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The serotonin 2C receptor (5-HT2CR)-melanocortin pathway plays well-established roles in the regulation of feeding behavior and body weight homeostasis. Dysfunctions in this system, such as loss-of-function mutations in the Htr2c gene, can lead to hyperphagia and obesity. In this study, we aimed to investigate the potential therapeutic strategies for ameliorating hyperphagia, hyperglycemia, and obesity associated with a loss-of-function mutation in the Htr2c gene (Htr2cF327L/Y). We demonstrated that reexpressing functional 5-HT2CR solely in hypothalamic pro-opiomelanocortin (POMC) neurons is sufficient to reduce food intake and body weight in Htr2cF327L/Y mice subjected to a high-fat diet (HFD). In addition, 5-HT2CR expression restores the responsiveness of POMC neurons to lorcaserin, a selective agonist for 5-HT2CR. Similarly, administration of melanotan II, an agonist of the melanocortin receptor 4 (MC4R), effectively suppresses feeding and weight gain in Htr2cF327L/Y mice. Strikingly, promoting wheel-running activity in Htr2cF327L/Y mice results in a decrease in HFD consumption and improved glucose homeostasis. Together, our findings underscore the crucial role of the melanocortin system in alleviating hyperphagia and obesity related to dysfunctions of the 5-HT2CR, and further suggest that MC4R agonists and lifestyle interventions might hold promise in counteracting hyperphagia, hyperglycemia, and obesity in individuals carrying rare variants of the Htr2c gene., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Melanocortin 4 receptor (MC4R) mutations are the most common cause of human monogenic obesity and are associated with hyperphagia and increased linear growth. While MC4R is known to activate Gsα/cAMP signaling, a substantial proportion of obesity-associated MC4R mutations do not affect MC4R/Gsα signaling. To further explore the role of specific MC4R signaling pathways in the regulation of energy balance, we examined the signaling properties of one such mutant, MC4R (F51L), as well as the metabolic consequences of MC4RF51L mutation in mice. The MC4RF51L mutation produced a specific defect in MC4R/Gq/11α signaling and led to obesity, hyperphagia, and increased linear growth in mice. The ability of a melanocortin agonist to acutely inhibit food intake when delivered to the paraventricular nucleus (PVN) was lost in MC4RF51L mice, as well as in WT mice in which a specific Gq/11α inhibitor was delivered to the PVN; this provided evidence that a Gsα-independent signaling pathway, namely Gq/11α, significantly contributes to the actions of MC4R on food intake and linear growth. These results suggest that a biased MC4R agonist that primarily activates Gq/11α may be a potential agent to treat obesity with limited untoward cardiovascular and other side effects.

Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain serious side effects of their use. Increased food intake leads to AP-induced weight gain, but the underlying molecular mechanisms remain unknown. In previous studies, we identified the neuropeptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) as significantly upregulated genes in the hypothalamus following AP-induced hyperphagia. While Agrp is expressed specifically in the arcuate nucleus of the hypothalamus and plays a critical role in appetite stimulation, Nr5a2 is expressed in both the CNS and periphery, but its role in food intake behaviors remains unknown. In this study, we investigated the role of hypothalamic Nr5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, olanzapine treatment resulted in a dose-dependent increase in gene expression of Nr5a2 and Agrp. In mice, the pharmacological inhibition of NR5A2 decreased olanzapine-induced hyperphagia and weight gain, while the knockdown of Nr5a2 in the arcuate nucleus partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation studies showed for the first time that NR5A2 directly binds to the Agrp promoter region. Lastly, the analysis of single-cell RNA seq data confirms that Nr5a2 and Agrp are co-expressed in a subset of neurons in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake. These findings can inform future clinical development of APs that do not activate hyperphagia and weight gain., (© 2023. The Author(s).)

High prevalence of obesity is attributable in part to consumption of highly palatable, fat-rich foods. However, the mechanism controlling dietary fat intake is largely unknown. In this study we investigated the role of brain-derived neurotrophic factor (BDNF) in the control of dietary fat intake in a mouse model that mimics the common human Val-to-Met (Val66Met) polymorphism that impairs BDNF release via the regulated secretory pathway. BdnfMet/Met mice gained weight much faster than wild-type (WT) mice and developed severe obesity due to marked hyperphagia when they were fed HFD. Hyperphagia in these mice worsened when the fat content in their diet was increased. Conversely, mice lacking leptin exhibited similar hyperphagia on chow and HFD. When 2 diets were provided simultaneously, WT and BdnfMet/Met mice showed a comparable preference for the more palatable diet rich in either fat or sucrose, indicating that increased hyperphagia on fat-rich diets in BdnfMet/Met mice is not due to enhanced hedonic drive. In support of this interpretation, WT and BdnfMet/Met mice increased calorie intake to a similar extent during the first day after chow was switched to HFD; however, WT mice decreased HFD intake faster than BdnfMet/Met mice in subsequent days. Furthermore, we found that refeeding after fasting or nocturnal feeding with HFD activated TrkB more strongly than with chow in the hypothalamus of WT mice, whereas TrkB activation under these 2 conditions was greatly attenuated in BdnfMet/Met mice. These results indicate that satiety factors generated during HFD feeding induce BDNF release to suppress excess dietary fat intake., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hyperphagia is a key symptom in patients with monogenic obesity, but the assessment is challenging., Objectives: We aimed to investigate the applicability of Dykens' Hyperphagia Questionnaire in patients with monogenic and syndromic obesity to assess the quality and severity of hyperphagia, and to compare our results with those reported in the literature., Methods: Patients with biallelic leptin receptor variants (LEPR, n = 8), heterozygous melanocortin-4 receptor variants (MC4R, n = 7) and 16p11.2 deletions, leading to a deletion of the Src homology 2B adaptor protein gene (n = 5) were included in the study. Hyperphagia was assessed by the parent-based, 13-item hyperphagia questionnaire from Dykens et al. (2007). A literature research was performed to identify published hyperphagia scores assessed by Dykens' Hyperphagia Questionnaire., Results: The total hyperphagia scores were similar in patients with biallelic LEPR and monoallelic MC4R variants (32.0 ± 9.3 vs. 31.4 ± 5.4), but significantly lower in patients with 16p11.2 deletions (21.4 ± 5.5, p < 0.05). Compared to patients with syndromic obesity (27.6 ± 9.0) from the literature, patients with LEPR and MC4R variants had higher total hyperphagia scores. Total hyperphagia scores in patients with 16p11.2 deletions were lower than for patients with other syndromic obesity forms (21.4 ± 5.5 vs. 24.6 ± 8.1), but similar to those for individuals with obesity without a genetic cause (22.9 ± 7.2)., Conclusions: Dykens' Hyperphagia Questionnaire seems to be a useful tool to assess hyperphagic behaviour in patients with monogenic and syndromic obesity., Competing Interests: Declaration of competing interest There are no potential conflicts of interest to disclose., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cyclic adenosine monophosphate responsive element-binding protein-1-regulated transcription coactivator-1 (CRTC1) is a cytoplasmic coactivator that translocates to the nucleus in response to cyclic adenosine monophosphate. Whole-body knockdown of Crtc1 causes obesity, resulting in increased food intake and reduced energy expenditure. CRTC1 is highly expressed in the brain; therefore, it might play an important role in energy metabolism via the neuronal pathway. However, the precise mechanism by which CRTC1 regulates energy metabolism remains unknown. Here, we showed that mice lacking CRTC1, specifically in steroidogenic factor-1 expressing cells (SF1 cells), were sensitive to high-fat diet (HFD)-induced obesity, exhibiting hyperphagia and increased body weight gain. The loss of CRTC1 in SF1 cells impaired glucose metabolism. Unlike whole-body CRTC1 knockout mice, SF1 cell-specific CRTC1 deletion did not affect body weight gain or food intake in normal chow feeding. Thus, CRTC1 in SF1 cells is required for normal appetite regulation in HFD-fed mice. CRTC1 is primarily expressed in the brain. Within the hypothalamus, which plays an important role for appetite regulation, SF1 cells are only found in ventromedial hypothalamus. RNA sequencing analysis of microdissected ventromedial hypothalamus samples revealed that the loss of CRTC1 significantly changed the expression levels of certain genes. Our results revealed the important protective role of CRTC1 in SF1 cells against dietary metabolic imbalance., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Exercise ameliorates nonalcoholic fatty liver disease (NAFLD) by inducing phenotypic changes in Kupffer cells (KCs). p62/Sqstm1-knockout (p62-KO) mice develop NAFLD alongside hyperphagia-induced obesity. We evaluated (1) the effects of long-term exercise on the foreign-body phagocytic capacity of KCs, their surface marker expression, and the production of steroid hormones in p62-KO mice; and (2) whether long-term exercise prevented the development of non-alcoholic steatohepatitis (NASH) in p62-KO mice fed a high-fat diet (HFD). In experiment 1, 30-week-old male p62-KO mice were allocated to resting (p62-KO-Rest) or exercise (p62-KO-Ex) groups, and the latter performed long-term exercise over 4 weeks. Then, the phenotype of their KCs was compared to that of p62-KO-Rest and wild-type (WT) mice. In experiment 2, 5-week-old male p62-KO mice that were fed a HFD performed long-term exercise over 12 weeks. In experiment 1, the phagocytic capacity of KCs and the proportion of CD68-positive cells were lower in the p62-KO-Rest group than in the WT group, but they increased with long-term exercise. The percentage of CD11b-positive KCs was higher in the p62-KO-Rest group than in the WT group, but lower in the p62-KO-Ex group. The circulating dehydroepiandrosterone (DHEA) concentration was higher in p62-KO-Ex mice than in p62-KO-Rest mice. In experiment 2, the body mass and composition of the p62-KO-Rest and p62-KO-Ex groups were similar, but the hepatomegaly, hepatic inflammation, and fibrosis were less marked in p62-KO-Ex mice. The DHEA concentration was higher in p62-KO-Ex mice than in WT or p62-KO-Rest mice. Thus, long-term exercise restores the impaired phagocytic capacity of KCs in NAFLD obese mice, potentially through greater DHEA production, and prevents the development of NASH by ameliorating hepatic inflammation and fibrogenesis. These results suggest a molecular mechanism for the beneficial effect of exercise in the management of patients with NAFLD., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Expression of synphilin-1 in neurons induces hyperphagia and obesity in a Drosophila model. However, the molecular pathways underlying synphilin-1-linked obesity remain unclear. Here, Drosophila models and genetic tools were used to study the synphilin-1-linked pathways in energy balance by combining molecular biology and pharmacological approaches. We found that expression of human synphilin-1 in flies increased AMP-activated kinase (AMPK) phosphorylation at Thr172 compared with that in non-transgenic flies. Knockdown of AMPK reduced AMPK phosphorylation and food intake in non-transgenic flies, and further suppressed synphilin-1-induced AMPK phosphorylation, hyperphagia, fat storage and body weight gain in transgenic flies. Expression of constitutively activated AMPK significantly increased food intake and body weight gain in non-transgenic flies, but it did not alter food intake in the synphilin-1 transgenic flies. In contrast, expression of dominant-negative AMPK reduced food intake in both non-transgenic and synphilin-1 transgenic flies. Treatment with STO-609 also suppressed synphilin-1-induced AMPK phosphorylation, hyperphagia and body weight gain. These results demonstrate that the AMPK signaling pathway plays a critical role in synphilin-1-induced hyperphagia and obesity. These findings provide new insights into the mechanisms of synphilin-1-controlled energy homeostasis., Competing Interests: Competing interestsThe human synphilin-1 transgenic Drosophila line is a tangible property of the University of Maryland., (© 2021. Published by The Company of Biologists Ltd.)

It is known that nutrition and immunity are connected, but the mechanism is not very clear. Endogenous retroviruses (ERV) account for 8 to 10% of the human and mouse genomes and play an important role in some biological processes of animals. Recent studies indicate that the activation of ERV can affect the expression of the immunity- or inflammation-related genes, and the activities of ERV are subjected to regulation of many factors including nutritional factors. Therefore, we hypothesize that nutritional status can affect the expression of the immunity- or inflammation-related genes via ERV. To verify this hypothesis, the nutritional status of animals was altered by fasting or overfeeding, and the expression of intact ERV (ERVK18P, ERVK25P) and immunity- or inflammation-related genes (DDX41, IFIH1, IFNG, IRF7, STAT3) in the liver was determined by quantitative PCR, followed by overexpressing ERVK25P in goose primary hepatocytes and determining the expression of the immunity- or inflammation-related genes. The data showed that compared with the control group (no fasting), the expression of ERV and the immunity- or inflammation-related genes was increased in the liver of the fasted chickens but decreased in the liver of the fasted geese. Moreover, compared with the control group (routinely fed), the expression of ERV and the immunity- or inflammation-related genes was increased in the liver of the overfed geese. In addition, overexpression of ERVK25P in goose primary hepatocytes can induce the expression of the immunity- or inflammation-related genes. In conclusion, these findings suggest that ERV mediate the effects of fasting and overfeeding on the expression of the immunity- or inflammation-related genes, the mediation varied with poultry species, and ERV and the immunity- or inflammation-related genes may be involved in the development of goose fatty liver. This study provides a potential mechanism for the connection between nutrition and immunity., (Copyright © 2020. Published by Elsevier Inc.)

Background: Increasing evidence suggests that postnatal overfeeding induces childhood obesity, which is strongly associated with metabolic syndrome. Insulin resistance is a risk factor for metabolic syndrome. MicroRNA-221 (miR-221) is involved in the development of obesity and has been reported to negatively regulate insulin sensitivity. However, the underlying mechanism remains unclear., Methods: Rats raised in small litters (SLs, three pups/dam, n = 10) and normal litters (NLs, 10 pups/dam, n = 10) were used to model early postnatal overfeeding and act as controls, respectively. miR-221 and proteins related to the phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT) pathway were assessed in the liver., Results: Early postnatal overfeeding significantly increased body weight, visceral fat index, blood glucose, serum triglycerides, and the homeostasis model assessment of insulin resistance at 9 weeks. Real-time polymerase chain reaction (PCR) and western blot analysis revealed that postnatal overfeeding induced insulin receptor and insulin receptor substrate 2 expression, but decreased PI3K and AKT phosphorylation in the liver. Quantitative real-time PCR showed that hepatic miR-221 was significantly overexpressed in the SL group., Conclusions: These results indicate that postnatal overfeeding induces hepatic miR-221 overexpression and impairs the PI3K/AKT signal pathway, which may cause insulin resistance., Impact: We first report postnatal overfeeding induces hepatic miR-221 expression. Postnatal overfeeding impairs PI3K/AKT pathway in the liver of adult rats. Postnatal overfeeding induces obesity and high blood glucose. Avoidance of overfeeding during early postnatal life may prevent obesity and T2DM.

The dysfunction of melanocortin signaling has been associated with obesity, given the important role in the regulation of energy homeostasis, food intake, satiety and body weight. In the hypothalamus, the melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) contribute to the stability of these processes, but MC3R and MC4R are also localized in the mesolimbic dopamine system, the region that responds to the reinforcing properties of highly palatable food (HPF) and where these two receptors seem to affect food reward and motivation. Loss of function of the MC4R, resulting from genetic mutations, leads to overeating in humans, but to date, a clear understanding of the underlying mechanisms and behaviors that promote overconsumption of caloric foods remains unknown. Moreover, the MC4R demonstrated to be a crucial modulator of the stress response, factor that is known to be strictly related to binge eating behavior. In this review, we will explore the preclinical and clinical studies, and the controversies regarding the involvement of melanocortin system in altered eating patterns, especially binge eating behavior, food reward and motivation.

The TrkB receptor is critical for the control of energy balance, as mutations in its gene (NTRK2) lead to hyperphagia and severe obesity. The main neural substrate mediating the appetite-suppressing activity of TrkB, however, remains unknown. Here, we demonstrate that selective Ntrk2 deletion within paraventricular hypothalamus (PVH) leads to severe hyperphagic obesity. Furthermore, chemogenetic activation or inhibition of TrkB-expressing PVH (PVH TrkB ) neurons suppresses or increases food intake, respectively. PVH TrkB neurons project to multiple brain regions, including ventromedial hypothalamus (VMH) and lateral parabrachial nucleus (LPBN). We find that PVH TrkB neurons projecting to LPBN are distinct from those to VMH, yet Ntrk2 deletion in PVH neurons projecting to either VMH or LPBN results in hyperphagia and obesity. Additionally, TrkB activation with BDNF increases firing of these PVH neurons. Therefore, TrkB signaling is a key regulator of a previously uncharacterized neuronal population within the PVH that impinges upon multiple circuits to govern appetite.

The vagus nerve conveys gastrointestinal cues to the brain to control eating behavior. In obesity, vagally mediated gut-brain signaling is disrupted. Here, we show that the cocaine- and amphetamine-regulated transcript (CART) is a neuropeptide synthesized proportional to the food consumed in vagal afferent neurons (VANs) of chow-fed rats. CART injection into the nucleus tractus solitarii (NTS), the site of vagal afferent central termination, reduces food intake. Conversely, blocking endogenous CART action in the NTS increases food intake in chow-fed rats, and this requires intact VANs. Viral-mediated Cartpt knockdown in VANs increases weight gain and daily food intake via larger meals and faster ingestion rate. In obese rats fed a high-fat, high-sugar diet, meal-induced CART synthesis in VANs is blunted and CART antibody fails to increase food intake. However, CART injection into the NTS retains its anorexigenic effect in obese rats. Restoring disrupted VAN CART signaling in obesity could be a promising therapeutic approach., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Melanocortin 4 receptor (MC4R)-deficient mice had been used for several years to study human nonalcoholic steatohepatitis (NASH). However, although liver pathologic and biochemical indicators have been examined, mice models do not always faithfully display the phenotype of the human disease. In this study, we investigated the MC4R knockout phenotype in miniature pigs. We found that pigs lacking MC4R exhibited hyperorexia, insulin resistance, hyperinsulinemia, disordered lipid metabolism and their livers accumulated significant amounts of fat. We have shown that deletion of MC4R results in hyperphagia and increased body fat, ultimately leading to hepatic steatosis without atherogenic diet., (Copyright © 2019. Published by Elsevier Inc.)

Melanin-concentrating hormone (MCH) is an important regulator of food intake, glucose metabolism, and adiposity. However, the mechanisms mediating these actions remain largely unknown. We used pharmacological and genetic approaches to show that the sirtuin 1 (SIRT1)/FoxO1 signaling pathway in the hypothalamic arcuate nucleus (ARC) mediates MCH-induced feeding, adiposity, and glucose intolerance. MCH reduces proopiomelanocortin (POMC) neuronal activity, and the SIRT1/FoxO1 pathway regulates the inhibitory effect of MCH on POMC expression. Remarkably, the metabolic actions of MCH are compromised in mice lacking SIRT1 specifically in POMC neurons. Of note, the actions of MCH are independent of agouti-related peptide (AgRP) neurons because inhibition of γ-aminobutyric acid receptor in the ARC did not prevent the orexigenic action of MCH, and the hypophagic effect of MCH silencing was maintained after chemogenetic stimulation of AgRP neurons. Central SIRT1 is required for MCH-induced weight gain through its actions on the sympathetic nervous system. The central MCH knockdown causes hypophagia and weight loss in diet-induced obese wild-type mice; however, these effects were abolished in mice overexpressing SIRT1 fed a high-fat diet. These data reveal the neuronal basis for the effects of MCH on food intake, body weight, and glucose metabolism and highlight the relevance of SIRT1/FoxO1 pathway in obesity., (© 2019 by the American Diabetes Association.)

The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor 1 . Although some MRAP2 mutations have been described in people with obesity 1-3 , their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance 4 . The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.

The pathophysiology of major depressive disorder (MDD) is highly heterogeneous. Previous evidence at the DNA level as well as on the serum protein level suggests that the role of inflammation in MDD pathology is stronger in patients with hyperphagia during an active episode. Which inflammatory pathways differ in MDD patients with hyperphagia inflammatory pathways in terms of gene expression is unknown. We analyzed whole-blood gene expression profiles of 881 current MDD cases and 331 controls from the Netherlands Study of Depression and Anxiety (NESDA). The MDD patients were stratified according to patients with hyperphagia (characterized by increased appetite and/or weight, N = 246) or hypophagia (characterized by decreased appetite and/or weight, N = 342). Using results of differential gene expression analysis between controls and the MDD subgroups, enrichment of curated inflammatory pathways was estimated. The majority of the pathways were significantly (FDR < 0.1) enriched in the expression profiles of MDD cases with hyperphagia, including top pathways related to factors responsible for the onset of inflammatory response ('caspase', 'GATA3', 'NFAT', and 'inflammasomes' pathways). Only two pathways ('adaptive immune system' and 'IL-8- and CXCR2-mediated signaling') were enriched in the MDD with hypophagia subgroup, these were also enriched in the total current MDD group and the group with hyperphagia. This confirms the importance of inflammation in MDD pathology of patients with hyperphagia, and suggests that distinguishing more uniform MDD phenotypes can help in finding their pathophysiological basis.

The BBSome, a complex of eight Bardet-Biedl syndrome (BBS) proteins involved in cilia function, has emerged as an important regulator of energy balance, but the underlying cellular and molecular mechanisms are not fully understood. Here, we show that the control of energy homeostasis by the anorexigenic proopiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons require intact BBSome. Targeted disruption of the BBSome by Bbs1 gene deletion in POMC or AgRP neurons increases body weight and adiposity. We demonstrate that obesity in mice lacking the Bbs1 gene in POMC neurons is associated with hyperphagia. Mechanistically, we present evidence implicating the BBSome in the trafficking of G protein-coupled neuropeptide Y Y2 receptor (NPY 2 R) and serotonin 5-hydroxytryptamine (HT) 2C receptor (5-HT 2C R) to cilia and plasma membrane, respectively. Consistent with this, loss of the BBSome reduced cell surface expression of the 5-HT 2C R, interfered with serotonin-evoked increase in intracellular calcium and membrane potential, and blunted the anorectic and weight-reducing responses evoked by the 5-HT 2c R agonist, lorcaserin. Finally, we show that disruption of the BBSome causes the 5-HT 2C R to be stalled in the late endosome. Our results demonstrate the significance of the hypothalamic BBSome for the control of energy balance through regulation of trafficking of important metabolic receptors., (© 2019 by the American Diabetes Association.)

Many eating-related psychological constructs have been proposed to explain obesity and overeating. However, these constructs, including food addiction, disinhibition, hedonic hunger, emotional eating, binge eating and the like all have similar definitions, emphasizing loss of control over intake. As questionnaires measuring the constructs correlate strongly (r > 0.5) with each other, we propose that these constructs should be reconsidered to be part of a single broad phenotype: uncontrolled eating. Such an approach enables reviewing and meta-analysing evidence obtained with each individual questionnaire. Here, we describe robust associations between uncontrolled eating, body mass index (BMI), food intake, personality traits and brain systems. Reviewing cross-sectional and longitudinal data, we show that uncontrolled eating is phenotypically and genetically intertwined with BMI and food intake. We also review evidence on how three psychological constructs are linked with uncontrolled eating: lower cognitive control, higher negative affect and a curvilinear association with reward sensitivity. Uncontrolled eating mediates all three constructs' associations with BMI and food intake. Finally, we review and meta-analyse brain systems possibly subserving uncontrolled eating: namely, (i) the dopamine mesolimbic circuit associated with reward sensitivity, (ii) frontal cognitive networks sustaining dietary self-control and (iii) the hypothalamus-pituitary-adrenal axis, amygdala and hippocampus supporting stress reactivity. While there are limits to the explanatory and predictive power of the uncontrolled eating phenotype, we conclude that treating different eating-related constructs as a single concept, uncontrolled eating, enables drawing robust conclusions on the relationship between food intake and BMI, psychological variables and brain structure and function., (© 2019 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

This study investigated the genetic and environmental contributions to emotional overeating (EOE) and depressive symptoms, and their covariation, in a Sri-Lankan population, using genetic model-fitting analysis. In total, 3957 twins and singletons in the Colombo Twin and Singleton Study-Phase 2 rated their EOE behaviour and depressive symptoms, which were significantly associated (men: r = 0.11, 95% confidence interval (CI) 0.06-0.16, women: r = 0.12, 95% CI 0.07-0.16). Non-shared environmental factors explained the majority of variance in men (EOE e 2 = 87%, 95% CI 78-95%; depressive symptoms e 2 = 72%, 95% CI 61-83%) and women (EOE e 2 = 76%, 95% CI 68-83%; depressive symptoms e 2 = 64%, 95% CI 55-74%). Genetic factors were more important for EOE in women ( h 2 = 21%, 95% CI 4-32%) than men ( h 2 = 9%, 95% CI 0-20%). Shared-environmental factors were more important for depressive symptoms in men ( c 2 = 25%, 95% CI 10-36%) than women ( c 2 = 9%, 95% CI 0-35%). Non-shared environmental factors explained the overlap between depressive symptoms and EOE in women but not in men. Results differed from high-income populations, highlighting the need for behavioural genetic research in global populations.

Obesity is a progressive, chronic disease, which can be caused by long-term miscommunication between organs. It remains challenging to understand how chronic dysfunction in a particular tissue remotely impairs other organs to eventually imbalance organismal energy homeostasis. Here we introduce RNAi Pulse Induction (RiPI) mediated by short hairpin RNA (shRiPI) or double-stranded RNA (dsRiPI) to generate chronic, organ-specific gene knockdown in the adult Drosophila fat tissue. We show that organ-restricted RiPI targeting Stromal interaction molecule (Stim), an essential factor of store-operated calcium entry (SOCE), results in progressive fat accumulation in fly adipose tissue. Chronic SOCE-dependent adipose tissue dysfunction manifests in considerable changes of the fat cell transcriptome profile, and in resistance to the glucagon-like Adipokinetic hormone (Akh) signaling. Remotely, the adipose tissue dysfunction promotes hyperphagia likely via increased secretion of Akh from the neuroendocrine system. Collectively, our study presents a novel in vivo paradigm in the fly, which is widely applicable to model and functionally analyze inter-organ communication processes in chronic diseases.

The social structure of populations plays a key role in shaping variation in sexual selection. In nature, sexual selection occurs in communities of interacting species; however, heterospecifics are rarely included in characterizations of social structure. Heterospecifics can influence the reproductive outcomes of intrasexual competition by interfering with intraspecific sexual interactions (interspecific reproductive interference [IRI]). We outline the need for studies of sexual selection to incorporate heterospecifics as part of the social environment. We use simulations to show that classic predictions for the effect of social structure on sexual selection are altered by an interaction between social structure and IRI. This interaction has wide-ranging implications for patterns of sexual conflict and kin-selected reproductive strategies in socially structured populations. Our work bridges the gap between sexual selection research on social structure and IRI, and highlights future directions to study sexual selection in interacting communities., (© 2019 The Author(s). Evolution published by Wiley Periodicals, Inc. on behalf of The Society for the Study of Evolution.)

Glial cells have emerged as key players in the central control of energy balance and etiology of obesity. Astrocytes play a central role in neural communication via the release of gliotransmitters. Acyl-CoA binding protein (ACBP)-derived endozepines are secreted peptides that modulate the GABAA receptor. In the hypothalamus, ACBP is enriched in arcuate nucleus (ARC) astrocytes, ependymocytes and tanycytes. Central administration of the endozepine octadecaneuropeptide (ODN) reduces feeding and improves glucose tolerance, yet the contribution of endogenous ACBP in energy homeostasis is unknown. We demonstrated that ACBP deletion in GFAP+ astrocytes, but not in Nkx2.1-lineage neural cells, promoted diet-induced hyperphagia and obesity in both male and female mice, an effect prevented by viral rescue of ACBP in ARC astrocytes. ACBP-astrocytes were observed in apposition with proopiomelanocortin (POMC) neurons and ODN selectively activated POMC neurons through the ODN-GPCR but not GABAA, and supressed feeding while increasing carbohydrate utilization via the melanocortin system. Similarly, ACBP overexpression in ARC astrocytes reduced feeding and weight gain. Finally, the ODN-GPCR agonist decreased feeding and promoted weight loss in ob/ob mice. These findings uncover ACBP as an ARC gliopeptide playing a key role in energy balance control and exerting strong anorectic effects via the central melanocortin system.

Triclosan (TCS), as a broad spectrum antibacterial agent, is commonly utilized in personal care and household products. Maternal urinary TCS level has been associated with changes in birth weight of infants. We in the present study investigated whether exposure of mice to 8 mg/kg TCS from gestational day (GD) 6 to GD14 alters prenatal and postnatal growth and development, and metabolic phenotypes in male and female offspring (TCS-offspring). Compared with control offspring, body weight in postnatal day (PND) 1 male or female TCS-offspring was reduced, but body weight gain was faster within postnatal 5 days. PND30 and PND60 TCS-offspring showed overweight with increases in visceral fat and adipocyte size. PND60 TCS-offspring displayed delayed glucose clearance and insulin resistance. PND30 TCS-offspring showed an increase in food intake without the changes in the oxygen consumption and respiratory exchange ratio (RER). The expression levels of proopiomelanocortin (POMC), α-melanocyte-stimulating hormone (α-MSH) and single-minded 1 (SIM1) in hypothalamus arcuate nucleus (ARC) and paraventricular nucleus (PVN), respectively, were significantly reduced in PND30 TCS-offspring compared to controls. The hypermethylation of CpG sites at the POMC promoter was observed in PND30 TCS-offspring, while the concentration of serum leptin was elevated and the level of STAT3 phosphorylation in ARC had no significant difference from control. This study demonstrates that TCS exposure during early/mid-gestation through the hypermethylation of the POMC promoter reduces the expression of anorexigenic neuropeptides to cause the postnatal hyperphagic obesity, leading to metabolic syndrome in adulthood.

Obesity is caused by an imbalance between energy intake and output, influenced by numerous environmental, biological, and genetic factors. Only a minority of people with obesity have a genetic defect that is the main cause of their obesity. A key symptom for most of these disorders is early-onset obesity and hyperphagia. For some genetic obesity disorders, the hyperphagia is the main characteristic, often caused by disruptions of the leptin-melanocortin pathway, the central pathway that regulates the body's satiety and energy balance. For other disorders, obesity is part of a distinct combination of other clinical features such as intellectual disability, dysmorphic facial features, or organ abnormalities. This chapter focuses on genetic obesity disorders and also summarizes the present knowledge on the genetics of the more common polygenic/multifactorial obesity.

Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) is a member of the basic helix-loop-helix/PER-ARNT-SIM (bHLH/PAS) transcription factor family. ARNT2 heterodimerizes with several members of the family, including single-minded homolog-1 (SIM1) and neuronal PAS domain protein 4 (NPAS4), primarily in neurons of the central nervous system. We screened 64,424 third-generation germline mutant mice derived from N -ethyl- N -nitrosourea (ENU)-mutagenized great-grandsires for weight abnormalities. Among 17 elevated body weight phenotypes identified and mapped, one strongly correlated with an induced missense mutation in Arnt2 using a semidominant model of inheritance. Causation was confirmed by CRISPR/Cas9 gene targeting to recapitulate the original ENU allele, specifying Arg74Cys (R74C). The CRISPR/Cas9-targeted ( Arnt2 ) mice demonstrated hyperphagia and increased adiposity as well as hepatic steatosis and abnormalities in glucose homeostasis. The mutant ARNT2 protein showed decreased transcriptional activity when coexpressed with SIM1. These findings establish a requirement for ARNT2-dependent genes in the maintenance of the homeostatic feeding response, necessary for prevention of obesity and obesity-related diseases.R74C/R74C ) mice demonstrated hyperphagia and increased adiposity as well as hepatic steatosis and abnormalities in glucose homeostasis. The mutant ARNT2 protein showed decreased transcriptional activity when coexpressed with SIM1. These findings establish a requirement for ARNT2-dependent genes in the maintenance of the homeostatic feeding response, necessary for prevention of obesity and obesity-related diseases., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Antipsychotic (AP) drugs are used to treat psychiatric disorders but are associated with significant weight gain and metabolic disease. Increased food intake (hyperphagia) appears to be a driving force by which APs induce weight gain but the mechanisms are poorly understood. Here we report that administration of APs to C. elegans induces hyperphagia by a mechanism that is genetically distinct from basal food intake. We exploit this finding to screen for adjuvant drugs that suppress AP-induced hyperphagia in C. elegans and mice. In mice AP-induced hyperphagia is associated with a unique hypothalamic gene expression signature that is abrogated by adjuvant drug treatment. Genetic analysis of this signature using C. elegans identifies two transcription factors, nhr-25/Nr5a2 and nfyb-1/NFYB to be required for AP-induced hyperphagia. Our study reveals that AP-induced hyperphagia can be selectively suppressed without affecting basal food intake allowing for novel drug discovery strategies to combat AP-induced metabolic side effects.

Background: Mutations in the genes encoding leptin (LEP), the leptin receptor (LEPR), and the melanocortin 4 receptor (MC4R) are known to cause severe early-onset childhood obesity. The aim of the current study was to examine the prevalence of damaging LEP, LEPR, and MC4R mutations in Pakistani families having a recessive heritance of early-onset obesity., Methods: Using targeted resequencing, the presence of rare mutations in LEP, LEPR, and MC4R, was investigated in individuals from 25 families suspected of having autosomal recessive early-onset obesity. Segregation patterns of variants were assessed based on chip-based genotyping., Results: Homozygous LEPR variants were identified in two probands. One carried a deletion (c.3260AG) resulting in the frameshift mutation p.Ser1090Trpfs*6, and the second carried a substitution (c.2675C > G) resulting in the missense mutation p.Pro892Arg. Both mutations were located within regions of homozygosity shared only among affected individuals. Both probands displayed early-onset obesity, hyperphagia and diabetes. No mutations were found in LEP and MC4R., Conclusions: The current study highlights the implication of LEPR mutations in cases of severe early-onset obesity in consanguineous Pakistani families. Through targeted resequencing, we identified novel damaging mutations, and our approach may therefore be utilized in clinical testing or diagnosis of known forms of monogenic obesity with the aim of optimizing obesity treatment.

Alzheimer's disease (AD), a progressive neurodegenerative disease is highly associated with metabolic syndromes. We previously demonstrated that glycemic dysregulation and obesity are augmented in high fat diet (HFD)-treated APPswe/PS1dE9 (APP/PS1) transgenic mice. In the current study, the underlying mechanism mediating exacerbated metabolic stresses in HFD APP/PS1 transgenic mice was further examined. APP/PS1 mice developed insulin resistance and, consequently, impaired glucose homeostasis after 10 weeks on HFD. [ 18 F]-2-fluoro-2-deoxy-d-glucose ([ 18 F]-FDG) positron emission tomography showed that interscapular brown adipose tissue is vulnerable to HFD and AD-related pathology. Chronic HFD induced hyperphagia, with limited effects on basal metabolic rates in APP/PS1 transgenic mice. Excessive food intake may be caused by impairment of leptin signaling in the hypothalamus because leptin failed to suppress the food intake of HFD APP/PS1 transgenic mice. Leptin-induced pSTAT3 signaling in the arcuate nucleus was attenuated. Dysregulated energy homeostasis including hyperphagia and exacerbated obesity was elicited prior to the presence of the amyloid pathology in the hypothalamus of HFD APP/PS1 transgenic mice; nevertheless, cortical neuroinflammation and the level of serum Aβ and IL-6 were significantly elevated. Our study demonstrates the pivotal role of AD-related pathology in augmenting HFD-induced insulin and leptin resistance and impairing hypothalamic regulation of energy homeostasis.

Congenital Leptin receptor (LEPR) deficiency is a rare genetic cause of early-onset morbid obesity characterised by severe early onset obesity, major hyperphagia, hypogonadotropic hypogonadism and immune and neuroendocrine/metabolic dysfunction. We identified a homozygous loss-of-function mutation, NM&#95;002303.5:c.464 T > G; p.(Tyr155*), in the LEPR in an extended consanguineous family with multiple individuals affected by early-onset severe obesity and hyperphagia. Interestingly, the LEPR-deficient adult females have extremely high body mass index (BMI) with hypogonadal infertility, the BMI of the affected males began to decline around the onset of puberty (13-15 years) with fertility being preserved. These findings lead to the speculation that LEPR deficiency may have a gender-specific effect on the regulation of body weight. In order to elucidate gender-specific effects of LEPR deficiency on reproduction further investigations are needed. The limitations of this study are that our conclusion is based on observations of two males and two females. Further LEPR deficient males and females are required for comparison in order to support this finding more confidently., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The coupling of energy homeostasis to thermoregulation is essential to maintain homeothermy in changing external environments. We studied the role of the cold thermoreceptor TRPM8 in this interplay in mice of both sexes. We demonstrate that TRPM8 is required for a precise thermoregulation in response to cold, in fed and fasting. Trpm8 -/- mice raised at mild cold temperatures developed late-onset obesity and metabolic dysfunction, with daytime hyperphagia and reduction of fat oxidation as plausible causal factors. In conclusion, TRPM8 fine-tunes eating behavior and fuel utilization during thermoregulatory adjustments to mild cold. Persistent imbalances in these responses result in obesity. Trpm8 The thermosensitive ion channel TRPM8 is required for a precise thermoregulatory response to cold and fasting, playing an important role in tail vasoconstriction, and therefore heat conservation, as well as in the regulation of ingestive behavior and metabolic fuel selection upon cooling. Indeed, TRPM8-deficient mice, housed in a mild cold environment, displayed an increase in tail heat loss and lower core body temperature, associated with the development of late-onset obesity with glucose and lipid metabolic dysfunction. A persistent diurnal hyperphagia and reduced fat oxidation constitute plausible underlying mechanisms in the background of a deficient thermoregulatory adjustment to mild cold ambient temperatures.-/- mice raised at mild cold temperatures developed late-onset obesity and metabolic dysfunction, with daytime hyperphagia and reduction of fat oxidation as plausible causal factors. In conclusion, TRPM8 fine-tunes eating behavior and fuel utilization during thermoregulatory adjustments to mild cold. Persistent imbalances in these responses result in obesity. SIGNIFICANCE STATEMENT The thermosensitive ion channel TRPM8 is required for a precise thermoregulatory response to cold and fasting, playing an important role in tail vasoconstriction, and therefore heat conservation, as well as in the regulation of ingestive behavior and metabolic fuel selection upon cooling. Indeed, TRPM8-deficient mice, housed in a mild cold environment, displayed an increase in tail heat loss and lower core body temperature, associated with the development of late-onset obesity with glucose and lipid metabolic dysfunction. A persistent diurnal hyperphagia and reduced fat oxidation constitute plausible underlying mechanisms in the background of a deficient thermoregulatory adjustment to mild cold ambient temperatures., (Copyright © 2018 the authors 0270-6474/18/383643-14$15.00/0.)

Profound hyperphagia is a major disabling feature of Prader-Willi syndrome (PWS). Characterization of the mechanisms that underlie PWS-associated hyperphagia has been slowed by the paucity of animal models with increased food intake or obesity. Mice with a microdeletion encompassing the Snord116 cluster of noncoding RNAs encoded within the Prader-Willi minimal deletion critical region have previously been reported to show growth retardation and hyperphagia. Here, consistent with previous reports, we observed growth retardation in Snord116+/-P mice with a congenital paternal Snord116 deletion. However, these mice neither displayed increased food intake nor had reduced hypothalamic expression of the proprotein convertase 1 gene PCSK1 or its upstream regulator NHLH2, which have recently been suggested to be key mediators of PWS pathogenesis. Specifically, we disrupted Snord116 expression in the mediobasal hypothalamus in Snord116fl mice via bilateral stereotaxic injections of a Cre-expressing adeno-associated virus (AAV). While the Cre-injected mice had no change in measured energy expenditure, they became hyperphagic between 9 and 10 weeks after injection, with a subset of animals developing marked obesity. In conclusion, we show that selective disruption of Snord116 expression in the mediobasal hypothalamus models the hyperphagia of PWS.

Ghrelin is a potent orexigenic peptide hormone that acts through the growth hormone secretagogue receptor (GHSR), a G protein-coupled receptor highly expressed in the hypothalamus. In vitro studies have shown that GHSR displays a high constitutive activity, whose physiological relevance is uncertain. As GHSR gene expression in the hypothalamus is known to increase in fasting conditions, we tested the hypothesis that constitutive GHSR activity at the hypothalamic level drives the fasting-induced hyperphagia. We found that refed wild-type (WT) mice displayed a robust hyperphagia that continued for 5 days after refeeding and changed their food intake daily pattern. Fasted WT mice showed an increase in plasma ghrelin levels, as well as in GHSR expression levels and ghrelin binding sites in the hypothalamic arcuate nucleus. When fasting-refeeding responses were evaluated in ghrelin- or GHSR-deficient mice, only the latter displayed an ∼15% smaller hyperphagia, compared with WT mice. Finally, fasting-induced hyperphagia of WT mice was significantly smaller in mice centrally treated with the GHSR inverse agonist K-(D-1-Nal)-FwLL-NH2, compared with mice treated with vehicle, whereas it was unaffected in mice centrally treated with the GHSR antagonists D-Lys3-growth hormone-releasing peptide 6 or JMV2959. Taken together, genetic models and pharmacological results support the notion that constitutive GHSR activity modulates the magnitude of the compensatory hyperphagia triggered by fasting. Thus, the hypothalamic GHSR signaling system could affect the set point of daily food intake, independently of plasma ghrelin levels, in situations of negative energy balance., (Copyright © 2018 Endocrine Society.)

Context and Objective: Prader-Willi syndrome (PWS) is characterized by early-onset hyperphagia and increased circulating levels of the orexigenic Acylated Ghrelin (AG) hormone with a relative deficit of Unacylated Ghrelin (UAG). AZP-531, a first-in-class UAG analog, was shown to inhibit the orexigenic effect of AG in animals, to improve glycemic control and decrease body weight in humans. We aimed to investigate the safety and efficacy of AZP-531 in patients with PWS for whom no approved treatment for hyperphagia is currently available., Methods and Design: Multi-center, randomized, double-blind, placebo-controlled trial. Forty-seven patients with genetically confirmed PWS and evidence of hyperphagia received daily subcutaneous injections of AZP-531 (3 and 4 mg for 50-70 kg and >70 kg body weight, respectively) or matching placebo for 14 days. Assessments included adverse events, vital signs, safety laboratory tests, the Hyperphagia Questionnaire (HQ), patient-reported appetite, body composition and glycemic measures., Results: AZP-531 was well tolerated. There was a significant improvement with AZP-531 versus placebo in the mean total score, the 9-item score and the severity domain score of the HQ (p < .05). The highest reduction in the total and 9-item scores was observed in AZP-531 subjects with the highest hyperphagia score at baseline. Findings were supported by a reduction in appetite scores observed with AZP-531 only. Body weight did not change in both groups while a significant reduction in waist circumference and fat mass was observed only with AZP-531. AZP-531 significantly decreased post-prandial glucose levels in a baseline glucose dependent fashion., Conclusions: AZP-531 may constitute a new treatment strategy to improve hyperphagia and metabolic issues in patients with PWS. These findings support further investigation in longer-term clinical trials.

Objective: Leptin is a cytokine produced by adipose tissue that acts mainly on the hypothalamus to regulate appetite and energy homeostasis. Previous studies revealed that the leptin receptor is expressed not only in neurons, but also in glial cells. Microglia are resident immune cells in the brain that play an essential role in immune defense and neural network development. Previously we reported that microglial morphology and cytokine production are changed in the leptin receptor deficient db/db mouse, suggesting that leptin's central effects on metabolic control might involve signaling through microglia. In the current study, we aimed to uncover the role of leptin signaling in microglia in systemic metabolic control., Methods: We generated a mouse model with leptin receptor deficiency, specifically in the myeloid cells, to determine the role of microglial leptin signaling in the development of metabolic disease and to investigate microglial functions., Results: We discovered that these mice have increased body weight with hyperphagia. In the hypothalamus, pro-opiomelanocortin neuron numbers in the arcuate nucleus (ARC) and α-MSH projections from the ARC to the paraventricular nucleus (PVN) decreased, which was accompanied by the presence of less ramified microglia with impaired phagocytic capacity in the PVN., Conclusions: Myeloid cell leptin receptor deficient mice partially replicate the db/db phenotype. Leptin signaling in hypothalamic microglia is important for microglial function and a correct formation of the hypothalamic neuronal circuit regulating metabolism., (Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.)

This case report of an infant with severe early-onset obesity illustrates the societal condemnation of persons with obesity. In addition, it underlines the importance of diagnosing rare forms of monogenic obesity, even if no drug treatment is available. Here, we describe a 2-year-old girl with severe progressive obesity from birth onwards due to insatiable hunger. Genetic studies eventually reveal that the girl has a monogenic form of obesity caused by two mutations in the LEPR gene. No drug treatment is available (as yet) for this disease. Parents describe the stigmatic remarks they have to deal with every day. Diagnosing this rare genetic disorder was very important for understanding that satiety regulation is a complex system, of which willpower is only a small portion. In these patients, reduction of obesity can be achieved, but a different approach to lifestyle intervention is needed., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Emotional overeating (EOE) has been associated with increased obesity risk, while emotional undereating (EUE) may be protective. Interestingly, EOE and EUE tend to correlate positively, but it is unclear whether they reflect different aspects of the same underlying trait, or are distinct behaviours with different aetiologies. Data were from 2054 five-year-old children from the Gemini twin birth cohort, including parental ratings of child EOE and EUE using the Child Eating Behaviour Questionnaire. Genetic and environmental influences on variation and covariation in EUE and EOE were established using a bivariate Twin Model. Variation in both behaviours was largely explained by aspects of the environment completely shared by twin pairs (EOE: C = 90%, 95% CI: 89%-92%; EUE: C = 91%, 95% CI: 90%-92%). Genetic influence was low (EOE: A = 7%, 95% CI: 6%-9%; EUE: A = 7%, 95% CI: 6%-9%). EOE and EUE correlated positively (r = 0.43, p < 0.001), and this association was explained by common shared environmental influences (BivC = 45%, 95% CI: 40%-50%). Many of the shared environmental influences underlying EUE and EOE were the same (r C  = 0.50, 95% CI: 0.44, 0.55). Childhood EOE and EUE are etiologically distinct. The tendency to eat more or less in response to emotion is learned rather than inherited.

Compulsive eating behavior is a transdiagnostic construct that is characteristic of medical and psychiatric conditions such as forms of obesity and eating disorders. Although feeding research is moving toward a better understanding of the proposed addictive properties of food, the components and the mechanisms contributing to compulsive eating are not yet clearly defined or understood. Current understanding highlights three elements of compulsive behavior as it applies to pathological overeating: (1) habitual overeating; (2) overeating to relieve a negative emotional state; and (3) overeating despite aversive consequences. These elements emerge through mechanisms involving pathological habit formation through an aberrant learning process, the emergence of a negative emotional state, and dysfunctions in behavioral control. Dysfunctions in systems within neurocircuitries that comprise the basal ganglia, the extended amygdala, and the prefrontal cortex result in compulsive eating behaviors. Here, we present evidence to relate compulsive eating behavior and addiction and to characterize their underlying neurobiological mechanisms. A major need to improve understanding of compulsive eating through the integration of complex motivational, emotional, and cognitive constructs is warranted.

Background/objectives: Oxytocin (OXT) is an evolutionarily ancient neuropeptide with strong links to affiliative and prosocial behaviors, and the management of stress. Increases in OXT also tend to decrease food intake, especially of sweet carbohydrates. The social correlates of low OXT levels mesh with the social deficits and stress proneness identified in interpersonal models of overeating, as well as the increased appetite for highly palatable foods typically seen in chronic overeaters. The objectives of this study were to investigate links between polymorphisms of the oxytocin receptor (OXTR) gene and overeating, and to examine OXTR links with relevant endophenotypes of overeating related to reward and stress sensitivity, and to food preferences., Subject/methods: The sample comprised 460 adults between the ages of 25 and 50 years recruited from the community, and representing a broad range of body weights. Overeating, reward and punishment sensitivity, and food preferences, were quantified as composite variables using well-validated questionnaires. In addition, seven single-nucleotide polymorphisms (rs237878, rs237885, rs2268493, rs2268494, rs2254298, rs53576, rs2268498) of the OXTR gene were genotyped., Results: Analyses identified a four-marker haplotype that was significantly related to food preferences. Individual genotype analyses also found that at least one of the markers was related to each of the phenotypic variables. In addition, an empirically derived structural equation model linking genetic and phenotype variables produced a good fit to the data., Conclusions: The results of this preliminary study have demonstrated that OXTR variation is associated with overeating, and with endophenotypic traits such as sweet and fatty food preferences, and reward and punishment sensitivity. In general, the genetic findings also favor the view that overeating may be associated with relatively low basal OXT levels.

N-Acyl amino acids (NAAAs) are conjugate products of fatty acids and amino acids, which are available in animal-derived food. We compared the effects of N-arachidonoylglycine (NAGly), N-arachidonoylserine (NASer), and N-oleoylglycine (OLGly) on in vivo food intake and in vitro [Ca 2+ ] i of Agouti-related protein (AgRP) neurons to identify the role of these compounds in energy homeostasis. Hypothalamic neuropeptide expression and anxiety behavior in response to OLGly were also tested. To further identify the underlying mechanism of OLGly on food intake, we first detected the expression level of potential OLGly receptors. The cannabinoid receptor type 1 (CB1R) antagonist was cotreated with OLGly to analyze the activation of AgRP neuron, including [Ca 2+ ] i , expression levels of PKA, CREB, and c-Fos, and neuropeptide secretion. Results demonstrated that only OLGly (intrapertioneal injection of 6 mg/kg) can induce hyperphagia without changing the expression of hypothalamic neuropeptides and anxiety-like behavior. Moreover, 20 μM OLGly robustly enhances [Ca 2+ ] i , c-Fos protein expression in AgRP neuron, and AgRP content in the culture medium. OLGly-induced activation of AgRP neuron was completely abolished by the CB1R-specific antagonist, AM251. In summary, this study is the first to demonstrate the association of OLGly-induced hyperphagia with activation of the AgRP neuron by CB1R. These findings open avenues for investigation and application of OLGly to modulate energy homeostasis.

Studies conducted in monozygotic and dizygotic twins have established a strong genetic component in eating behavior. Rare mutations and common variants of the melanocortin 4 receptor (MC4R) gene have been linked to obesity and eating behavior scores. However, few studies have assessed common variants in MC4R gene with the rewarding value of food in children. The objective of the study was to evaluate the association between the MC4R rs17782313 polymorphism with homeostatic and non-homeostatic eating behavior patterns in Chileans children. This is a cross-sectional study in 258 Chilean children (44 % female, 8-14 years old) showing a wide variation in BMI. Anthropometric measurements (weight, height, Z-score of BMI and waist circumference) were performed by standard procedures. Eating behavior was assessed using the Eating in Absence of Hunger Questionnaire (EAHQ), the Child Eating Behavior Questionnaire (CEBQ), the Three-Factor Eating Questionnaire (TFEQ), and the Food Reinforcement Value Questionnaire (FRVQ). Genotype of the rs17782313 nearby MC4R was determined by a Taqman assay. Association of the rs17782313 C allele with eating behavior was assessed using non-parametric tests. We found that children carrying the CC genotype have higher scores of food responsiveness (p value = 0.02). In obese girls, carriers of the C allele showed lower scores of satiety responsiveness (p value = 0.02) and higher scores of uncontrolled eating (p value = 0.01). Obese boys carrying the C allele showed lower rewarding value of food in relation to non-carriers. The rs17782313 C allele is associated with eating behavior traits that may predispose obese children to increased energy intake and obesity.

Neuroligins are post-synaptic, cellular adhesion molecules implicated in synaptic formation and function. NLGN2 is strongly linked to inhibitory, GABAergic signaling and is crucial for maintaining the excitation-inhibition balance in the brain. Disruption of the excitation-inhibition balance is associated with neuropsychiatric disease. In animal models, altered NLGN2 expression causes anxiety, developmental delay, motor discoordination, social impairment, aggression, and sensory processing defects. In humans, mutations in NLGN3 and NLGN4 are linked to autism and schizophrenia; NLGN2 missense variants are implicated in schizophrenia. Copy number variants encompassing NLGN2 on 17p13.1 are associated with autism, intellectual disability, metabolic syndrome, diabetes, and dysmorphic features, but an isolated NLGN2 nonsense variant has not yet been described in humans. Here, we describe a 15-year-old male with severe anxiety, obsessive-compulsive behaviors, developmental delay, autism, obesity, macrocephaly, and some dysmorphic features. Exome sequencing identified a heterozygous, de novo, c.441C>A p.(Tyr147Ter) variant in NLGN2 that is predicted to cause loss of normal protein function. This is the first report of an NLGN2 nonsense variant in humans, adding to the accumulating evidence that links synaptic proteins with a spectrum of neurodevelopmental phenotypes. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background/objective: Exposure to food advertisements may cue overeating among children, especially among those genetically predisposed to respond to food cues. We aimed to assess how television food advertisements affect eating in the absence of hunger among children in a randomized trial. We hypothesized that the fat mass and obesity-associated gene (FTO) rs9939609 single-nucleotide polymorphism would modify the effect of food advertisements., Subjects/methods: In this randomized experiment, 200 children aged 9-10 years were served a standardized lunch and then shown a 34-min television show embedded with either food or toy advertisements. Children were provided with snack food to consume ad libitum while watching the show and we measured caloric intake. Children were genotyped for rs9939609 and analyses were conducted in the overall sample and stratified by genotype. A formal test for interaction of the food advertisement effect on consumption by rs9939609 was conducted., Results: About 172 unrelated participants were included in this analysis. Children consumed on average 453 (s.d.=185) kcals during lunch and 482 (s.d.=274) kcals during the experimental exposure. Children who viewed food advertisements consumed an average of 48 kcals (95% confidence interval: 10, 85; P=0.01) more of a recently advertised food than those who viewed toy advertisements. There was a statistically significant interaction between genotype and food advertisement condition (P for interaction=0.02), where the difference in consumption of a recently advertised food related to food advertisement exposure increased linearly with each additional FTO risk allele, even after controlling for body mass index percentile., Conclusions: Food advertisement exposure was associated with greater caloric consumption of a recently advertised food, and this effect was modified by an FTO genotype. Future research is needed to understand the neurological mechanism underlying these associations., Competing Interests: Declaration The authors declare they have no actual or potential competing financial interests related to the described work.

Chromosome 22q11.2 deletion syndrome is a clinically heterogeneous condition of intellectual disability, parathyroid and thyroid hypoplasia, palatal abnormalities, cardiac malformations and psychiatric symptoms. Hyperphagia and childhood obesity is widely reported in Prader-Willi Syndrome (PWS) but there is only one previous report of this presentation in chromosome 22q11.2 deletion syndrome. We describe two further cases of chromosome 22q11.2 deletion syndrome in which hyperphagia and childhood obesity were the presenting features. This may be a manifestation of obsessive behaviour secondary to some of the psychiatric features commonly seen in chromosome 22q11.2 deletion syndrome. Serious complications may result from hyperphagia and childhood obesity therefore early recognition and intervention is crucial. Due to the similar clinical presentation of these two patients to patients with PWS, it is suggested that the hyperphagia seen here should be managed in a similar way to how it is managed in PWS., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2).

Depression is often associated with weight gain but underlying mechanisms are unclear. This study assessed whether three psychological eating styles (emotional eating, external eating and restrained eating) act as mediators between depression and weight gain. We used structural equation modelling to test the hypothesized mediation models in a sample of 298 fathers and 294 mothers by assessing self-reported eating styles (Dutch Eating Behavior Questionnaire), depressive feelings (Depressive Mood List) and body mass index (BMI) at baseline and BMI after five years. In the model with emotional eating we also assessed the moderation effect of 5-HTTLPR genotype in a sub-sample of 520 Caucasians. All analyses were performed separately for the two sexes. Although the overall effect of depression on weight gain was statistically non-significant in both sexes, there was a causal chain between depression, emotional eating and weight gain in the mothers. Depressive symptoms were related to higher emotional eating and emotional eating predicted greater increases in BMI independently of depression. Moreover, the indirect effect (via emotional eating) of depression on BMI change was significant (Beta = 0.18, P = 0.026). This mediation effect was found to be independent of 5-HTTLPR genotype. No such mediation effect was found for the fathers. Further, external eating and restrained eating did not act as mediators between depression and weight gain in either sex. The finding that emotional eating acted as mediator between depression and weight gain in the mothers suggests that obesity interventions should take emotional eating into account., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Maternal overnutrition results in programmed offspring obesity, mediated in part, by hyperphagia. This is remarkably similar to the effects of maternal undernutrition on offspring hyperphagia and obesity. In view of the marked differences in the energy environment of the over and under-nutrition exposures, we studied the expression of select epigenetic modifiers associated with energy imbalance including neurogenic factors and appetite/satiety neuropeptides which are indicative of neurogenic differentiation. HF offspring were exposed to maternal overnutrition (high fat diet; HF) during pregnancy and lactation. We determined the protein expression of energy sensors (mTOR, pAMPK), epigenetic factors (DNA methylase, DNMT1; histone deacetylase, SIRT1/HDAC1), neurogenic factors (Hes1, Mash1, Ngn3) and appetite/satiety neuropeptides (AgRP/POMC) in newborn hypothalamus and adult arcuate nucleus (ARC). Despite maternal obesity, male offspring born to obese dams had similar body weight at birth as Controls. However, when nursed by the same dams, male offspring of obese dams exhibited marked adiposity. At 1 day of age, HF newborn males had significantly decreased energy sensors, DNMT1 including Hes1 and Mash1, which may impact neuroprogenitor cell proliferation and differentiation. This is consistent with increased AgRP in HF newborns. At 6 months of age, HF adult males had significantly increased energy sensors and decreased histone deactylases. In addition, the persistent decreased Hes1, Mash1 as well as Ngn3 are consistent with increased AgRP and decreased POMC. Thus, altered energy sensors and epigenetic responses which modulate gene expression and adult neuronal differentiation may contribute to hyperphagia and obesity in HF male offspring., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Maintaining energy homeostasis is crucial for the survival and health of organisms. The brain regulates feeding by responding to dietary factors and metabolic signals from peripheral organs. It is unclear how the brain interprets these signals. O-GlcNAc transferase (OGT) catalyzes the posttranslational modification of proteins by O-GlcNAc and is regulated by nutrient access. Here, we show that acute deletion of OGT from αCaMKII-positive neurons in adult mice caused obesity from overeating. The hyperphagia derived from the paraventricular nucleus (PVN) of the hypothalamus, where loss of OGT was associated with impaired satiety. These results identify O-GlcNAcylation in αCaMKII neurons of the PVN as an important molecular mechanism that regulates feeding behavior., (Copyright © 2016, American Association for the Advancement of Science.)