Abstract
SummaryDespite 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.
Highlights
Obesity affects an estimated 34.9% of adults in the United States and is a major contributor to chronic diseases associatedCell Metabolism 23, 821–836, May 10, 2016 a 2016 The Authors
Generation and Analysis of R299Q g2 AMPK Knockin Mice To test the consequences of chronic AMPK activation in vivo, we introduced an R299Q mutation into the murine Prkag2 gene
Using a pan-b AMPK subunit antibody for immunoprecipitation, we observed a corresponding increase in total AMPK activity in hepatocytes from homozygous R299Q g2 mice (Figure 1C); this increase was observed in white adipose tissue (WAT) and striated muscle rapidly extracted under anesthesia to prevent changes in AMPK activation during tissue harvesting (Figures S1A and S1B, available online)
Summary
Cell Metabolism 23, 821–836, May 10, 2016 a 2016 The Authors. With premature death or disability, including the metabolic syndrome type 2 diabetes mellitus (T2DM) and malignancy (Bauer et al, 2014; Ogden et al, 2014). While substantial progress has been made in understanding the mammalian energy balance circuitry (Flier, 2004; Yeo and Heisler, 2012), existing obesity medications exploiting these pathways are few and of limited efficacy, complicating longterm treatment strategies (Dietrich and Horvath, 2012). An attractive target for obesity and related complications is AMP-activated protein kinase (AMPK). AMPK triggers catabolic ATP-generating processes while repressing anabolic biosynthesis, to restore cellular energy homeostasis (Hardie, 2014)
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