Putting a brake on hunger

doi:10.1126/science.abi8942

GSTDTAP > 气候变化

DOI	10.1126/science.abi8942
	Putting a brake on hunger
	Sadaf Farooqi
	2021-05-21
发表期刊	Science
出版年	2021
英文摘要	G protein–coupled receptors (GPCRs) interact with heterotrimeric guanine nucleotide-binding (G) proteins to modulate many physiological processes. Their structural properties make them highly druggable targets; 30% of currently prescribed medications target GPCRs. The melanocortin-4 receptor (MC4R) is a brain-expressed GPCR that plays a critical role in the regulation of body weight and for this reason has been the subject of intense focus as a target for weight loss therapy. On page 808 of this issue, Israeli et al. ([ 1 ][1]) present the structure of MC4R in complex with its main effector G protein (Gαs) and a weight loss drug that targets MC4R, setmelanotide. These findings provide mechanistic insights into how MC4R is activated and could inform the rational design of new weight loss therapies to tackle the substantial health burden faced by people with obesity. Obesity (an excess of adipose tissue that adversely affects health) is a global public health problem because of the associated comorbidities of type 2 diabetes, cardiovascular disease, and cancer. Morbidity and mortality are greatest in people with severe obesity [defined as a body mass index (BMI) >40 kg/m2], for whom new medical treatments are urgently needed. Weight loss of 5 to 10% of baseline weight is sufficient to substantially reduce the risk of complications in severely obese individuals. One of the major challenges in developing anti-obesity medications is that the brain pathways that regulate weight overlap with those that modulate mood, anxiety, and behavior. Neurons in one particular region, the hypothalamus, are pivotal to weight regulation ([ 2 ][2]). Hypothalamic neuronal circuits receive inputs from, and project to, multiple parts of the brain, allowing them to respond to innate biological signals and environmental cues (such as sight, smell, and taste) to modulate hunger (drive to eat) and satiety (fullness after a meal) to maintain body weight. Because receptors that mediate the effects of neurotransmitters and neuropeptides such as dopamine, serotonin, and norepinephrine are widely expressed on these hypothalamic neurons, it has been challenging to target specific appetite-regulating molecules without affecting other centrally driven physiological systems. For this reason, many anti-obesity medications have been withdrawn because of concerns about the safety of long-term use. A key hypothalamic pathway involved in the regulation of weight comprises neurons that respond to leptin, the major hormonal signal of nutritional state ([ 3 ][3]), which defends against starvation. Leptin-responsive neurons express pro-opiomelanocortin (POMC) (which is posttranslationally processed to yield melanocortin peptides) and agouti-related protein (AgRP); these peptides function as neurotransmitters. POMC- and AgRP-expressing neurons synapse with second-order neurons expressing MC4R, which in turn connect to preganglionic sympathetic neurons that regulate blood pressure. In the fasted state, a fall in circulating leptin concentrations stimulates AgRP+ neurons while inhibiting POMC+ neurons, the net effect being to reduce activation of MC4R (the brake in the circuit), driving hunger and food intake to restore energy homeostasis. In the fed state, increased leptin concentrations stimulate POMC+ neurons while inhibiting AgRP+ neurons, resulting in increased activation of MC4R, which puts a brake on hunger and eating. Targeted deletion of Mc4r in mice causes weight gain ([ 4 ][4]), and in humans, heterozygous loss-of-function MC4R mutations that reduce Gαs-mediated cyclic adenosine monophosphate (cAMP) production have been identified in cohorts of obese children and adults in many populations ([ 5 ][5], [ 6 ][6]). Common variants near to the MC4R locus are associated with increased BMI in the population ([ 7 ][7]), and gain-of-function MC4R variants are associated with protection from obesity and type 2 diabetes ([ 8 ][8]). Cumulatively, a substantial amount of genetic evidence supports the critical role of this GPCR in the regulation of food intake and body weight (see the figure). Unsurprisingly, therefore, the development of MC4R agonists for weight loss therapy has been a major focus of drug development for 20 years ([ 9 ][9]). The study by Israeli et al. may provide answers to a number of questions in the field. The development of cryo–electron microscopy (cryo-EM) and related methods has led to the characterization of structures for many GPCRs in the inactive state or bound to inverse agonists and antagonists, including recently for MC4R ([ 10 ][10]). However, structural determination of agonist-bound GPCRs in the fully active state, coupled to a heterotrimeric G protein, has been more challenging. Outstanding questions include the structural basis of the interaction between MC4R and other effectors. MC4R mutations can affect the recruitment of β-arrestins, which are scaffolding proteins that drive endocytosis, signaling, and gene transcription through mitogen-activated protein kinase (MAPK) pathway activation; MC4R mutations can also affect receptor recycling and homodimerization ([ 11 ][11]). Several accessory proteins regulate MC4R activity; specifically, understanding how melanocortin-2 receptor accessory protein 2 (MRAP2) interacts with MC4R to regulate weight remains an important question because mice lacking Mrap2 develop severe obesity ([ 12 ][12]). Structures of MC4R may guide predictions of how genetic variants in other melanocortin receptors affect their function. MC1R, expressed on melanocytes in skin and hair, is highly polymorphic; variants are associated with red hair, fair skin, freckles, and melanoma risk. Additionally, MC3Rs expressed on AgRP+ neurons modulate the activity of MC4R+ neurons in response to caloric restriction or to a calorie-rich diet and are implicated in weight gain. The structure reported by Israeli et al. may clarify the mechanisms by which germline inactivating mutations in the gene encoding Gαs ( GNAS ) cause an imprinted monogenic disorder that is characterized by developmental delay and obesity with or without hormone resistance. Brain-specific deletion of the maternal Gnas allele impairs the ability of an MC4R agonist to reduce body weight, suggesting that MC4Rs are involved in obesity in GNAS deficiency. As such, modeling of GNAS mutations may provide new insights into whether human GNAS mutations may directly impair downstream MC4R signaling. Structural models can provide valuable information to inform drug development and may illuminate the mechanisms that underlie variation in response within a class of drugs. First-generation MC4R agonists increased blood pressure in clinical trials, effects that halted their development; MC4R deficiency in mice and humans leads to reduced blood pressure because of impaired sympathetic tone, suggesting that the coupling of changes in weight and blood pressure is mediated by central melanocortin signaling ([ 13 ][13]). Yet, for reasons that are not understood, setmelanotide reduces body weight without increasing blood pressure. As a result of its efficacy and safety profile (main side effect being hyperpigmentation due to agonism at MC1R), it has recently been approved by the U.S. Food and Drug Administration (FDA) for chronic weight management in POMC and leptin receptor deficiency ([ 14 ][14]). Understanding the molecular basis for the unexpected divergence between first- and second-generation MC4R agonists could aid the design of new drugs targeting MC4R and indeed other GPCRs because activation domains are often highly conserved between receptors. Another potential therapeutic strategy may be informed by phenotypic studies of obese people with loss-of-function MC4R mutations who have an increase in lean body mass ([ 6 ][6]). These findings, which align with findings in mice ([ 4 ][4]), suggest that therapeutic antagonism of MC4R could potentially be useful in conditions characterized by weight loss and suppression of appetite, such as cancer cachexia. ![Figure][15] A drug target for obesity In the hypothalamus, leptin-responsive neurons express pro-opiomelanocortin (POMC), which is processed to yield α- and β-melanocyte stimulating hormone (MSH), which activate melanocortin-4 receptor (MC4R). MC4R activation decreases hunger and food intake and also regulates blood pressure. Loss-of-function MC4R mutations are associated with increased body mass index, whereas gain-of-function mutations are associated with protection from obesity. GRAPHIC: KELLIE HOLOSKI/ SCIENCE As highlighted by Israeli et al. , there is considerable interest in whether some obese people with pathogenic MC4R mutations will respond to setmelanotide. Potential mechanisms by which the agonist could lead to weight loss in those with nonfunctioning MC4Rs include action as a pharmacological chaperone to rescue plasma membrane expression of mutant forms of MC4R that exhibit impaired trafficking. Alternatively, because most people are carriers of heterozygous MC4R mutations, setmelanotide may increase signaling through normal (wild type) MC4R. The MC4R structure provided by Israeli et al. may allow more precise modeling of the effects of specific obesity-associated MC4R mutations and structural prediction of their responsiveness to setmelanotide. Given the prevalence of MC4R deficiency, which could be up to 0.3% of people according to data from a UK birth cohort ([ 15 ][16]), the potential to treat a substantial number of people with severe obesity has major implications for their clinical care. This work advances the much-anticipated potential of precision medicine for the treatment of people with severe obesity. 1. [↵][17]1. H. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/328818
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Sadaf Farooqi. Putting a brake on hunger[J]. Science,2021.
APA	Sadaf Farooqi.(2021).Putting a brake on hunger.Science.
MLA	Sadaf Farooqi."Putting a brake on hunger".Science (2021).