上海生科院发现:糖皮质激素引起肥胖的中枢调控机制
近日,中国科学院上海生命科学研究院(人口健康领域)营养代谢与食品安全重点实验室郭非凡组的研究论文,以SGK1/FOXO3 signaling in hypothalamic POMC neurons mediates glucocorticoid-increased adiposity为题,在线发表在Diabetes上,该研究发现下丘脑在慢性糖皮质激素引起肥胖中的作用与机理。


本文转载自“上海生命科学研究院”。

糖皮质激素,因为由肾上腺皮质分泌且调节糖代谢而得名,它对机体的发育、生长、代谢以及免疫功能等起重要调节作用,是机体应激反应最重要的调节激素,也是临床上使用最广泛与有效的抗炎、抗休克药物和免疫抑制剂。这类药物虽然非常有效,但存在许多副作用,比如造成脂肪组织的异常堆积等。长期服用该药物的病人呈现向心性肥胖,而其中的调控机制仍不清楚。

下丘脑是间脑的组成部分,是调节内脏及内分泌活动的中枢。在下丘脑弓形核(ARC)中,含有两类调节能量代谢的神经元:一类是促进食欲的刺鼠肽基因相关蛋白(AgRP)神经元;另一类是抑制食欲的阿黑皮素原(POMC)神经元。POMC神经元通过释放阿黑皮素原的剪切产物促黑激素(α-MSH),一方面抑制食欲,另一方面通过调节交感神经系统的兴奋性来影响机体的能量消耗。而特异神经元如POMC是否及如何调控糖皮质激素引起的肥胖未有报道。

在上海生科院研究员郭非凡的指导下博士研究生邓雅岚等发现,虽然血清和糖皮质激素调控激酶1(SGK1)是地塞米松激活的经典下游,但其在POMC神经元中的表达却可被慢性地塞米松处理所抑制。这暗示POMC神经元中SGK1可能在糖皮质激素引起的肥胖中有重要作用。研究人员利用组织特异性基因敲除技术,在受精卵和成年小鼠POMC神经元中特异性敲除SGK1基因。分析发现这些基因敲除鼠可以模拟慢性地塞米松引起的肥胖和能量消耗降低。与之相反,在小鼠的POMC神经元中特异性持续过表达SGK1会出现相反表型,并能够缓解慢性地塞米松处理诱导的肥胖。进一步对其作用机制的探究发现,地塞米松通过SGK1/FOXO3信号通路降低下丘脑的Pomc的表达以及α-MSH的含量,在脑室注射α-MSH或利用腺病毒介导弓状核部位FOXO3的敲低都能极大逆转SGK1敲除小鼠变胖的代谢表型。


下丘脑POMC神经元SGK1/FOXO3信号调控慢性糖皮质激素引起的肥胖

该研究发现SGK1/FOXO3信号在下丘脑POMC神经元中调节糖皮质激素引起的肥胖的重要功能,为了解糖皮质激素与脂肪异常堆积之间的关系提供了新的见解与思路,也提示下丘脑中SGK1/FOXO3信号可能是治疗肥胖以及相关代谢性疾病新的潜在药物靶点。

研究工作得到了国家自然科学基金、上海市科委以及中科院等科研基金的支持。

所有文章仅代表作者观点,不代表本站立场。如若转载请联系原作者。
查看更多
  • SGK1/FOXO3 Signaling in Hypothalamic POMC Neurons Mediates Glucocorticoid-Increased Adiposity

    Although central nervous system has been implicated in glucocorticoid-induced fat mass gain, the underlying mechanisms are poorly understood. The aim of our current study was to investigate the possible involvement of hypothalamic serum- and glucocorticoid-regulated kinase 1 (SGK1) in glucocorticoid-increased adiposity. It is well-known that SGK1 expression is induced by acute glucocorticoid treatment, interestingly, we found its expression was decreased in the arcuate nucleus of the hypothalamus, including POMC neurons, following chronic dexamethasone (Dex) treatment. To study a role of SGK1 in POMC neurons, mice with development or adult-onset SGK1 deletion in POMC neurons (PSKO) were then produced. As observed in Dex-treated mice, PSKO mice exhibited increased adiposity and decreased energy expenditure. Consistently, mice overexpressing constitutively active SGK1 in POMC neurons (PSOE) had the opposite phenotype and prevented from Dex-increased adiposity. Finally, Dex decreased hypothalamic α-melanocyte stimulating hormone (α-MSH) content and its precursor Pomc expression via SGK1/Forkhead box O3 (FOXO3) signaling and intracerebroventricular injection of α-MSH or adenovirus-mediated FOXO3 knockdown in ARC largely reversed the metabolic alterations in PSKO mice. These results demonstrate that POMC SGK1/FOXO3 signaling mediates glucocorticoid-increased adiposity, providing new insights into mechanistic link between glucocorticoid and fat accumulation and important hints for possible treatment targets for obesity.

    展开 收起
发表评论 我在frontend\modules\comment\widgets\views\文件夹下面 test