Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons.
Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons.
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DOI：
10.1016/j.molmet.2016.01.005
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发表时间：
2016-03
影响因子：
8.1
通讯作者：
Heisler LK
中科院分区：
文献类型：
--
作者：
Burke LK;Doslikova B;D'Agostino G;Greenwald-Yarnell M;Georgescu T;Chianese R;Martinez de Morentin PB;Ogunnowo-Bada E;Cansell C;Valencia-Torres L;Garfield AS;Apergis-Schoute J;Lam DD;Speakman JR;Rubinstein M;Low MJ;Rochford JJ;Myers MG;Evans ML;Heisler LK
肥胖是21世纪主要的医疗保健挑战之一。传递能量需求信息的信号在大脑内被整合，从而影响体重。这些整合节点的中心是脑促鸦片黑素皮质素（POMC）肽，其扰动破坏能量平衡并促进严重肥胖。然而，POMC神经元具有神经化学多样性，调节能量稳态和体重的POMC肽的关键来源仍有待完全阐明。鉴于5-羟色胺2c受体（5-HT2CR）激动剂是目前的一种肥胖药物，而5-HT2CR激动剂对食欲的影响主要是通过POMC神经元介导的，我们假设POMC调节食物摄入和体重的关键来源是在含有5-HT2CR的细胞中特异性合成的。为了只在含有5-HT2CR的细胞中操纵Pomc合成，我们培育了一种新的5-HT2CRCRE小鼠系，并将其与依赖于Cre重组酶和下丘脑特异性可再激活的PomcNEO小鼠杂交，以限制Pomc合成在含有5-HT2CR的下丘脑细胞亚群中。这提供了一种方法来澄清POMC肽在能量平衡和体重中的特定贡献。本研究通过靶向恢复表达5-HT2CR细胞内的Pomc功能，将缺乏下丘脑Pomc、食欲增加、体力活动减少、棕色脂肪组织（BAT）受损的基因程序性肥胖和高胰岛素血症雄性小鼠转化为瘦削、健康的小鼠。值得注意的是，同样的代谢转变不会发生在雌性身上，尽管雌性动物的摄食行为得到了纠正，胰岛素水平也趋于正常，但它们仍然缺乏运动，能量消耗较低，BAT受损，并发生肥胖。这些数据为下丘脑POMC神经元的功能异质性提供了支持，揭示了在表达5-HT2CR的神经元中POMC的表达足以调节雌雄小鼠的能量摄入和胰岛素敏感性。然而，在能量消耗方面，POMC神经元的这一子集的功能存在意想不到的性别差异。我们发现，在身体活动、能量消耗和肥胖发展方面的巨大性别差异是由这一亚群驱动的，这一亚群约占下丘脑弓状核中所有POMC神经元的40%。这可能对用于对抗肥胖的策略有广泛的影响，目前这些策略在很大程度上忽略了肥胖个体的性别。5-HT2CRYFP小鼠系的生成显示，雄性和雌性小鼠下丘脑POMC神经元中有40%共表达5-HT2CRs。在5-HT2CR细胞中表达的Pomc调节雄性和雌性小鼠的能量摄入和胰岛素敏感性。在体力活动和能量消耗方面意想不到的性别差异是由下丘脑Pomc调节的。仅在5-HT2CR细胞内表达的Pomc对雄性和雌性小鼠体重积累的影响是不同的。
Obesity is one of the primary healthcare challenges of the 21st century. Signals relaying information regarding energy needs are integrated within the brain to influence body weight. Central among these integration nodes are the brain pro-opiomelanocortin (POMC) peptides, perturbations of which disrupt energy balance and promote severe obesity. However, POMC neurons are neurochemically diverse and the crucial source of POMC peptides that regulate energy homeostasis and body weight remains to be fully clarified. Given that a 5-hydroxytryptamine 2c receptor (5-HT2CR) agonist is a current obesity medication and 5-HT2CR agonist's effects on appetite are primarily mediated via POMC neurons, we hypothesized that a critical source of POMC regulating food intake and body weight is specifically synthesized in cells containing 5-HT2CRs. To exclusively manipulate Pomc synthesis only within 5-HT2CR containing cells, we generated a novel 5-HT2CRCRE mouse line and intercrossed it with Cre recombinase-dependent and hypothalamic specific reactivatable PomcNEO mice to restrict Pomc synthesis to the subset of hypothalamic cells containing 5-HT2CRs. This provided a means to clarify the specific contribution of a defined subgroup of POMC peptides in energy balance and body weight. Here we transform genetically programed obese and hyperinsulinemic male mice lacking hypothalamic Pomc with increased appetite, reduced physical activity and compromised brown adipose tissue (BAT) into lean, healthy mice via targeted restoration of Pomc function only within 5-HT2CR expressing cells. Remarkably, the same metabolic transformation does not occur in females, who despite corrected feeding behavior and normalized insulin levels remain physically inactive, have lower energy expenditure, compromised BAT and develop obesity. These data provide support for the functional heterogeneity of hypothalamic POMC neurons, revealing that Pomc expression within 5-HT2CR expressing neurons is sufficient to regulate energy intake and insulin sensitivity in male and female mice. However, an unexpected sex difference in the function of this subset of POMC neurons was identified with regard to energy expenditure. We reveal that a large sex difference in physical activity, energy expenditure and the development of obesity is driven by this subpopulation, which constitutes approximately 40% of all POMC neurons in the hypothalamic arcuate nucleus. This may have broad implications for strategies utilized to combat obesity, which at present largely ignore the sex of the obese individual. Generation of 5-HT2CRYFP mouse line revealed 40% of hypothalamic POMC neurons co-express 5-HT2CRs in male and female mice. Pomc expressed exclusively within 5-HT2CR cells modulates energy intake and insulin sensitivity in male and female mice. An unexpected sex difference in physical activity and energy expenditure is modulated by hypothalamic Pomc. Pomc expressed exclusively within 5-HT2CR cells differentially impacts body weight accumulation in male and female mice.