An integrative framework to prioritize genes in more than 500 loci associated with body mass index.

Obesity is a major risk factor for a myriad of diseases, affecting >600 million people worldwide. Genome-wide association studies (GWASs) have identified hundreds of genetic variants that influence body mass index (BMI), a commonly used metric to assess obesity risk. Most variants are non-coding and likely act through regulating genes nearby. Here, we apply multiple computational methods to prioritize the likely causal gene(s) within each of the 536 previously reported GWAS-identified BMI-associated loci. We performed summary-data-based Mendelian randomization (SMR), FINEMAP, DEPICT, MAGMA, transcriptome-wide association studies (TWASs), mutation significance cutoff (MSC), polygenic priority score (PoPS), and the nearest gene strategy. Results of each method were weighted based on their success in identifying genes known to be implicated in obesity, ranking all prioritized genes according to a confidence score (minimum: 0; max: 28). We identified 292 high-scoring genes (≥11) in 264 loci, including genes known to play a role in body weight regulation (e.g., DGKI, ANKRD26, MC4R, LEPR, BDNF, GIPR, AKT3, KAT8, MTOR) and genes related to comorbidities (e.g., FGFR1, ISL1, TFAP2B, PARK2, TCF7L2, GSK3B). For most of the high-scoring genes, however, we found limited or no evidence for a role in obesity, including the top-scoring gene BPTF. Many of the top-scoring genes seem to act through a neuronal regulation of body weight, whereas others affect peripheral pathways, including circadian rhythm, insulin secretion, and glucose and carbohydrate homeostasis. The characterization of these likely causal genes can increase our understanding of the underlying biology and offer avenues to develop therapeutics for weight loss.

Incretin hormones and type 2 diabetes.

Incretin hormones (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) play a role in the pathophysiology of type 2 diabetes. Along with their derivatives they have shown therapeutic success in type 2 diabetes, with the potential for further improvements in glycaemic, cardiorenal and body weight-related outcomes. In type 2 diabetes, the incretin effect (greater insulin secretory response after oral glucose than with 'isoglycaemic' i.v. glucose, i.e. with an identical glycaemic stimulus) is markedly reduced or absent. This appears to be because of a reduced ability of GIP to stimulate insulin secretion, related either to an overall impairment of beta cell function or to specific defects in the GIP signalling pathway. It is likely that a reduced incretin effect impacts on postprandial glycaemic excursions and, thus, may play a role in the deterioration of glycaemic control. In contrast, the insulinotropic potency of GLP-1 appears to be much less impaired, such that exogenous GLP-1 can stimulate insulin secretion, suppress glucagon secretion and reduce plasma glucose concentrations in the fasting and postprandial states. This has led to the development of incretin-based glucose-lowering medications (selective GLP-1 receptor agonists or, more recently, co-agonists, e.g. that stimulate GIP and GLP-1 receptors). Tirzepatide (a GIP/GLP-1 receptor co-agonist), for example, reduces HbA1c and body weight in individuals with type 2 diabetes more effectively than selective GLP-1 receptor agonists (e.g. semaglutide). The mechanisms by which GIP receptor agonism may contribute to better glycaemic control and weight loss after long-term exposure to tirzepatide are a matter of active research and may change the pessimistic view that developed after the disappointing lack of insulinotropic activity in people with type 2 diabetes when exposed to GIP in short-term experiments. Future medications that stimulate incretin hormone and other receptors simultaneously may have the potential to further increase the ability to control plasma glucose concentrations and induce weight loss.

The Homeodomain Transcription Factor NKX2.1 Is Essential for the Early Specification of Melanocortin Neuron Identity and Activates Pomc Expression in the Developing Hypothalamus.

Food intake is tightly regulated by a group of neurons present in the arcuate nucleus of the hypothalamus, which release Pomc-encoded melanocortins, the absence of which induces marked hyperphagia and early-onset obesity. Although the relevance of hypothalamic POMC neurons in the regulation of body weight and energy balance is well appreciated, little is known about the transcription factors that establish the melanocortin neuron identity during brain development and its phenotypic maintenance in postnatal life. Here, we report that the transcription factor NKX2.1 is present in mouse hypothalamic POMC neurons from early development to adulthood. Electromobility shift assays showed that NKX2.1 binds in vitro to NKX binding motifs present in the neuronal Pomc enhancers nPE1 and nPE2 and chromatin immunoprecipitation assays detected in vivo binding of NKX2.1 to nPE1 and nPE2 in mouse hypothalamic extracts. Transgenic and mutant studies performed in mouse embryos of either sex and adult males showed that the NKX motifs present in nPE1 and nPE2 are essential for their transcriptional enhancer activity. The conditional early inactivation of Nkx2.1 in the ventral hypothalamus prevented the onset of Pomc expression. Selective Nkx2.1 ablation from POMC neurons decreased Pomc expression in adult males and mildly increased their body weight and adiposity. Our results demonstrate that NKX2.1 is necessary to activate Pomc expression by binding to conserved canonical NKX motifs present in nPE1 and nPE2. Therefore, NKX2.1 plays a critical role in the early establishment of hypothalamic melanocortin neuron identity and participates in the maintenance of Pomc expression levels during adulthood.SIGNIFICANCE STATEMENT Food intake and body weight regulation depend on hypothalamic neurons that release satiety-inducing neuropeptides, known as melanocortins. Central melanocortins are encoded byPomc, and Pomc mutations may lead to hyperphagia and severe obesity. Although the importance of central melanocortins is well appreciated, the genetic program that establishes and maintains fully functional POMC neurons remains to be explored. Here, we combined molecular, genetic, developmental, and functional studies that led to the discovery of NKX2.1, a transcription factor that participates in the early morphogenesis of the developing hypothalamus, as a key player in establishing the early identity of melanocortin neurons by activating Pomc expression. Thus, Nkx2.1 adds to the growing list of genes that participate in body weight regulation and adiposity.

[Innovative medical care concepts for adolescents with severe obesity]. / Innovative medizinische Betreuungskonzepte für Jugendliche mit extremer Adipositas.

There is no convincing, science-based treatment or care concept for adolescents with severe obesity in Germany or other countries. The affected young people have an increased risk of numerous somatic comorbidities (e.g. type 2 diabetes mellitus, orthopaedic disorders and sleep apnoea syndrome), mental disorders (e.g. depression and anxiety disorders, social phobia and self-harming behaviour), as well as social isolation (e.g. avoidance of school and unemployment), which develops due to functional impairments and stigmatisation. Despite the negative effects of severe obesity in adolescence, these young people are medically difficult to reach and treat. Only a small percentage of patients actively seek treatment.Aware of these difficulties, the German multi-centre Youth with Extreme Obesity (YES) Study (funded by the German Ministry of Education and Science; 01 GI 1120 A and B) was carried out between 2012 and 2019 with the aim of improving care concepts for this neglected group of young people. In our article, we show possible supply routes. These consist of accompanying the adolescents and treating their comorbidities, sustainable lifestyle interventions in a protected environment and treatment for weight reduction through bariatric surgery. The overriding goals for patients are an increase in self-esteem, early diagnosis and treatment of secondary diseases and integration into the training and labour market.

Seafood intake and the development of obesity, insulin resistance and type 2 diabetes.

We provide an overview of studies on seafood intake in relation to obesity, insulin resistance and type 2 diabetes. Overweight and obesity development is for most individuals the result of years of positive energy balance. Evidence from intervention trials and animal studies suggests that frequent intake of lean seafood, as compared with intake of terrestrial meats, reduces energy intake by 4-9 %, sufficient to prevent a positive energy balance and obesity. At equal energy intake, lean seafood reduces fasting and postprandial risk markers of insulin resistance, and improves insulin sensitivity in insulin-resistant adults. Energy restriction combined with intake of lean and fatty seafood seems to increase weight loss. Marine n-3 PUFA are probably of importance through n-3 PUFA-derived lipid mediators such as endocannabinoids and oxylipins, but other constituents of seafood such as the fish protein per se, trace elements or vitamins also seem to play a largely neglected role. A high intake of fatty seafood increases circulating levels of the insulin-sensitising hormone adiponectin. As compared with a high meat intake, high intake of seafood has been reported to reduce plasma levels of the hepatic acute-phase protein C-reactive protein level in some, but not all studies. More studies are needed to confirm the dietary effects on energy intake, obesity and insulin resistance. Future studies should be designed to elucidate the potential contribution of trace elements, vitamins and undesirables present in seafood, and we argue that stratification into responders and non-responders in randomised controlled trials may improve the understanding of health effects from intake of seafood.

Obesity Energetics: Body Weight Regulation and the Effects of Diet Composition.

Weight changes are accompanied by imbalances between calorie intake and expenditure. This fact is often misinterpreted to suggest that obesity is caused by gluttony and sloth and can be treated by simply advising people to eat less and move more. Rather various components of energy balance are dynamically interrelated and weight loss is resisted by counterbalancing physiological processes. While low-carbohydrate diets have been suggested to partially subvert these processes by increasing energy expenditure and promoting fat loss, our meta-analysis of 32 controlled feeding studies with isocaloric substitution of carbohydrate for fat found that both energy expenditure (26 kcal/d; P <.0001) and fat loss (16 g/d; P <.0001) were greater with lower fat diets. We review the components of energy balance and the mechanisms acting to resist weight loss in the context of static, settling point, and set-point models of body weight regulation, with the set-point model being most commensurate with current data.

Impact of dietary macronutrient profile on feline body weight is not consistent with the protein leverage hypothesis.

The protein leverage hypothesis proposes that the need to prioritise protein intake drives excess energy intake (EI) when the dietary ratio of protein to fat and carbohydrate is reduced. We hypothesised that cats may become prone to overconsuming energy content when moderate protein diets were offered, and considered the potential influence of fat and carbohydrate on intake. To determine the effect of dietary protein and macronutrient profile (MNP) on EI, weight and body composition, cats (1-4 years) were offered food in excess of energy requirements (ER). A total of six diets were formulated, containing moderate (approximately 7 % w/w; approximately 22 % metabolisable energy (ME)) or high (approximately 10 % w/w; approximately 46 % ME) protein and varying levels of carbohydrate and fat. For 4 weeks, 120 cats were offered 100 % of their individual ER of a diet at the MNP selected by adult cats (50:40:10 protein energy ratio:fat energy ratio:carbohydrate energy ratio). EI, body weight (BW), body composition, activity and palatability were measured. Subsequently, cats were offered one of the six diets at 200 % of their individual ER for 4 weeks when measurements were repeated. Cats offered excess high protein diets had higher EI (kJ/kg) throughout, but at 4 weeks BW was not significantly different to baseline. Cats offered excess moderate protein diets reduced EI and gradually lost weight (average loss of 0·358 (99 % CI 0·388, 0·328) kg), irrespective of fat:carbohydrate and initial palatability. The data do not support the protein leverage hypothesis. Furthermore, cats were able to adapt intake of a wet diet with high protein in an overfeeding environment within 28 d.

Energy expenditure in the etiology of human obesity: spendthrift and thrifty metabolic phenotypes and energy-sensing mechanisms.

The pathogenesis of human obesity is the result of dysregulation of the reciprocal relationship between food intake and energy expenditure (EE), which influences daily energy balance and ultimately leads to weight gain. According to principles of energy homeostasis, a relatively lower EE in a setting of energy balance may lead to weight gain; however, results from different study groups are contradictory and indicate a complex interaction between EE and food intake which may differentially influence weight change in humans. Recently, studies evaluating the adaptive response of one component to perturbations of the other component of energy balance have revealed both the existence of differing metabolic phenotypes ("spendthrift" and "thrifty") resulting from overeating or underfeeding, as well as energy-sensing mechanisms linking EE to food intake, which might explain the propensity of an individual to weight gain. The purpose of this review is to debate the role that human EE plays on body weight regulation and to discuss the physiologic mechanisms linking EE and food intake. An increased understanding of the complex interplay between human metabolism and food consumption may provide insight into pathophysiologic mechanisms underlying weight gain, which may eventually lead to prevention and better treatment of human obesity.

Effectiveness of exercise interventions in the prevention of excessive gestational weight gain and postpartum weight retention: a systematic review and meta-analysis.

OBJECTIVE: Gestational weight gain (GWG) has been identified as a critical modifier of maternal and fetal health. This systematic review and meta-analysis aimed to examine the relationship between prenatal exercise, GWG and postpartum weight retention (PPWR). DESIGN: Systematic review with random effects meta-analysis and meta-regression. Online databases were searched up to 6 January 2017. STUDY ELIGIBILITY CRITERIA: Studies of all designs in English, Spanish or French were eligible (except case studies and reviews) if they contained information on the population (pregnant women without contraindication to exercise), intervention (frequency, intensity, duration, volume or type of exercise, alone ["exercise-only"] or in combination with other intervention components [eg, dietary; "exercise + co-intervention"]), comparator (no exercise or different frequency, intensity, duration, volume or type of exercise) and outcomes (GWG, excessive GWG (EGWG), inadequate GWG (IGWG) or PPWR). RESULTS: Eighty-four unique studies (n=21 530) were included. 'Low' to 'moderate' quality evidence from randomised controlled trials (RCTs) showed that exercise-only interventions decreased total GWG (n=5819; -0.9 kg, 95% CI -1.23 to -0.57 kg, I2=52%) and PPWR (n=420; -0.92 kg, 95% CI -1.84 to 0.00 kg, I2=0%) and reduced the odds of EGWG (n=3519; OR 0.68, 95% CI 0.57 to 0.80, I2=12%) compared with no exercise. 'High' quality evidence indicated higher odds of IGWG with prenatal exercise-only (n=1628; OR 1.32, 95% CI 1.04 to 1.67, I2=0%) compared with no exercise. CONCLUSIONS: Prenatal exercise reduced the odds of EGWG and PPWR but increased the risk of IGWG. However, the latter result should be interpreted with caution because it was based on a limited number of studies (five RCTs).

Organic food consumption during pregnancy and its association with health-related characteristics: the KOALA Birth Cohort Study.

OBJECTIVE: To investigate the associations of organic food consumption with maternal pre-pregnancy BMI, hypertension and diabetes in pregnancy, and several blood biomarkers of pregnant women. DESIGN: Prospective cohort study. SETTING: Pregnant women were recruited at midwives' practices and through channels related to consumption of food from organic origin. SUBJECTS: Pregnant women who filled in FFQ and donated a blood sample (n 1339). Participant groups were defined based on the share of consumed organic products; to discriminate between effects of food origin and food patterns, healthy diet indicators were considered in some statistical models. RESULTS: Consumption of organic food was associated with a more favourable pre-pregnancy BMI and lower prevalence of gestational diabetes. Compared with participants consuming no organic food (reference group), a marker of dairy products intake (pentadecanoic acid) and trans-fatty acids from natural origin (vaccenic and rumenic acids) were higher among participants consuming organic food (organic groups), whereas elaidic acid, a marker of the intake of trans-fatty acids found in industrially hydrogenated fats, was lower. Plasma levels of homocysteine and 25-hydroxyvitamin D were lower in the organic groups than in the reference group. Differences in pentadecanoic acid, vaccenic acid and vitamin D retained statistical significance when correcting for indicators of the healthy diet pattern associated with the consumption of organic food. CONCLUSIONS: Consumption of organic food during pregnancy is associated with several health-related characteristics and blood biomarkers. Part of the observed associations is explained by food patterns accompanying the consumption of organic food.

A compendium of human genes regulating feeding behavior and body weight, its functional characterization and identification of GWAS genes involved in brain-specific PPI network.

BACKGROUND: Obesity is heritable. It predisposes to many diseases. The objectives of this study were to create a compendium of genes relevant to feeding behavior (FB) and/or body weight (BW) regulation; to construct and to analyze networks formed by associations between genes/proteins; and to identify the most significant genes, biological processes/pathways, and tissues/organs involved in BW regulation. RESULTS: The compendium of genes controlling FB or BW includes 578 human genes. Candidate genes were identified from various sources, including previously published original research and review articles, GWAS meta-analyses, and OMIM (Online Mendelian Inheritance in Man). All genes were ranked according to knowledge about their biological role in body weight regulation and classified according to expression patterns or functional characteristics. Substantial and overrepresented numbers of genes from the compendium encoded cell surface receptors, signaling molecules (hormones, neuropeptides, cytokines), transcription factors, signal transduction proteins, cilium and BBSome components, and lipid binding proteins or were present in the brain-specific list of tissue-enriched genes identified with TSEA tool. We identified 27 pathways from KEGG, REACTOME and BIOCARTA whose genes were overrepresented in the compendium. Networks formed by physical interactions or homological relationships between proteins or interactions between proteins involved in biochemical/signaling pathways were reconstructed and analyzed. Subnetworks and clusters identified by the MCODE tool included genes/proteins associated with cilium morphogenesis, signal transduction proteins (particularly, G protein-coupled receptors, kinases or proteins involved in response to insulin stimulus) and transcription regulation (particularly nuclear receptors). We ranked GWAS genes according to the number of neighbors in three networks and revealed 22 GWAS genes involved in the brain-specific PPI network. On the base of the most reliable PPIs functioning in the brain tissue, new regulatory schemes interpreting relevance to BW regulation are proposed for three GWAS genes (ETV5, LRP1B, and NDUFS3). CONCLUSIONS: A compendium comprising 578 human genes controlling FB or BW was designed, and the most significant functional groups of genes, biological processes/pathways, and tissues/organs involved in BW regulation were revealed. We ranked genes from the GWAS meta-analysis set according to the number and quality of associations in the networks and then according to their involvement in the brain-specific PPI network and proposed new regulatory schemes involving three GWAS genes (ETV5, LRP1B, and NDUFS3) in BW regulation. The compendium is expected to be useful for pathology risk estimation and for design of new pharmacological approaches in the treatment of human obesity.

Sedentary behaviour and diet across the lifespan: an updated systematic review.

BACKGROUND: Sedentary behaviour and its association with dietary intake in young people and adults are important topics and were systematically reviewed in 2011. There is a need to update this evidence given the changing nature of sedentary behaviour and continued interest in this field. This review aims to assist researchers in better interpreting the diversity of findings concerning sedentary behaviour and weight status. OBJECTIVE: To provide an update of the associations between sedentary behaviour and dietary intake across the lifespan. METHODS: Electronic databases searched were MEDLINE, PsychInfo, Cochrane Library, Web of Science and Science Direct for publications between January 2010 and October 2013, thus updating a previous review. Included were observational studies assessing an association between at least one sedentary behaviour and at least one aspect of dietary intake in preschool children (<5 years), school-aged children (6-11 years), adolescents (12-18 years) and adults (>18 years). RESULTS: 27 papers met inclusion criteria (preschool k=3, school-aged children k=9, adolescents k=15, adults k=3). For all three groups of young people, trends were evident for higher levels of sedentary behaviour, especially TV viewing, to be associated with a less healthful diet, such as less fruit and vegetable and greater consumption of energy-dense snacks and sugar sweetened beverages. Data for the three studies with adults were less conclusive. CONCLUSIONS: Sedentary behaviour continues to be associated with unhealthy diet in young people in mostly cross-sectional studies. More studies utilising a prospective design are needed to corroborate findings and more studies are needed with adults.

Injury initiates unfavourable weight gain and obesity markers in youth.

OBJECTIVE: The purpose of this study was to examine the association of knee injuries with subsequent changes in body mass index and body composition during maturation in young females. METHODS: A prospective longitudinal study design was employed to evaluate young females active in soccer or basketball (N=862). Participants who completed at least 1-year follow-up to provide consecutive annual measures of BMIZ and %fat were included in the study analysis to determine the effect of knee injuries on the trajectory of these obesity markers in youth. RESULTS: Of the 71 reported knee injuries, 12 (17%) occurred in athletes at the prepubertal stage, 24 (34%) in athletes at the pubertal stage, and 35 (49%) in postpubertal athletes. Controlling for the effects of maturation, female athletes who reported knee injury demonstrated a greater yearly increase in BMIZ (LS means and 95% CI for the injured group=0.039 (-0.012 to 0.089), for the non-injured group=-0.019 (-0.066 to 0.029), and group difference=0.057 (0.005 to 0.11), p=0.03) and in %body fat (LS means and 95% CI for the injured group=1.05 (0.45 to 1.65), for the non-injured group=0.22 (-0.21 to 0.064), and group difference=0.83 (0.21 to 1.45), p=0.009), compared to those without knee injuries. This indicates that the athletes with knee injuries will increase their body mass index percentile by up to 5 units more than someone of the same age without an injury, and in body fat by up to 1.5%, compared to their non-injured peers. CONCLUSIONS: The present findings indicate that knee injury during the growing years may be associated with unfavourable changes in body composition.

The IOC consensus statement: beyond the Female Athlete Triad--Relative Energy Deficiency in Sport (RED-S).

Protecting the health of the athlete is a goal of the International Olympic Committee (IOC). The IOC convened an expert panel to update the 2005 IOC Consensus Statement on the Female Athlete Triad. This Consensus Statement replaces the previous and provides guidelines to guide risk assessment, treatment and return-to-play decisions. The IOC expert working group introduces a broader, more comprehensive term for the condition previously known as 'Female Athlete Triad'. The term 'Relative Energy Deficiency in Sport' (RED-S), points to the complexity involved and the fact that male athletes are also affected. The syndrome of RED-S refers to impaired physiological function including, but not limited to, metabolic rate, menstrual function, bone health, immunity, protein synthesis, cardiovascular health caused by relative energy deficiency. The cause of this syndrome is energy deficiency relative to the balance between dietary energy intake and energy expenditure required for health and activities of daily living, growth and sporting activities. Psychological consequences can either precede RED-S or be the result of RED-S. The clinical phenomenon is not a 'triad' of the three entities of energy availability, menstrual function and bone health, but rather a syndrome that affects many aspects of physiological function, health and athletic performance. This Consensus Statement also recommends practical clinical models for the management of affected athletes. The 'Sport Risk Assessment and Return to Play Model' categorises the syndrome into three groups and translates these classifications into clinical recommendations.

Pleasure and pain: teaching neuroscientific principles of hedonism in a large general education undergraduate course.

In a large (250 registrants) general education lecture course, neuroscience principles were taught by two professors as co-instructors, starting with simple brain anatomy, chemistry, and function, proceeding to basic brain circuits of pleasure and pain, and progressing with fellow expert professors covering relevant philosophical, artistic, marketing, and anthropological issues. With this as a base, the course wove between fields of high relevance to psychology and neuroscience, such as food addiction and preferences, drug seeking and craving, analgesic pain-inhibitory systems activated by opiates and stress, neuroeconomics, unconscious decision-making, empathy, and modern neuroscientific techniques (functional magnetic resonance imaging and event-related potentials) presented by the co-instructors and other Psychology professors. With no formal assigned textbook, all lectures were PowerPoint-based, containing links to supplemental public-domain material. PowerPoints were available on Blackboard several days before the lecture. All lectures were also video-recorded and posted that evening. The course had a Facebook page for after-class conversation and one of the co-instructors communicated directly with students on Twitter in real time during lecture to provide momentary clarification and comment. In addition to graduate student Teaching Assistants (TAs), to allow for small group discussion, ten undergraduate students who performed well in a previous class were selected to serve as discussion leaders. The Discussion Leaders met four times at strategic points over the semester with groups of 20-25 current students, and received one credit of Independent Study, thus creating a course within a course. The course grade was based on weighted scores from two multiple-choice exams and a five-page writing assignment in which each student reviewed three unique, but brief original peer-review research articles (one page each) combined with expository writing on the first and last pages. A draft of the first page, collected early in the term, was returned to each student by graduate TAs to provide individual feedback on scientific writing. Overall the course has run three times at ful or near enrollment capacity despite being held at an 8:00 AM time slot. Student-generated teaching evaluations place it well within the normal range, while this format importantly contributes to budget efficiency permitting the teaching of more required small-format courses (e.g., freshman writing). The demographics of the course have changed to one in which the vast majority of the students are now outside the disciplines of neuroscience or psychology and are taking the course to fulfill a General Education requirement. This pattern allows the wide dissemination of basic neuroscientific knowledge to a general college audience.

Targeting Clic1 for the treatment of obesity: A novel therapeutic strategy to reduce food intake and body weight.

OBJECTIVE: Despite great advances in obesity therapeutics in recent years, there is still a need to identify additional therapeutic targets for the treatment of this disease. We previously discovered a signature of genes, including Chloride intracellular channel 1 (Clic1), whose expression was associated with drug-induced weight gain, and in these studies, we assess the effect of Clic1 inhibition on food intake and body weight in mice. METHODS: We studied the impact of Clic1 inhibition in mouse models of binge-eating, diet-induced obese mice and genetic models of obesity (Magel2 KO mice). RESULTS: Clic1 knockout (KO) mice ate significantly less and had a lower body weight than WT littermates when either fed chow or high fat diet. Furthermore, pharmacological inhibition of Clic1 in diet-induced obese mice resulted in suppression of food intake and promoted highly efficacious weight loss. Clic1 inhibition also reduced food intake in binge-eating models and hyperphagic Magel2 KO mice. We observed that chronic obesity resulted in a significant change in subcellular localization of Clic1 with an increased ratio of Clic1 in the membrane in the obese state. These observations provide a novel therapeutic strategy to block Clic1 translocation as a potential mechanism to reduce food intake and lower body weight. CONCLUSIONS: These studies attribute a novel role of Clic1 as a driver of food intake and overconsumption. In summary, we have identified hypothalamic expression of Clic1 plays a key role in food intake, providing a novel therapeutic target to treat overconsumption that is the root cause of modern obesity.

Control of energy homeostasis by the lateral hypothalamic area.

The lateral hypothalamic area (LHA) is a subcortical brain region that exerts control over motivated behavior, feeding, and energy balance across species. Recent single-cell sequencing studies have defined at least 30 distinct LHA neuron types. Some of these influence specific aspects of energy homeostasis; however, the functions of many LHA cell types remain unclear. This review addresses the rapidly emerging evidence from cell-type-specific investigations that the LHA leverages distinct neuron populations to regulate energy balance through complex connections with other brain regions. It will highlight recent findings demonstrating that LHA control of energy balance extends beyond mere food intake and propose outstanding questions to be addressed by future research.

Highly recruited brown adipose tissue does not in itself protect against obesity.

OBJECTIVE: The possibility to counteract the development of obesity in humans by recruiting brown or brite/beige adipose tissue (and thus UCP1) has attracted much attention. Here we examine if a diet that can activate diet-induced thermogenesis can exploit pre-enhanced amounts of UCP1 to counteract the development of diet-induced obesity. METHODS: To investigate the anti-obesity significance of highly augmented amounts of UCP1 for control of body energy reserves, we physiologically increased total UCP1 amounts by recruitment of brown and brite/beige tissues in mice. We then examined the influence of the augmented UCP1 levels on metabolic parameters when the mice were exposed to a high-fat/high-sucrose diet under thermoneutral conditions. RESULTS: The total UCP1 levels achieved were about 50-fold higher in recruited than in non-recruited mice. Contrary to underlying expectations, in the mice with highly recruited UCP1 and exposed to a high-fat/high-sucrose diet the thermogenic capacity of this UCP1 was completely inactivate. The mice even transiently (in an adipostat-like manner) demonstrated a higher metabolic efficiency and fat gain than did non-recruited mice. This was accomplished without altering energy expenditure or food absorption efficiency. The metabolic efficiency here was indistinguishable from that of mice totally devoid of UCP1. CONCLUSIONS: Although UCP1 protein may be available, it is not inevitably utilized for diet-induced thermogenesis. Thus, although attempts to recruit UCP1 in humans may become successful as such, it is only if constant activation of the UCP1 is also achieved that amelioration of obesity development could be attained.