Association between endocrine and neuropsychological endophenotypes and gambling disorder severity.

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 variables, with GD severity-related variables according to gambling preferences. METHODS: The sample included 297 outpatients with GD. We analyzed endocrine concentrations of different appetite-related hormones (ghrelin, liver antimicrobial peptide 2 [LEAP-2], leptin, adiponectin), and neuropsychological performance (working memory, cognitive flexibility, inhibition, decision making, premorbid intelligence). Path analysis assessed mechanisms between neuroendocrine features and GD severity, including mediational GD variables (impulsivity traits and gambling-related cognitive distortions). Partial correlations evaluated the associations between neuroendocrine variables, including impulsivity traits, and variables related to GD severity (DSM-5, South Oaks Gambling Screen, illness duration, and gambling-related cognitive distortions). RESULTS: Lower adiponectin concentrations predicted greater GD severity, while higher LEAP-2 concentrations predicted more gambling-related cognitive distortions. Likewise, better neuropsychological performance directly predicted GD severity, but worse neuropsychological performance was associated with GD severity through the mediational variables of impulsivity traits and gambling-related cognitive distortions. Also, in non-strategic individuals with GD, poor working memory was associated with gambling expectancies and predictive control. In strategic individuals with GD, poor cognitive flexibility was associated with illusion of control, predictive control, and inability to stop gambling. CONCLUSIONS: These results provide updated information about the comprehension of the interaction between neuroendocrine features, clinical variables, and severity of GD. Thus, neurobiological functions seem to be strongly related to GD severity.

Cluster analysis in gambling disorder based on sociodemographic, neuropsychological, and neuroendocrine features regulating energy homeostasis.

BACKGROUND: The heterogeneity of gambling disorder (GD) has led to the identification of different subtypes, mostly including phenotypic features, with distinctive implications on the GD severity and treatment outcome. However, clustering analyses based on potential endophenotypic features, such as neuropsychological and neuroendocrine factors, are scarce so far. AIMS: This study firstly aimed to identify empirical clusters in individuals with GD based on sociodemographic (i.e., age and sex), neuropsychological (i.e., cognitive flexibility, inhibitory control, decision making, working memory, attention, and set-shifting), and neuroendocrine factors regulating energy homeostasis (i.e., leptin, ghrelin, adiponectin, and liver-expressed antimicrobial peptide 2, LEAP-2). The second objective was to compare the profiles between clusters, considering the variables used for the clustering procedure and other different sociodemographic, clinical, and psychological features. METHODS: 297 seeking-treatment adult outpatients with GD (93.6% males, mean age of 39.58 years old) were evaluated through a semi-structured clinical interview, self-reported psychometric assessments, and a protocolized neuropsychological battery. Plasma concentrations of neuroendocrine factors were assessed in peripheral blood after an overnight fast. Agglomerative hierarchical clustering was applied using sociodemographic, neuropsychological, and neuroendocrine variables as indicators for the grouping procedure. Comparisons between the empirical groups were performed using Chi-square tests (χ2) for categorical variables, and analysis of variance (ANOVA) for quantitative measures. RESULTS: Three-mutually-exclusive groups were obtained, being neuropsychological features those with the greatest weight in differentiating groups. The largest cluster (Cluster 1, 65.3%) was composed by younger males with strategic and online gambling preferences, scoring higher on self-reported impulsivity traits, but with a lower cognitive impairment. Cluster 2 (18.2%) and 3 (16.5%) were characterized by a significantly higher proportion of females and older patients with non-strategic gambling preferences and a worse neuropsychological performance. Particularly, Cluster 3 had the poorest neuropsychological performance, especially in cognitive flexibility, while Cluster 2 reported the poorest inhibitory control. This latter cluster was also distinguished by a poorer self-reported emotion regulation, the highest prevalence of food addiction, as well as a metabolic profile characterized by the highest mean concentrations of leptin, adiponectin, and LEAP-2. CONCLUSIONS: To the best of our knowledge, this is the first study to identify well-differentiated GD clusters using neuropsychological and neuroendocrine features. Our findings reinforce the heterogeneous nature of the disorder and emphasize a role of potential endophenotypic features in GD subtyping. This more comprehensive characterization of GD profiles could contribute to optimize therapeutic interventions based on a medicine of precision.

Plasma concentration of leptin is related to food addiction in gambling disorder: Clinical and neuropsychological implications.

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 understood. Aims: To compare plasma concentrations of ghrelin, leptin, adiponectin, and liver-expressed antimicrobial peptide 2 (LEAP-2) between patients with GD, with and without FA, and to explore the association between circulating hormonal concentrations and neuropsychological and clinical features in individuals with GD and FA. Methods: The sample included 297 patients diagnosed with GD (93.6% males). None of the patients with GD had lifetime diagnosis of an eating disorder. FA was evaluated with the Yale Food Addiction Scale 2.0. All patients were assessed through a semi-structured clinical interview and a psychometric battery including neuropsychological tasks. Blood samples to measure hormonal variables and anthropometric variables were also collected. Results: From the total sample, FA was observed in 23 participants (FA+) (7.7% of the sample, 87% males). When compared participants with and without FA, those with FA+ presented both higher body mass index (BMI) (p < 0.001) and leptin concentrations, after adjusting for BMI (p = 0.013). In patients with FA, leptin concentrations positively correlated with impulsivity, poorer cognitive flexibility, and poorer inhibitory control. Other endocrine measures did not differ between groups. Discussion and conclusions: The present study implicates leptin in co-occurring GD and FA. Among these patients, leptin concentration has been associated with clinical and neuropsychological features, such as impulsivity and cognitive performance in certain domains.

Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism.

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 actions of counter-regulatory hormones. Furthermore, people with type 2 diabetes display elevated hepatic neddylation levels. Mechanistically, fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues-K278, K342, and K387. We find that mutating the three PCK1 lysines that are neddylated reduces their gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.

Are Signals Regulating Energy Homeostasis Related to Neuropsychological and Clinical Features of Gambling Disorder? A Case-Control Study.

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 neuropsychological factors between individuals with GD and healthy controls (HC) and to explore endocrine interactions with neuropsychological and clinical variables. A case−control design was performed in 297 individuals with GD and 41 individuals without (healthy controls; HCs), assessed through a semi-structured clinical interview and a psychometric battery. For the evaluation of endocrine and anthropometric variables, 38 HCs were added to the 41 HCs initially evaluated. Individuals with GD presented higher fasting plasma ghrelin (p < 0.001) and lower LEAP2 and adiponectin concentrations (p < 0.001) than HCs, after adjusting for body mass index (BMI). The GD group reported higher cognitive impairment regarding cognitive flexibility and decision-making strategies, a worse psychological state, higher impulsivity levels, and a more dysfunctional personality profile. Despite failing to find significant associations between endocrine factors and either neuropsychological or clinical aspects in the GD group, some impaired cognitive dimensions (i.e., WAIS Vocabulary test and WCST Perseverative errors) and lower LEAP2 concentrations statistically predicted GD presence. The findings from the present study suggest that distinctive neuropsychological and endocrine dysfunctions may operate in individuals with GD and predict GD presence. Further exploration of endophenotypic vulnerability pathways in GD appear warranted, especially with respect to etiological and therapeutic potentials.

Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21.

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 protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phenotyping in this rat model as well as in transgenic mice reveals that the effects of prolonged suckling are mediated by increased hepatic fibroblast growth factor 21 (FGF21) production and tanycyte-controlled access to the hypothalamus in adulthood. Specifically, FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta. Prolonged breastfeeding thus constitutes a protective mechanism against obesity by affecting long-lasting physiological changes in liver-to-hypothalamus communication and hypothalamic metabolic regulation.

Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism.

Hypothalamic interleukin-6 (IL6) exerts a broad metabolic control. Here, we demonstrated that IL6 activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mouse skeletal muscle. Bioinformatics analysis revealed that the hypothalamic IL6/ERK1/2 axis is closely associated with fatty acid oxidation- and mitochondrial-related genes in the skeletal muscle of isogenic BXD mouse strains and humans. We showed that the hypothalamic IL6/ERK1/2 pathway requires the α2-adrenergic pathway to modify fatty acid skeletal muscle metabolism. To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuit is required to underpin AMPK/ACC signaling activation and fatty acid oxidation after exercise. Last, the selective down-regulation of IL6 receptor in VMH abolished the effects of exercise to sustain AMPK and ACC phosphorylation and fatty acid oxidation in the muscle after exercise. Together, these data demonstrated that the IL6/ERK axis in VMH controls fatty acid metabolism in the skeletal muscle.

Obesity induces resistance to central action of BMP8B through a mechanism involving the BBSome.

OBJECTIVE: Bone morphogenetic protein 8B (BMP8B) plays a major role in the regulation of energy homeostasis by modulating brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. Here, we investigated whether BMP8B's role in metabolism is affected by obesity and the possible molecular mechanisms underlying that action. METHODS: Central treatments with BMP8B were performed in rats fed a standard (SD) and high-fat diet (HFD), as well as in genetically modified mice. Energy balance studies, infrared thermographic analysis of BAT and molecular analysis of the hypothalamus, BAT and WAT were carried out. RESULTS: We show for the first time that HFD-induced obesity elicits resistance to the central actions of BMP8B on energy balance. This obesity-induced BMP8B resistance is explained by i) lack of effects on AMP-activated protein kinase (AMPK) signaling, ii) decreased BMP receptors signaling and iii) reduced expression of Bardet-Biedl Syndrome 1 (BBS1) protein, a key component of the protein complex BBSome in the ventromedial nucleus of the hypothalamus (VMH). The possible mechanistic involvement of BBS1 in this process is demonstrated by lack of a central response to BMP8B in mice carrying a single missense disease-causing mutation in the Bbs1 gene. CONCLUSIONS: Overall, our data uncover a new mechanism of central resistance to hormonal action that may be of relevance in the pathophysiology of obesity.

LEAP-2 Counteracts Ghrelin-Induced Food Intake in a Nutrient, Growth Hormone and Age Independent Manner.

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 this work, using rats and mice, we study fasting-induced food intake as well as testing the effect of diet exposure, e.g., standard diet and high fat diet, in terms of ghrelin-induced food intake. The anorexigenic effect of LEAP-2 on fasting induced food intake appears to be dependent on energy stores, being more evident in ob/ob than in wild type mice and also in animals exposed to high fat diet. On the other hand, LEAP-2 administration markedly inhibited ghrelin-induced food intake in lean, obese (ob/ob and DIO) mice, aged rats and GH-deficient dwarf rats. In contrast, the inhibitory effect on glucose levels can only be observed in some specific experimental models indicating that the mechanisms involved are likely to be quite different. Taken together from these data, LEAP-2 emerged as a potential candidate to be therapeutically useful in obesity.

O-GlcNAcylated p53 in the liver modulates hepatic glucose production.

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 and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.

A nanoemulsion/micelles mixed nanosystem for the oral administration of hydrophobically modified insulin.

The potential of nanoemulsions for the oral administration of peptides is still in its early stage. The aim of the present work was to rationally design, develop, and fully characterize a new nanoemulsion (NE) intended for the oral administration of hydrophobically modified insulin (HM-insulin). Specific components of the NE were selected based on their enhancing permeation properties as well as their ability to improve insulin association efficiency (Miglyol 812, sodium taurocholate), stability in the intestinal fluids, and mucodiffusion (PEGylated phospholipids and poloxamer 407). The results showed that the NE co-existed with a population of micelles, forming a mixed system that exhibited a 100% of HM-insulin association efficiency. The nanosystem showed good stability and miscibility in different bio-relevant media and displayed an acceptable mucodiffusive behavior in porcine mucus. In addition, it exhibited a high interaction with cell mono-cultures (Caco -2 and C2BBe1 human colon carcinoma Caco-2 clone cells) and co-cultures (C2BBe1 human colon carcinoma Caco-2 clone/HT29-MTX cells). The internalization in Caco-2 monolayers was also confirmed by confocal microscopy. Finally, the promising in vitro behavior of the nanosystem in terms of overcoming the biological barriers of the intestinal tract was translated into a moderate, although significant, hypoglycemic response (≈ 20-30%), following intestinal administration to both healthy and diabetic rat models. Overall, this information underlines the crucial steps to address when designing peptide-based nanoformulations to successfully overcome the intestinal barriers associated to the oral modality of administration.

Circulating LEAP-2 is associated with puberty in girls.

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 role of ghrelin in childhood, puberty, and childhood obesity, the potential implication of LEAP-2 in these aspects remains totally unknown. We aimed to investigate the regulation of circulating plasma LEAP-2 in childhood and adolescent either lean or obese. METHODS AND RESULTS: Plasma levels of LEAP-2 were analyzed in a cross-sectional study with lean and obese children and adolescents (n = 150). Circulating LEAP-2 levels were significantly higher in girls than in boys independently of whether they were obese or lean. In addition, LEAP-2 was significantly increased (p < 0.001) in pubertal than in prepubertal girls, while no changes were found in boys between both developmental stages. Moreover, in girls LEAP-2 was positively correlated with insulin, IGF-1, HOMA-IR and triglycerides and negatively with ghrelin. In boys, LEAP-2 was positively correlated with leptin and negatively with vitamin D levels. CONCLUSION: This study reveals a sexual dimorphism in LEAP-2 levels in children and adolescents. These changes and the higher levels during puberty imply that LEAP-2 may contribute to some of the biological adaptations occurring during pubertal development in terms of food intake, energy balance, growth rate, and puberty onset. Future studies assessing LEAP-2 levels in longitudinal studies and its implications in growth rate, puberty onset, and reproductive hormones will help to understand the relevance of this hormone in this stage of life.

Pre-Clinical Evaluation of a Modified Cyclodextrin-Based Nanoparticle for Intestinal Delivery of Liraglutide.

New therapeutic approaches have been developed during recent years for the management of diabetic patients, with glucagon-like peptides analogues (GLP-1 analogues) emerging as one of the most useful therapies. However, as with human insulin analogues, translation of GLP-1 analogues into oral pharmaceutical products has been limited due to reduced oral bioavailability. Nanoparticle (NP) formulations have been investigated due to their potential to protect the drug cargo and enhance bioavailability. This study describes the pre-clinical development of a cyclodextrin-based NP formulation containing the GLP-1 analogue liraglutide for intestinal administration. A cationic amphiphilic cyclodextrin (click propyl-amine cyclodextrin (CD)) was selected as the primary complexing agent for the peptide. The resulting NPs presented an average size of 101 ± 8 nm, low polydispersity index (0.240), a negative zeta potential (-35 ± 7 mV), complete association efficiency and peptide loading of 5.0%. The optimized prototype exhibited colloidal stability in intestinal-biorelevant media up to 4 h, protecting the entrapped liraglutide from degradation by proteolytic enzymes. Intestinal administration in rats revealed effective protection and delivery of liraglutide, with a similar pharmacological response in blood glucose levels relative to subcutaneous administration of free solution. These results demonstrate the potential of the CD based formulation for further development.

Levels of the Novel Endogenous Antagonist of Ghrelin Receptor, Liver-Enriched Antimicrobial Peptide-2, in Patients with Rheumatoid Arthritis.

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 (LEAP2) as an endogenous inverse agonist/antagonist of the ghrelin receptor makes feasible the development of a more rational pharmacological approach. This work aimed to assess the serum LEAP2 levels, in a cohort of RA patients, in comparison with healthy individuals and determine its correlation with inflammatory parameters. LEAP2 levels were determined by a commercial ELISA kit, plasma C-reactive protein (CRP) levels were evaluated using immunoturbidimetry, and serum levels of inflammatory mediators, namely IL-6, IL-8, IL-1ß, MIP1α, MCP1, and LCN2, were measured by XMap multiplex assay. LEAP2 serum levels were significantly increased in RA patients (n = 101) compared with control subjects (n = 26). Furthermore, the LEAP2 levels significantly correlated with CRP and inflammatory cytokines, but not with BMI. These data reveal LEAP2 as a new potential RA biomarker and indicated the pharmacological control of LEAP2 levels as a novel approach for the treatment of diseases with alterations on the ghrelin levels, such as rheumatoid cachexia.

p107 Deficiency Increases Energy Expenditure by Inducing Brown-Fat Thermogenesis and Browning of White Adipose Tissue.

SCOPE: The tumor suppressor p107, a pocket protein member of the retinoblastoma susceptibility protein family, plays an important role in the cell cycle and cellular adipocyte differentiation. Nonetheless, the mechanism by which it influences whole body Energy homeostasis is unknown. METHODS AND RESULTS: The phenotype of p107 knockout (KO) mixed-background C57BL6/129 mice phenotype is studied by focusing on the involvement of white and brown adipose tissue (WAT and BAT) in energy metabolism. It is shown that p107 KO mice are leaner and have high-fat diet resistence. This phenomenon is explained by an increase of energy expenditure. The higher energy expenditure is caused by the activation of thermogenesis and may be mediated by both BAT and the browning of WAT. Consequently, it leads to the resistance of p107 KO mice to high-fat diet effects, prevention of liver steatosis, and improvement of the lipid profile and glucose homeostasis. CONCLUSION: These data allowed the unmasking of a mechanism by which a KO of p107 prevents diet-induced obesity by increasing energy expenditure via increased thermogenesis in BAT and browning of WAT, indicating the relevance of p107 as a modulator of metabolic activity of both brown and white adipocytes. Therefore, it can be targeted for the development of new therapies to ameliorate the metabolic syndrome.

Protamine nanocapsules as carriers for oral peptide delivery.

Peptides represent a promising therapeutic class with the potential to alleviate many severe diseases. A key limitation of these active molecules relies on the difficulties for their efficient oral administration. The objective of this work has been the rational design of polymer nanocapsules (NCs) intended for the oral delivery of peptide drugs. For this purpose, we selected insulin glulisine as a model peptide. The polymer shell of the NCs was made of a single layer of protamine, a cationic polypeptide selected for its cell penetration properties, or a double protamine/polysialic acid (PSA) layer. Insulin glulisine-loaded protamine and protamine/PSA NCs, prepared by the solvent displacement method, exhibited a size that varied in the range of 200-400 nm and a neutral surface charge (from +8 mV to -6 mV), depending on the formulation. The stability of the encapsulated peptide was assessed using circular dichroism and an in vitro cell activity study. Colloidal stability studies were also performed in simulated intestinal media containing enzymes and the results indicated that protamine NCs were stable and able to protect insulin from the harsh intestinal environment, and that this capacity could be further enhanced with a double PSA-Protamine layer. These NCs were freeze-dried and stored at room temperature without alteration of the physicochemical properties. When the insulin-loaded protamine NCs were administered intra-intestinally to diabetic rats (12 h fasting) it resulted in a prolonged glucose reduction (60%) as compared to the control insulin solution. This work raises prospects that protamine NCs may have a potential as oral peptide delivery nanocarriers.

Regulation of Chemerin and CMKLR1 Expression by Nutritional Status, Postnatal Development, and Gender.

Chemerin (also known as tazarotene-induced gene 2 and retinoic acid receptor responder 2) has been identified as an adipokine that exerts effects on many biological processes, including adipogenesis, angiogenesis, inflammation, immune responses, and food intake. This variety of effects has led to its implication in obesity and co-morbidities including diabetes and a risk of cardiovascular disease. The biological effects are mostly mediated by a so-called G protein-coupled receptor, chemokine-like receptor 1 (CMKLR1). Given the association of chemerin with obesity and related diseases, we decided to study in detail the regulation of chemerin and CMKLR1 expression in white adipose tissue (WAT). Specifically, we focused on their expression levels in physiological and pathophysiological settings involved in energy balance: e.g., fasting, postnatal development, and gender. We used Sprague Dawley rats with different nutritional statuses, levels of hormonal deficiency, and states of development as well as ob/ob (leptin-deficient) mice. We analysed the protein expression of both the ligand and receptor (chemerin and CMKLR1) in gonadal WAT by western blotting. We found that chemerin and CMKLR1 protein levels were regulated in WAT by different conditions associated with metabolic changes such as nutritional status, sex steroids, pregnancy, and food composition. Our data indicate that regulation of the expression of this new adipokine and its receptor by nutritional status and gonadal hormones may be a part of the adaptive mechanisms related to altered fat mass and its metabolic complications.

mTOR signaling in the arcuate nucleus of the hypothalamus mediates the anorectic action of estradiol.

Current evidence suggests that estradiol (E2), the main ovarian steroid, modulates energy balance by regulating both feeding and energy expenditure at the central level, through the energy sensor AMP-activated protein kinase (AMPK). We hypothesized that the hypothalamic mechanistic target of rapamycin (mTOR) pathway, a well-established nutrient sensor and modulator of appetite and puberty, could also mediate the anorectic effect of E2. Our data showed that ovariectomy (OVX) elicited a marked downregulation of the mTOR signaling in the arcuate nucleus of the hypothalamus (ARC), an effect that was reversed by either E2 replacement or central estrogen receptor alpha (ERα) agonism. The significance of this molecular signaling was given by the genetic inactivation of S6 kinase B1 (S6K1, a key downstream mTOR effector) in the ARC, which prevented the E2-induced hypophagia and weight loss. Overall, these data indicate that E2 induces hypophagia through modulation of mTOR pathway in the ARC.

Hypothalamic Mitochondrial Dysfunction as a Target in Obesity and Metabolic Disease.

Mitochondria are important organelles for the adaptation to energy demand that play a central role in bioenergetics metabolism. The mitochondrial architecture and mitochondrial machinery exhibits a high degree of adaptation in relation to nutrient availability. On the other hand, its disruption markedly affects energy homeostasis. The brain, more specifically the hypothalamus, is the main hub that controls energy homeostasis. Nevertheless, until now, almost all studies in relation to mitochondrial dysfunction and energy metabolism have focused in peripheral tissues like brown adipose tissue, muscle, and pancreas. In this review, we highlight the relevance of the hypothalamus and the influence on mitochondrial machinery in its function as well as its consequences in terms of alterations in both energy and metabolic homeostasis.