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Martin Reincke, Martin Fassnacht and colleagues identify somatic mutations in the USP8 deubiquitinase gene in corticotroph adenomas in Cushing's disease. The mutations enhanced proteolytic cleavage and catalytic activity of USP8, which led to activation of EGF receptor signaling. Cushing's disease is caused by corticotroph adenomas of the pituitary. To explore the molecular mechanisms of endocrine autonomy in these tumors, we performed exome sequencing of 10 corticotroph adenomas. We found somatic mutations in the USP8 deubiquitinase gene in 4 of 10 adenomas. The mutations clustered in the 14-3-3 protein binding motif and enhanced the proteolytic cleavage and catalytic activity of USP8. Cleavage of USP8 led to increased deubiqutination of the EGF receptor, impairing its downregulation and sustaining EGF signaling. USP8 mutants enhanced promoter activity of the gene encoding proopiomelanocortin. In summary, our data show that dominant mutations in USP8 cause Cushing's disease via activation of EGF receptor signaling.

This study showed that cortisol secretion by the adrenals in patients with macronodular hyperplasia is probably regulated by corticotropin produced within the adrenals. Thus, hypercortisolism associated with this form of adrenal hyperplasia is probably corticotropin-dependent. Chronic excess of glucocorticoids may lead to a constellation of symptoms that include central obesity and arterial hypertension, termed Cushing's syndrome, which is associated with increased mortality. In 10 to 20% of cases, Cushing's syndrome is caused by primary adrenal cortisol hypersecretion. 1 Among patients with primary hypersecretion of adrenal cortisol, bilateral macronodular adrenal disease is extremely rare, representing less than 2% of all cases of Cushing's syndrome. Hypersecretion of cortisol by the enlarged adrenal glands suppresses the release of corticotropin by the anterior pituitary, leading to low plasma levels of corticotropin. For this reason, the disease has also been called . . .

Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor agonists on energy and glucose homeostasis are unknown. Here, we show that mice lacking serotonin 2C receptors (Htr2c) specifically in pro-opiomelanocortin (POMC) neurons had normal body weight but developed glucoregulatory defects including hyperinsulinemia, hyperglucagonemia, hyperglycemia, and insulin resistance. Moreover, these mice did not show anorectic responses to serotonergic agents that suppress appetite and developed hyperphagia and obesity when they were fed a high-fat/high-sugar diet. A requirement of serotonin 2C receptors in POMC neurons for the maintenance of normal energy and glucose homeostasis was further demonstrated when Htr2c loss was induced in POMC neurons in adult mice using a tamoxifen-inducible POMC-cre system. These data demonstrate that serotonin 2C receptor-expressing POMC neurons are required to control energy and glucose homeostasis and implicate POMC neurons as the target for the effect of serotonin 2C receptor agonists on weight-loss induction and improved glycemic control.

The hypothalamic arcuate–median eminence (Arc-ME) complex is rich with functionally distinct cell types, a fraction of which have been characterized. The authors profile 20,921 individual cells by single-cell RNA-seq, identifying 50 Arc-ME cell types and their markers, determining each's response to energy status and implicating two neuron populations in the genetic control of obesity. The hypothalamic arcuate–median eminence complex (Arc-ME) controls energy balance, fertility and growth through molecularly distinct cell types, many of which remain unknown. To catalog cell types in an unbiased way, we profiled gene expression in 20,921 individual cells in and around the adult mouse Arc-ME using Drop-seq. We identify 50 transcriptionally distinct Arc-ME cell populations, including a rare tanycyte population at the Arc-ME diffusion barrier, a new leptin-sensing neuron population, multiple agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) subtypes, and an orexigenic somatostatin neuron population. We extended Drop-seq to detect dynamic expression changes across relevant physiological perturbations, revealing cell type–specific responses to energy status, including distinct responses in AgRP and POMC neuron subtypes. Finally, integrating our data with human genome-wide association study data implicates two previously unknown neuron populations in the genetic control of obesity. This resource will accelerate biological discovery by providing insights into molecular and cell type diversity from which function can be inferred.

Absence of proopiomelanocortin results in early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism. Two affected patients received setmelanotide, a new melanocortin-4 receptor agonist, which led to sustainable reduction of hunger and substantial weight loss. Melanocyte-stimulating hormone, which is produced from proopiomelanocortin, plays a pivotal role in the regulation of satiety and energy expenditure. In the hypothalamic leptin–melanocortin signaling pathway, melanocyte-stimulating hormone transmits the anorexic effect of leptin through the melanocortin-4 receptor. 1 Patients with a mutation in the gene encoding proopiomelanocortin ( POMC ), a very rare condition, have early-onset obesity due to severe hyperphagia as a result of the lack of hypothalamic melanocyte-stimulating hormone. Furthermore, the lack of melanocyte-stimulating hormone at the melanocortin-1 receptor in melanocytes and hair follicles may lead to pale skin and red hair. In addition, affected persons have secondary hypocortisolism . . .

Cell-specific expression of many genes is conveyed by multiple enhancers, with each individual enhancer controlling a particular expression domain. In contrast, multiple enhancers drive similar expression patterns of some genes involved in embryonic development, suggesting regulatory redundancy. Work in Drosophila has indicated that functionally overlapping enhancers canalize development by buffering gene expression against environmental and genetic disturbances. However, little is known about regulatory redundancy in vertebrates and in genes mainly expressed during adulthood. Here we study nPE1 and nPE2, two phylogenetically conserved mammalian enhancers that drive expression of the proopiomelanocortin gene (Pomc) to the same set of hypothalamic neurons. The simultaneous deletion of both enhancers abolished Pomc expression at all ages and induced a profound metabolic dysfunction including early-onset extreme obesity. Targeted inactivation of either nPE1 or nPE2 led to very low levels of Pomc expression during early embryonic development indicating that both enhancers function synergistically. In adult mice, however, Pomc expression is controlled additively by both enhancers, with nPE1 being responsible for ∼80% and nPE2 for ∼20% of Pomc transcription. Consequently, nPE1 knockout mice exhibit mild obesity whereas nPE2-deficient mice maintain a normal body weight. These results suggest that nPE2-driven Pomc expression is compensated by nPE1 at later stages of development, essentially rescuing the earlier phenotype of nPE2 deficiency. Together, these results reveal that cooperative interactions between the enhancers confer robustness of Pomc expression against gene regulatory disturbances and preclude deleterious metabolic phenotypes caused by Pomc deficiency in adulthood. Thus, our study demonstrates that enhancer redundancy can be used by genes that control adult physiology in mammals and underlines the potential significance of regulatory sequence mutations in common diseases.

Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB 1 R) is critical for the central regulation of food intake. Here we test whether CB 1 R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB 1 R activity increases feeding, and notably, CB 1 R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB 1 R-induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances CB 1 R-driven feeding. The Pomc gene encodes both the anorexigenic peptide α-melanocyte-stimulating hormone, and the opioid peptide β-endorphin. CB 1 R activation selectively increases β-endorphin but not α-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB 1 R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB 1 R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids. Cannabinoid-induced feeding signals are shown to enhance pro-opiomelanocortin (POMC) neuronal activity in mice, causing an enhancement of β-endorphin release, which is crucial in causing this cannabinoid-induced response; these results uncover an overlooked role of hypothalamic POMC neurons in the promotion of feeding by cannabinoids. Complex effects of cannabinoids on feeding Previous work has established a role for hypothalamic pro-opiomelanocortin (POMC) neurones in reducing feeding due to satiety, suggesting that signals promoting feeding may reduce POMC neuronal activity. Tamas Horvath and colleagues have tested this idea and find that, surprisingly, cannabinoid feeding signals enhance POMC neuronal activity. This paradoxical POMC neuronal activation is indispensable for appropriate promotion of feeding triggered by cannabinoid receptor 1 activation in the state of satiety. The authors conclude that the overall effect of cannabinoids on feeding may be driven by both pre- and post-synaptic effects — possibly independently from one another — and that it is their temporal synchrony that brings about the overall behavioural changes.

Aponte et al . show that optogenetic activation of a population of hypothalamic neurons expressing agouti-related peptide (AGRP) is sufficient to evoke voracious feeding behavior in mice. This feeding was not dependent on suppressing the activity of anorexigenic pro-opiomelanocortin–expressing neurons, suggesting that AGRP neurons directly engage feeding circuits. Two intermingled hypothalamic neuron populations specified by expression of agouti-related peptide (AGRP) or pro-opiomelanocortin (POMC) positively and negatively influence feeding behavior, respectively, possibly by reciprocally regulating downstream melanocortin receptors. However, the sufficiency of these neurons to control behavior and the relationship of their activity to the magnitude and dynamics of feeding are unknown. To measure this, we used channelrhodopsin-2 for cell type–specific photostimulation. Activation of only 800 AGRP neurons in mice evoked voracious feeding within minutes. The behavioral response increased with photoexcitable neuron number, photostimulation frequency and stimulus duration. Conversely, POMC neuron stimulation reduced food intake and body weight, which required melanocortin receptor signaling. However, AGRP neuron–mediated feeding was not dependent on suppressing this melanocortin pathway, indicating that AGRP neurons directly engage feeding circuits. Furthermore, feeding was evoked selectively over drinking without training or prior photostimulus exposure, which suggests that AGRP neurons serve a dedicated role coordinating this complex behavior.

The coordination of food intake, energy storage, and expenditure involves complex interactions between hypothalamic neurons and peripheral tissues including pancreatic islets, adipocytes, muscle, and liver. Previous research shows that deficiency of the transcription factor Alx3 alters pancreatic islet-dependent glucose homeostasis. In this study we carried out a comprehensive assessment of metabolic alterations in Alx3 deficiency. We report that Alx3-deficient mice exhibit decreased food intake without changes in body weight, along with reduced energy expenditure and altered respiratory exchange ratio. Magnetic resonance imaging reveals increased adiposity and decreased muscle mass, which was associated with markers of motor and sympathetic denervation. By contrast, Alx3-deficient mice on a high-fat diet show attenuated weight gain and improved insulin sensitivity, compared to control mice. Gene expression analysis demonstrates altered lipogenic and lipolytic gene profiles. In wild type mice Alx3 is expressed in hypothalamic arcuate nucleus neurons, but not in major peripheral metabolic organs. Functional diffusion-weighted magnetic resonance imaging reveals selective hypothalamic responses to fasting in the arcuate nucleus of Alx3-deficient mice. Additionally, altered expression of proopiomelanocortin and melanocortin-3 receptor mRNA in the hypothalamus suggests impaired regulation of feeding behavior. This study highlights the crucial role for Alx3 in governing food intake, energy homeostasis, and metabolic nutrient partitioning, thereby influencing body mass composition.

Multiple hormones controlling energy homeostasis regulate the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. Nevertheless, inactivation of the genes encoding NPY and/or AgRP has no impact on food intake in mice. Here we demonstrate that induced selective ablation of AgRP-expressing neurons in adult mice results in acute reduction of feeding, demonstrating direct evidence for a critical role of these neurons in the regulation of energy homeostasis.