AMPK and insulin action

The 59-AMP-activated protein kinase (AMPK) is considered ‘‘a metabolic master-switch’’ in skeletal muscle reducing ATPconsuming processes whilst stimulating ATP regeneration. Within recent years, AMPK has also been proposed as a potential target to attenuate insulin resistance, although the exact role of AMPK is not well understood. Here we hypothesized that mice lacking a2AMPK activity in muscle would be more susceptible to develop insulin resistance associated with ageing alone or in combination with high fat diet. Young (,4 month) or old (,18 month) wild type and muscle specific a2AMPK kinase-dead mice on chow diet as well as old mice on 17 weeks of high fat diet were studied for whole body glucose homeostasis (OGTT, ITT and HOMA-IR), insulin signaling and insulin-stimulated glucose uptake in muscle. We demonstrate that high fat diet in old mice results in impaired glucose homeostasis and insulin stimulated glucose uptake in both the soleus and extensor digitorum longus muscle, coinciding with reduced insulin signaling at the level of Akt (pSer473 and pThr308), TBC1D1 (pThr590) and TBC1D4 (pThr642). In contrast to our hypothesis, the impact of ageing and high fat diet on insulin action was not worsened in mice lacking functional a2AMPK in muscle. It is concluded that a2AMPK deficiency in mouse skeletal muscle does not cause muscle insulin resistance in young and old mice and does not exacerbate obesityinduced insulin resistance in old mice suggesting that decreased a2AMPK activity does not increase susceptibility for insulin resistance in skeletal muscle. Citation: Frøsig C, Jensen TE, Jeppesen J, Pehmøller C, Treebak JT, et al. (2013) AMPK and Insulin Action Responses to Ageing and High Fat Diet. PLoS ONE 8(5): e62338. doi:10.1371/journal.pone.0062338 Editor: Hemachandra Reddy, Oregon Health & Science University, United States of America Received December 13, 2012; Accepted March 20, 2013; Published May 6, 2013 Copyright: 2013 Frøsig et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the Lundbaek Foundation, Denmark, The Danish Medical Research Council, Denmark, The Danish Agency of Science, Technology and Innovation, The Danish Ministry of Food, Agriculture and Fisheries, The Novo Nordisk Foundation, and the Danish Diabetes Association. The Molecular Physiology group, Department of Nutrition, Exercise and Sports is part of the August Krogh Centre and the UNIversal Kit Project: Food, Fitness & Pharma for Health and Disease, supported by the Danish Ministry of Science, Technology and Innovation. TEJ and JTT were supported by a postdoctoral fellowship from The Danish Agency for Science, Technology and Innovation. JJ was supported by a research fellowship from The Alfred Benzon Foundation. PS was supported by the Nordea Foundation (Healthy Aging Grant). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center, based at the University of Copenhagen, Denmark and partially funded by an unconditional donation from the Novo Nordisk Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: cfrosig@ifi.ku.dk ¤a Current address: Section on Integrative Physiology, The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark ¤b Current address: Clinical Pharmacology Oral Delivery, Novo Nordisk, Søborg, Denmark ¤c Current address: Department of Endocrinology, Odense University Hospital, and Section of Molecular Diabetes & Metabolism, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark