Loss of transient receptor potential channel 5 causes obesity and postpartum depression.

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.

Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance.

Hypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to the development of these circuits. In genetic studies, we found 40 rare variants in SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) in 573 severely obese individuals; variants disrupted secretion and/or signaling through multiple molecular mechanisms. Rare variants in this set of genes were significantly enriched in 982 severely obese cases compared to 4,449 controls. In a zebrafish mutagenesis screen, deletion of 7 genes in this pathway led to increased somatic growth and/or adiposity demonstrating that disruption of Semaphorin 3 signaling perturbs energy homeostasis. In mice, deletion of the Neuropilin-2 receptor in Pro-opiomelanocortin neurons disrupted their projections from the arcuate to the paraventricular nucleus, reduced energy expenditure, and caused weight gain. Cumulatively, these studies demonstrate that SEMA3-mediated signaling drives the development of hypothalamic melanocortin circuits involved in energy homeostasis.

Leptin mediates the increase in blood pressure associated with obesity.

Obesity is associated with increased blood pressure (BP), which in turn increases the risk of cardiovascular diseases. We found that the increase in leptin levels seen in diet-induced obesity (DIO) drives an increase in BP in rodents, an effect that was not seen in animals deficient in leptin or leptin receptors (LepR). Furthermore, humans with loss-of-function mutations in leptin and the LepR have low BP despite severe obesity. Leptin's effects on BP are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), as blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH caused a rapid reduction of BP in DIO mice, independent of changes in weight. Re-expression of LepRs in the DMH of DIO LepR-deficient mice caused an increase in BP. These studies demonstrate that leptin couples changes in weight to changes in BP in mammalian species.

KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.

Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.

Obesity-Associated GNAS Mutations and the Melanocortin Pathway.

BACKGROUND: GNAS encodes the Gαs (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. GNAS mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism). METHODS: We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 GNAS mutation carriers. We investigated whether the effect of GNAS mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays. RESULTS: Almost all GNAS mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, -0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. GNAS mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have GNAS mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONS: Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for GNAS deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. GNAS mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.).

Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with delayed gastric emptying.

OBJECTIVE: People who are severely obese due to melanocortin-4 receptor (MC4R) deficiency experience hyperphagia and impaired fullness after a meal (satiety). Meal-induced satiety is influenced by hormones, such as peptide-YY (PYY), which are released by enteroendocrine cells upon nutrient delivery to the small intestine. DESIGN: We investigated whether gastric emptying and PYY levels are altered in MC4R deficiency. METHODS: Gastric emptying was measured with a gastric scintigraphy protocol using technetium-99m (99 Tcm )-Tin Colloid for 3.5 h in individuals with loss of function MC4R variants and a control group of similar age and weight. In a separate study, we measured plasma PYY levels before and at multiple time points after three standardised meals given to individuals with MC4R deficiency and controls. Fasting PYY (basal secretion) and postprandial PYY levels were measured and the area under the curve and inter-meal peak were calculated. RESULTS: We found that gastric emptying time was significantly delayed and percentage meal retention increased in individuals with MC4R deficiency compared to obese controls. In addition, fasting and mean PYY secretion throughout the day were decreased in MC4R deficiency, whereas postprandial PYY secretion was unaltered. CONCLUSION: Delayed gastric emptying and reduced basal PYY secretion may contribute to impaired satiety in people with obesity due to MC4R deficiency.

Genetic architecture of human thinness compared to severe obesity.

The variation in weight within a shared environment is largely attributable to genetic factors. Whilst many genes/loci confer susceptibility to obesity, little is known about the genetic architecture of healthy thinness. Here, we characterise the heritability of thinness which we found was comparable to that of severe obesity (h2 = 28.07 vs 32.33% respectively), although with incomplete genetic overlap (r = -0.49, 95% CI [-0.17, -0.82], p = 0.003). In a genome-wide association analysis of thinness (n = 1,471) vs severe obesity (n = 1,456), we identified 10 loci previously associated with obesity, and demonstrate enrichment for established BMI-associated loci (pbinomial = 3.05x10-5). Simulation analyses showed that different association results between the extremes were likely in agreement with additive effects across the BMI distribution, suggesting different effects on thinness and obesity could be due to their different degrees of extremeness. In further analyses, we detected a novel obesity and BMI-associated locus at PKHD1 (rs2784243, obese vs. thin p = 5.99x10-6, obese vs. controls p = 2.13x10-6 pBMI = 2.3x10-13), associations at loci recently discovered with much larger sample sizes (e.g. FAM150B and PRDM6-CEP120), and novel variants driving associations at previously established signals (e.g. rs205262 at the SNRPC/C6orf106 locus and rs112446794 at the PRDM6-CEP120 locus). Our ability to replicate loci found with much larger sample sizes demonstrates the value of clinical extremes and suggest that characterisation of the genetics of thinness may provide a more nuanced understanding of the genetic architecture of body weight regulation and may inform the identification of potential anti-obesity targets.

Neural deletion of Sh2b1 results in brain growth retardation and reactive aggression.

Psychiatric disorders are associated with aberrant brain development and/or aggressive behavior and are influenced by genetic factors; however, genes that affect brain aggression circuits remain elusive. Here, we show that neuronal Src-homology-2 (SH2)B adaptor protein-1 ( Sh2b1) is indispensable for both brain growth and protection against aggression. Global and brain-specific deletion of Sh2b1 decreased brain weight and increased aggressive behavior. Global and brain-specific Sh2b1 knockout (KO) mice exhibited fatal, intermale aggression. In a resident-intruder paradigm, latency to attack was markedly reduced, whereas the number and the duration of attacks was significantly increased in global and brain-specific Sh2b1 KO mice compared with wild-type littermates. Consistently, core aggression circuits were activated to a higher level in global and brain-specific Sh2b1 KO males, based on c-fos immunoreactivity in the amygdala and periaqueductal gray. Brain-specific restoration of Sh2b1 normalized brain size and reversed pathologic aggression and aberrant activation of core aggression circuits in Sh2b1 KO males. SH2B1 mutations in humans were linked to aberrant brain development and behavior. At the molecular level, Sh2b1 enhanced neurotrophin-stimulated neuronal differentiation and protected against oxidative stress-induced neuronal death. Our data suggest that neuronal Sh2b1 promotes brain development and the integrity of core aggression circuits, likely through enhancing neurotrophin signaling.-Jiang, L., Su, H., Keogh, J. M., Chen, Z., Henning, E., Wilkinson, P., Goodyer, I., Farooqi, I. S., Rui, L. Neural deletion of Sh2b1 results in brain growth retardation and reactive aggression.

Energy expenditure in frontotemporal dementia: a behavioural and imaging study.

SEE FINGER DOI101093/AWW312 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Abnormal eating behaviour and metabolic parameters including insulin resistance, dyslipidaemia and body mass index are increasingly recognized as important components of neurodegenerative disease and may contribute to survival. It has previously been established that behavioural variant frontotemporal dementia is associated with abnormal eating behaviour characterized by increased sweet preference. In this study, it was hypothesized that behavioural variant frontotemporal dementia might also be associated with altered energy expenditure. A cohort of 19 patients with behavioural variant frontotemporal dementia, 13 with Alzheimer's disease and 16 (age- and sex-matched) healthy control subjects were studied using Actiheart devices (CamNtech) to assess resting and stressed heart rate. Actiheart devices were fitted for 7 days to measure sleeping heart rate, activity levels, and resting, active and total energy expenditure. Using high resolution structural magnetic resonance imaging the neural correlates of increased resting heart rate were investigated including cortical thickness and region of interest analyses. In behavioural variant frontotemporal dementia, resting (P = 0.001), stressed (P = 0.037) and sleeping heart rate (P = 0.038) were increased compared to control subjects, and resting heart rate (P = 0.020) compared to Alzheimer disease patients. Behavioural variant frontotemporal dementia was associated with decreased activity levels compared to controls (P = 0.002) and increased resting energy expenditure (P = 0.045) and total energy expenditure (P = 0.035). Increased resting heart rate correlated with behavioural (Cambridge Behavioural Inventory) and cognitive measures (Addenbrooke's Cognitive Examination). Increased resting heart rate in behavioural variant frontotemporal dementia correlated with atrophy involving the mesial temporal cortex, insula, and amygdala, regions previously suggested to be involved exclusively in social and emotion processing in frontotemporal dementia. These neural correlates overlap the network involved in eating behaviour in frontotemporal dementia, suggesting a complex interaction between eating behaviour, autonomic function and energy homeostasis. As such the present study suggests that increased heart rate and autonomic changes are prevalent in behavioural variant frontotemporal dementia, and are associated with changes in energy expenditure. An understanding of these changes and neural correlates may have potential relevance to disease progression and prognosis.

Role of melanocortin signalling in the preference for dietary macronutrients in human beings.

BACKGROUND: Signalling though the melanocortin 4 receptor (MC4R), which is widely expressed in the hypothalamus, mediates food intake and macronutrient preference in rodents. Studies in patients with MC4R deficiency can provide insights into the role of this pathway in man. We investigated the role of melanocortin signalling in fat and sucrose preference in human beings by studying patients with loss of function mutations in MC4R. METHODS: We studied 24 obese patients with MC4R deficiency, and 80 healthy controls (40 obese, 40 lean). We used an ad-libitum meal protocol consisting of three meals covertly manipulated to provide 20% (low), 40% (medium), and 60% (high) fat content. We used the same procedure for meals manipulated to provide 8% (low), 26% (medium), and 54% (high) sucrose content. We measured food intake and rated liking for the meals with visual analogue scores. Data were analysed by ANOVA and Tukey's post-hoc tests or a linear mixed-effects model with an interaction term for study group and study meal when appropriate. FINDINGS: Although the liking of the three different fat meals did not differ between the three groups, patients with MC4R mutations consumed 95% more of the high fat meal than did lean controls and 65% more of the high fat meal than did obese controls (p=0·0222 for the interaction of group by meal). By contrast, although liking ratings for low and medium sucrose meals were comparable in the individuals with MC4R deficiency, liking ratings for the high sucrose meal were significantly reduced (p=0·0252 in linear mixed-effects model, intercept 57·8, MC4R group factor -26·2, factors in the model for MC4R-low sucrose 27·7, MC4R-medium sucrose 22·6). Similarly, patients with MC4R deficiency consumed less of all three sucrose meals than did healthy controls (p=0·0064). INTERPRETATION: Our study shows that the central melanocortin system has divergent effects on macronutrient preference and intake in human beings. FUNDING: Wellcome Trust, NIHR Cambridge Biomedical Research Centre, Bernard Wolfe Health Neuroscience Fund, NeuroFAST consortium, which is funded by the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 245009.