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Key Points The energy homeostasis system effectively ensures stability of body fat stores under usual conditions by processing humoral inputs related to both total body energy stores and current nutrient availability and transducing them into neuronal signals that powerfully influence the perception of satiety on the one hand and of food reward on the other. During conditions of negative energy balance (for example, starvation or a calorically restricted diet), homeostatic responses are engaged to promote increased food intake by reducing the satiating while enhancing the rewarding properties of food. Two well-studied leptin-sensing neuronal subpopulations involved in feeding are those that co-express neuropeptide Y, agouti-related protein (AGRP; an antagonist of melanocortin signalling) and GABA, and those that express pro-opiomelanocortin (POMC). Optogenetic and pharmacogenetic (designer receptors exclusively activated by a designer drug) strategies demonstrate that AGRP neuronal activation is sufficient to rapidly and potently stimulate food and increase the motivation to work for food. Conversely, stimulation and inhibition of POMC neurons using either optogenetics or DREADDs in mice reduces and increases food intake, respectively through the melanocortin receptor 4. Neurocircuits exist that are normally inhibited, but when activated in response to emergent or stressful stimuli, can override the homeostatic control of energy balance. In response to the lack of either immediately available fuel (such as hypoglycaemia) or the amount of stored fuel (leptin deficiency), the brain triggers an overlapping set of responses that drive increased food intake. During conditions of stress, trauma and illness, a neurocircuit involving calcitonin gene-related peptide-containing neurons in the parabrachial nucleus is activated that functions as an 'off' switch' for feeding. Improved knowledge of how these emergency-activated circuits interact with the energy homeostasis system is fundamental for understanding the control of food intake and may bear on the pathogenesis of disorders at both ends of the body weight spectrum. The energy homeostasis system maintains stability of body fat stores over time but can be overridden by activation of feeding neurocircuits during emergent or stressful conditions. In this Review, Schwartz and colleagues highlight crosstalk between homeostatic and emergency feeding circuits in the regulation of energy balance. Under normal conditions, food intake and energy expenditure are balanced by a homeostatic system that maintains stability of body fat content over time. However, this homeostatic system can be overridden by the activation of 'emergency response circuits' that mediate feeding responses to emergent or stressful stimuli. Inhibition of these circuits is therefore permissive for normal energy homeostasis to occur, and their chronic activation can cause profound, even life-threatening, changes in body fat mass. This Review highlights how the interplay between homeostatic and emergency feeding circuits influences the biologically defended level of body weight under physiological and pathophysiological conditions.

Eating disorders (anorexia nervosa, bulimia nervosa and binge-eating disorder) are a heterogeneous class of complex illnesses marked by weight and appetite dysregulation coupled with distinctive behavioral and psychological features. Our understanding of their genetics and neurobiology is evolving thanks to global cooperation on genome-wide association studies, neuroimaging, and animal models. Until now, however, these approaches have advanced the field in parallel, with inadequate cross-talk. This review covers overlapping advances in these key domains and encourages greater integration of hypotheses and findings to create a more unified science of eating disorders. We highlight ongoing and future work designed to identify implicated biological pathways that will inform staging models based on biology as well as targeted prevention and tailored intervention, and will galvanize interest in the development of pharmacologic agents that target the core biology of the illnesses, for which we currently have few effective pharmacotherapeutics.Eating disorders are prevalent and, in far too many cases, fatal. This review covers advances in genetics, neuroimaging, and animal models, and encourages a more unified science of eating disorders.

Eating disorders and their core symptoms (eg, binge eating, body weight/shape concerns) disproportionately affect females, and these sex-differentiated effects become prominent during and after puberty. Although psychosocial influences such as heightened sociocultural pressures for thinness in girls and women contribute to this sex imbalance, biological factors could also play an important role. This narrative review summarizes evidence of biological factors underlying the sex-differentiated prevalence of eating pathology as well as within-sex variability in risk. There are sex differences in the pubertal emergence of genetic effects on eating pathology (adrenarche in males; gonadarche in females), and at least some genetic contributions to eating pathology seem to vary between the sexes. Furthermore, sex steroid hormones (eg, testosterone, estradiol, progesterone) are leading contributors to differential risk for eating pathology in males and females across the life span. Emerging data suggest that between-sex and within-sex variability in risk might occur via hormone-driven modulation (activation/deactivation) of genetic influences and neural responsiveness to food-related cues. There is a biological basis to heightened risk for eating pathology in females, relative to males, as well as unique biological influences within each sex. Findings from this review highlight the importance of studying both sexes and considering sex-specific biological mechanisms that may underlie differential risk for eating pathology •Some genetic effects on eating pathology vary between the sexes.•Sex steroids impact sex-specific genetic and phenotypic effects on eating pathology.•Testosterone exerts protective effects that reduce eating pathology in males.•Lower estradiol enhances genetic and phenotypic eating pathology risk in girls/women.•Neural responses to palatable food differ between the sexes, possibly via estradiol.

Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.

Purpose Pathogenic variations in genes encoding aminoacyl-tRNA synthetases (ARSs) are increasingly associated with human disease. Clinical features of autosomal recessive ARS deficiencies appear very diverse and without apparent logic. We searched for common clinical patterns to improve disease recognition, insight into pathophysiology, and clinical care. Methods Symptoms were analyzed in all patients with recessive ARS deficiencies reported in literature, supplemented with unreported patients evaluated in our hospital. Results In literature, we identified 107 patients with AARS, DARS, GARS, HARS, IARS, KARS, LARS, MARS, RARS, SARS, VARS, YARS, and QARS deficiencies. Common symptoms (defined as present in ≥4/13 ARS deficiencies) included abnormalities of the central nervous system and/or senses (13/13), failure to thrive, gastrointestinal symptoms, dysmaturity, liver disease, and facial dysmorphisms. Deep phenotyping of 5 additional patients with unreported compound heterozygous pathogenic variations in IARS , LARS , KARS , and QARS extended the common phenotype with lung disease, hypoalbuminemia, anemia, and renal tubulopathy. Conclusion We propose a common clinical phenotype for recessive ARS deficiencies, resulting from insufficient aminoacylation activity to meet translational demand in specific organs or periods of life. Assuming residual ARS activity, adequate protein/amino acid supply seems essential instead of the traditional replacement of protein by glucose in patients with metabolic diseases.

Enabled by advances in high throughput genomic sequencing and an unprecedented level of global data sharing, molecular genetic research is beginning to unlock the biological basis of eating disorders. This invited review provides an overview of genetic discoveries in eating disorders in the genome-wide era. To date, five genome-wide association studies on eating disorders have been conducted – all on anorexia nervosa (AN). For AN, several risk loci have been detected, and ~11–17% of the heritability has been accounted for by common genetic variants. There is extensive genetic overlap between AN and psychological traits, especially obsessive-compulsive disorder, and intriguingly, with metabolic phenotypes even after adjusting for body mass index (BMI) risk variants. Furthermore, genetic risk variants predisposing to lower BMI may be causal risk factors for AN. Causal genes and biological pathways of eating disorders have yet to be elucidated and will require greater sample sizes and statistical power, and functional follow-up studies. Several studies are underway to recruit individuals with bulimia nervosa and binge-eating disorder to enable further genome-wide studies. Data collections and research labs focused on the genetics of eating disorders have joined together in a global effort with the Psychiatric Genomics Consortium. Molecular genetics research in the genome-wide era is improving knowledge about the biology behind the established heritability of eating disorders. This has the potential to offer new hope for understanding eating disorder etiology and for overcoming the therapeutic challenges that confront the eating disorder field.

Girls with predispositions for disordered eating (DE) may select into weight-conscious peer groups (i.e. peer groups that emphasize body weight/shape). However, factors driving selection into these peer groups remain unknown, as genetic and/or environmental predisposition to DE may lead girls to select weight-conscious peers. To explore what may drive selection, the present study investigated whether genetic or shared environmental influences underlie associations between DE and exposure to weight-conscious peers and whether effects differ by pubertal status. Participants included 833 female twins (ages 8-15) from the Michigan State University Twin Registry. Bivariate twin models were conducted to explore etiologic overlap between DE and exposure to weight-conscious peers. Separate models were run for pre-early pubertal girls and mid-late pubertal girls given past research demonstrates differences in genetic and environmental contributions underlying eating pathology by pubertal status. During pre-early puberty, shared and non-shared environmental correlations accounted for the overlap between DE and weight-conscious peer group exposure. Furthermore, shared environmental and non-shared environmental influences underlying DE contributed to 33.3% and 20.0% of the individual differences in weight-conscious peer group membership, respectively. In mid-late puberty, the genetic and non-shared environmental correlations accounted for the overlap between DE and weight-conscious peer group exposure. Genetic and non-shared environmental influences underlying DE contributed to 37.5% and 19.4% of the variance in weight-conscious peer group membership, respectively. While selection effects may exist across development, these effects may be driven by variance in DE due to shared environment in pre-early puberty and genes in mid-late puberty.

Endometriosis is a common chronic gynecologic pathology with a large negative impact on women's health. Beyond severe physical symptoms, endometriosis is also associated with several psychiatric comorbidities, including depression and anxiety. To investigate whether pleiotropy contributes to the association of endometriosis with depression, anxiety, and eating disorders. This genetic association study was performed between September 13, 2021, and June 24, 2022, in 202 276 unrelated female participants. Genotypic and phenotypic information from the UK Biobank was combined with genome-wide association statistics available from the Psychiatric Genomics Consortium (11 countries), the Million Veteran Program (US), the FinnGen study (Finland), and the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium (5 countries). The main outcomes were the phenotypic and genetic associations of endometriosis with anxiety, depression, and eating disorders. A total of 8276 women with endometriosis (mean [SD] age, 53.1 [7.9] years) and 194 000 female controls (mean [SD] age, 56.7 [7.9] years) were included in the study. In a multivariate regression analysis accounting for age, body mass index, socioeconomic status, chronic pain-related phenotypes, irritable bowel syndrome, and psychiatric comorbidities, endometriosis was associated with increased odds of depression (odds ratio [OR], 3.61; 95% CI, 3.32-3.92), eating disorders (OR, 2.94; 95% CI, 1.96-4.41), and anxiety (OR, 2.61; 95% CI, 2.30-2.97). These associations were supported by consistent genetic correlations (rg) (depression rg, 0.36, P = 1.5 × 10-9; anxiety rg, 0.33, P = 1.17 × 10-5; and eating disorders rg, 0.61, P = .02). With the application of a 1-sample mendelian randomization, the genetic liabilities to depression and anxiety were associated with increased odds of endometriosis (depression: OR, 1.09; 95% CI, 1.08-1.11; anxiety: OR, 1.39; 95% CI, 1.13-1.65). A genome-wide analysis of pleiotropic associations shared between endometriosis and psychiatric disorders identified 1 locus, DGKB rs12666606, with evidence of pleiotropy between endometriosis and depression after multiple testing correction (z = -9.46 for endometriosis, z = 8.10 for depression, P = 5.56 × 10-8; false discovery rate q = 4.95 × 10-4). These findings highlight that endometriosis is associated with women's mental health through pleiotropic mechanisms. To our knowledge, this is the first large-scale study to provide genetic and phenotypic evidence of the processes underlying the psychiatric comorbidities of endometriosis.

Eating disorders are complex heritable conditions influenced by both genetic and environmental factors. Given the progress of genomic discovery in anorexia nervosa, with the identification of the first genome-wide significant locus, as well as animated discussion of epigenetic mechanisms in linking environmental factors with disease onset, our goal was to conduct a systematic review of the current body of evidence on epigenetic factors in eating disorders to inform future directions in this area. Following PRISMA guidelines, two independent authors conducted a search within PubMed and Web of Science and identified 18 journal articles and conference abstracts addressing anorexia nervosa (n = 13), bulimia nervosa (n = 6), and binge-eating disorder (n = 1), published between January 2003 and October 2017. We reviewed all articles and included a critical discussion of field-specific methodological considerations. The majority of epigenetic analyses of eating disorders investigated methylation at candidate genes (n = 13), focusing on anorexia and bulimia nervosa in very small samples with considerable sample overlap across published studies. Three studies used microarray-based technologies to examine DNA methylation across the genome of anorexia nervosa and binge-eating disorder patients. Overall, results were inconclusive and were primarily exploratory in nature. The field of epigenetics in eating disorders remains in its infancy. We encourage the scientific community to apply methodologically sound approaches using genome-wide designs including epigenome-wide association studies (EWAS), to increase sample sizes, and to broaden the focus to include all eating disorder types.

Eating disorders arise from a complex interaction of genetic and environmental influences. Here we provide comprehensive population-level estimates of the heritability of eating disorders and their genetic relationships with various mental health and cardiometabolic disorders (CMDs), expanding beyond genome-wide association studies. We examined the heritability of three eating disorders—anorexia nervosa (AN), bulimia nervosa (BN), and other eating disorders (OED)—and investigated shared familial and genetic risk factors with mental health disorders and CMDs. Using national register data from Denmark and Sweden (1972–2016), we analysed clinical diagnoses for over 67,000 individuals with eating disorders, their first-degree relatives, and matched controls from populations totalling 17 million. Heritability estimates were moderate, h 2 AN  = 36%, h 2 BN  = 39%, and h 2 OED  = 30% and genetic correlations revealed substantial overlap between AN and obsessive-compulsive disorder ( r g  = 0.65) and moderate correlations with other mental health disorders such as autism ( r g  = 0.36). Significant genetic associations were also identified between eating disorders and CMDs, showing strong replication across both countries. These findings emphasise the genetic foundations of eating disorders and their shared genetic architecture with mental health and CMDs. This research enhances our understanding of comorbidity patterns and has important implications for developing integrated treatment approaches. Here, the authors’ findings highlight genetic overlap between eating disorders, mental disorders, and cardiometabolic diseases, supporting the need for integrated treatment strategies across physical and mental health care.