysis from mice with ge...

p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation...

Pituitary adenomas (PAs) are intracranial tumors, often associated with excessive hormonal secretion and severe comorbidities. Some patients are resistant to medical therapies; therefore, novel treatment options are needed. Antagonists of growth hormone-releasing hormone (GHRH) exert potent anticancer effects, and early GHRH antagonists were found...

Energy restriction is a first therapy in the treatment of obesity, but the underlying biological mechanisms have not been completely clarified. We analyzed the effects of restriction of high-fat diet (HFD) on weight loss, circulating gut hormone levels and expression of hypothalamic neuropeptides. Ten-week-old male Wistar rats (n = 40) were randoml...

Anorexia nervosa (AN) is an eating disorder leading to malnutrition and, ultimately, to energy wasting and cachexia. Rodents develop activity-based anorexia (ABA) when simultaneously exposed to a restricted feeding schedule and allowed free access to running wheels. These conditions lead to a life-threatening reduction in body weight, resembling AN...

Introduction: Throughout normal pregnancy, different metabolic and hormonal adaptations are presented, among others, significant modifications in the profile of lipids and lipoprotein metabolism. On the other hands, Angiopoietin-like protein 3 (ANGPTL3) are involved in the regulation of triglyceride metabolism in the fed state by inhibiting the enz...

Objective Angiopoietin-like protein 3(ANGPTL3) is an important regulator of lipoprotein metabolism in the fed state by inhibiting the enzyme lipoprotein lipase in oxidative tissues. However, the possible role of ANGPTL3 throughout gestation and its relationship with hormonal and biochemical variables are still unknown. The aim of this study was to...

Sirtuin 3 (SIRT3) is one of the seven mammalian sirtuin homologs of the yeast Sir2 gene that has emerged as an important player in the regulation of energy metabolism in peripheral tissues. However, its role in the hypothalamus has not been explored. Herein, we show that the genetic inhibition of SIRT3 in the hypothalamic arcuate nucleus (ARC) indu...

Anorexia nervosa (AN) is an eating disorder leading to malnutrition and, ultimately, to energy wasting and cachexia. Rodents develop activity-based anorexia (ABA) when simultaneously exposed to a restricted feeding schedule and allowed free access to running wheels. These conditions lead to a life-threatening reduction in body weight, resembling AN...

Background/Objectives Liver-expressed antimicrobial peptide 2 (LEAP-2) was recently identified as an endogenous non-competitive allosteric antagonist of the growth hormone secretagogue receptor 1a (GHSR1a). LEAP-2 blunts ghrelin-induced feeding and its plasma levels are modulated in response to nutritional status in humans. Despite the relevant rol...

Obesity has reached pandemic proportions and is associated with severe comorbidities, such as type 2 diabetes mellitus, hepatic and cardiovascular diseases, and certain cancer types. However, the therapeutic options to treat obesity are limited. Extensive epidemiological studies have shown a strong relationship between smoking and body weight, with...

Several studies have reported that nicotine, the main bioactive component of tobacco, exerts a marked negative energy balance. Apart from its anorectic action, nicotine also modulates energy expenditure, by regulating brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. These effects are mainly controlled at the central...

Background & aims: G protein-coupled receptor 55 (GPR55) is a putative cannabinoid receptor, and l-α-lysophosphatidylinositol (LPI) is its only known endogenous ligand. Although GPR55 has been linked to energy homeostasis in different organs, its specific role in lipid metabolism in the liver and its contribution to the pathophysiology of non-alco...

The ratio leptin/soluble leptin receptor (sOB-r), free leptin index (FLI), is used as a marker of leptin sensitivity/resistance in different pathologies. The aim of this study was to evaluate FLI in healthy non-pregnant, healthy pregnant and mild preeclamptic women during pregnancy. We conducted a nested case-control study within a longitudinal obs...

Excessive consumption of high-fructose diets is associated with insulin resistance, obesity and non-alcoholic fatty liver disease (NAFLD). However, fructose differentially affects hepatic regulation of lipogenesis in males and females. Hence, additional studies are necessary in order to find strategies taking gender disparities in fructose-induced...

Since its discovery twenty-five years ago, the fat-derived hormone leptin has provided a revolutionary framework for studying the physiological role of adipose tissue as an endocrine organ. Leptin exerts pleiotropic effects on many metabolic pathways and is tightly connected with the liver, the major player in systemic metabolism. As a consequence,...

Background Reproduction is tightly coupled to body energy and metabolic status. GnRH neurons, master elements and final output pathway for the brain control of reproduction, directly or indirectly receive and integrate multiple metabolic cues to regulate reproductive function. Yet, the molecular underpinnings of such phenomenon remain largely unfol...

This study aimed to determine ANGPTL3 serum levels in healthy young lean and obese non-diabetic men during an oral glucose tolerance test (OGTT) and correlate them with anthropometric, biochemical and hormonal parameters. A case–control study was carried out and 30 young obese non-diabetic (23.90 ± 3.84 years and BMI 37.92 ± 4.85 kg/m²) and 28 age-...

Skeletal muscle promotes metabolic balance by regulating glucose uptake and the stimulation of multiple interorgan crosstalk. We show here that the catalytic activity of Vav2, a Rho GTPase activator, modulates the signaling output of the IGF1- and insulin-stimulated phosphatidylinositol 3-kinase pathway in that tissue. Consistent with this, mice be...

In the last thirty years, obesity has reached epidemic proportions and is now regarded as a major health issue in contemporary society trending to serious economic and social burdens. The latest projections of the World Health Organization are alarming. By 2030, nearly 60% of the worldwide population could be either obese or overweight, highlightin...

Confinement during the COVID-19 pandemic is expected to have a serious and complex impact on the mental health of patients with an eating disorder (ED) and of patients with obesity. The present manuscript has the following aims: (1) to analyse the psychometric properties of the COVID Isolation Eating Scale (CIES), (2) to explore changes that occurr...

GH (growth hormone) secretion/action is modulated by alterations in energy homeostasis, such as malnutrition and obesity. Recent data have uncovered the mechanism by which hypothalamic neurons sense nutrient bioavailability, with a relevant contribution of AMPK (AMP-activated protein kinase) and mTOR (mammalian Target of Rapamycin), as sensors of c...

Context Leptin is an adipokine involved in many pleiotropic and key physiological actions and circulates free and active, or inactive bound to the leptin binding protein and sOB-r. Thus, the ratio Leptin/sOB-r or free leptin index (FLI) is commonly used as a marker of leptin sensitivity in different pathologies. Objective Evaluate serum concentrati...

In the last thirty years, obesity has reached epidemic proportions and is now regarded as a major health issue in contemporary society trending to serious economic and social burdens. The latest projections of the World Health Organization are alarming. By 2030, nearly 60% of the worldwide population could be either obese or overweight, highlightin...

Rheumatoid arthritis (RA) is a debilitating, chronic, inflammatory, autoimmune disease associated with cachexia. The substitutive therapy of gut hormone ghrelin has been pointed at as a potential countermeasure for the management of metabolic and inflammatory complications in RA. The recent discovery of liver-expressed antimicrobial peptide 2 (LEAP...

the hypothesis linking hyperactivity with weight loss associated hypoleptinemia in anorexia nervosa gained momentum after a study showing that leptin suppressed semi-starvation induced hyperactivity in rats. Alternatively, ambient temperature is a key modulating factor of activity in semi-starved rats. The aim of the study is to compare the efficac...

Linaclotide is a synthetic peptide approved by the FDA for the treatment of constipation-predominant irritable bowel syndrome and chronic constipation. Linaclotide binds and activates the transmembrane receptor guanylate cyclase 2C (Gucy2c). Uroguanylin is a 16 amino acid peptide that is mainly secreted by enterochromaffin cells in the duodenum and...

The hypothalamus is a brain region in charge of many vital functions. Among them, BAT thermogenesis represents an essential physiological function to maintain body temperature. In the metabolic context, it has now been established that energy expenditure attributed to BAT function can contribute to the energy balance in a substantial extent. Thus,...

Food addiction (FA) has been associated with greater psychopathology in individuals with eating disorders (ED) and obesity (OBE). The current study aims to provide a better phenotypic characterization of the FA construct by conducting a clustering analysis of FA in both conditions (ED and OBE). The total sample was comprised of 234 participants tha...