Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.
Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.
复制标题
DOI：
10.1016/j.cmet.2016.04.003
复制
发表时间：
2016-05-10
期刊：
影响因子：
29
通讯作者：
Ashrafian H
中科院分区：
文献类型：
--
作者：
Yavari A;Stocker CJ;Ghaffari S;Wargent ET;Steeples V;Czibik G;Pinter K;Bellahcene M;Woods A;Martínez de Morentin PB;Cansell C;Lam BY;Chuster A;Petkevicius K;Nguyen-Tu MS;Martinez-Sanchez A;Pullen TJ;Oliver PL;Stockenhuber A;Nguyen C;Lazdam M;O'Dowd JF;Harikumar P;Tóth M;Beall C;Kyriakou T;Parnis J;Sarma D;Katritsis G;Wortmann DD;Harper AR;Brown LA;Willows R;Gandra S;Poncio V;de Oliveira Figueiredo MJ;Qi NR;Peirson SN;McCrimmon RJ;Gereben B;Tretter L;Fekete C;Redwood C;Yeo GS;Heisler LK;Rutter GA;Smith MA;Withers DJ;Carling D;Sternick EB;Arch JR;Cawthorne MA;Watkins H;Ashrafian H
尽管我们对决定全身能量稳态的生物学的理解取得了重大进展，但肥胖症的治疗仍然是一个医学挑战。腺苷酸活化蛋白激酶（AMPK）的激活已被提出作为一个有吸引力的策略，用于治疗肥胖及其并发症。AMPK是一种保守的、广泛表达的异源三聚体丝氨酸/苏氨酸激酶，其短期活化具有多种有益的代谢效应。这些是否转化为肥胖及其并发症的长期益处尚不清楚。在此，我们观察到AMPK γ2亚基突变导致AMPK慢性激活的小鼠表现出ghrelin信号依赖性食欲过盛、肥胖和胰岛胰岛素分泌受损。携带同源突变的人类表现出一致的表型。我们的研究强调，在所有组织中长期激活AMPK可能会产生不良的代谢后果，这对寻求长期全身激活AMPK以治疗代谢疾病的药理学策略具有影响。小鼠中γ2 AMPK的激活突变导致肥胖并损害胰岛素分泌这部分是由于生长激素释放肽信号依赖性摄食过多的增加。具有同源γ2突变的人类显示了小鼠表型的关键方面这些发现对旨在激活AMPK的治疗策略具有意义AMPK是肥胖症有希望的治疗靶点。Yavari等人揭示了携带活化γ2突变的小鼠中AMPK慢性活化的潜在后果，其导致肥胖、摄食过多和胰岛素分泌受损。在携带该突变的人中也观察到肥胖增加和β细胞功能降低。
Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease. An activating mutation of γ2 AMPK in mice causes obesity and impairs insulin secretion This occurs in part due to augmentation of ghrelin signaling-dependent hyperphagia Humans with the homologous γ2 mutation show key aspects of the murine phenotype These findings have implications for therapeutic strategies that aim to activate AMPK AMPK is a promising therapeutic target for obesity. Yavari et al. reveal the potential consequences of chronic AMPK activation in mice carrying an activating γ2 mutation, which results in obesity, hyperphagia, and impaired insulin secretion. Increased adiposity and reduced β cell function are also observed in humans bearing this mutation.