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Chronic Activation of ?2 AMPK Induces Obesity and Reduces ? Cell Function.


ABSTRACT: 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 ?2 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.

SUBMITTER: Yavari A 

PROVIDER: S-EPMC4873618 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.

Yavari Arash A   Stocker Claire J CJ   Stocker Claire J CJ   Ghaffari Sahar S   Wargent Edward T ET   Steeples Violetta V   Czibik Gabor G   Pinter Katalin K   Bellahcene Mohamed M   Woods Angela A   Martínez de Morentin Pablo B PB   Cansell Céline C   Lam Brian Y H BY   Chuster André A   Petkevicius Kasparas K   Nguyen-Tu Marie-Sophie MS   Martinez-Sanchez Aida A   Pullen Timothy J TJ   Oliver Peter L PL   Stockenhuber Alexander A   Nguyen Chinh C   Lazdam Merzaka M   O'Dowd Jacqueline F JF   Harikumar Parvathy P   Tóth Mónika M   Beall Craig C   Kyriakou Theodosios T   Parnis Julia J   Sarma Dhruv D   Katritsis George G   Wortmann Diana D J DD   Harper Andrew R AR   Brown Laurence A LA   Willows Robin R   Gandra Silvia S   Poncio Victor V   de Oliveira Figueiredo Márcio J MJ   Qi Nathan R NR   Peirson Stuart N SN   McCrimmon Rory J RJ   Gereben Balázs B   Tretter László L   Fekete Csaba C   Redwood Charles C   Yeo Giles S H GS   Heisler Lora K LK   Rutter Guy A GA   Smith Mark A MA   Withers Dominic J DJ   Carling David D   Sternick Eduardo B EB   Arch Jonathan R S JR   Cawthorne Michael A MA   Watkins Hugh H   Ashrafian Houman H  

Cell metabolism 20160428 5


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  ...[more]

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