Department of Molecular Pharmacology and Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
J Biol Chem. 2011 Sep 16;286(37):32324-32. doi: 10.1074/jbc.M111.254417. Epub 2011 Jul 22.
Autophagy has been recently demonstrated to control cell and tissue homeostasis, including the functions of various metabolic tissues. However, it remains unclear whether autophagy is critical for the central nervous system and particularly the hypothalamus for exerting metabolic regulation. Using autophagy-related protein 7 (Atg7) as an autophagic marker, this work showed that autophagy was highly active in the mediobasal hypothalamus of normal mice. In contrast, chronic development of dietary obesity was associated with autophagic decline in the mediobasal hypothalamus. To investigate the potential role of autophagy in the hypothalamic control of metabolic physiology, a mouse model was developed with autophagic inhibition in the mediobasal hypothalamus using site-specific delivery of lentiviral shRNA against Atg7. This model revealed that hypothalamic inhibition of autophagy increased energy intake and reduced energy expenditure. These metabolic changes were sufficient to increase body weight gain under normal chow feeding and exacerbate the progression of obesity and whole-body insulin resistance under high-fat diet feeding. To explore the underlying mechanism, this study found that defective hypothalamic autophagy led to hypothalamic inflammation, including the activation of proinflammatory IκB kinase β pathway. Using brain-specific IκB kinase β knockout mice, it was found that the effects of defective hypothalamic autophagy in promoting obesity were reversed by IκB kinase β inhibition in the brain. In conclusion, hypothalamic autophagy is crucial for the central control of feeding, energy, and body weight balance. Conversely, decline of hypothalamic autophagy under conditions of chronic caloric excess promotes hypothalamic inflammation and thus impairs hypothalamic control of energy balance, leading to accelerated development of obesity and comorbidities.
自噬最近被证明可以控制细胞和组织的稳态，包括各种代谢组织的功能。然而，自噬对于中枢神经系统，特别是下丘脑发挥代谢调节作用是否至关重要仍不清楚。本研究使用自噬相关蛋白 7（Atg7）作为自噬标志物，结果表明自噬在正常小鼠的中脑基底部下丘脑高度活跃。相比之下，饮食诱导的肥胖慢性发展与中脑基底部下丘脑的自噬下降有关。为了研究自噬在下丘脑代谢生理学控制中的潜在作用，利用针对 Atg7 的特异性慢病毒 shRNA 在中脑基底部下丘脑建立了自噬抑制的小鼠模型。该模型揭示了下丘脑自噬抑制增加了能量摄入并减少了能量消耗。这些代谢变化足以在正常饲料喂养下增加体重增加，并在高脂肪饮食喂养下加剧肥胖和全身胰岛素抵抗的进展。为了探索潜在的机制，本研究发现下丘脑自噬缺陷导致下丘脑炎症，包括促炎 IκB 激酶β通路的激活。利用大脑特异性 IκB 激酶β敲除小鼠发现，在大脑中抑制 IκB 激酶β可以逆转下丘脑自噬缺陷促进肥胖的作用。总之，下丘脑自噬对于摄食、能量和体重平衡的中枢控制至关重要。相反，在慢性热量过剩的情况下，下丘脑自噬的下降会促进下丘脑炎症，从而损害下丘脑对能量平衡的控制，导致肥胖及其合并症的加速发展。
