For reprint orders, please contact: reprints@futuremedicine.com 465 ISSN 1758-4299 Clin. Lipidol. (2009) 4(4), 465–477 10.2217/CLP.09.30 © 2009 Future Medicine Ltd Review Remodeling glucose and lipid metabolism through AMPK activation: relevance for treating obesity and Type 2 diabetes The prevalence of obesity has reached epidemic proportions worldwide and it is a major risk fac- tor for a number of disorders including Type 2 diabetes (T2D). The current nonpharmaco- logical strategies available to treat obesity involve a regimen of diet and exercise in order to maintain a negative energy balance condition for weight loss. Although relatively effective in the short term, these approaches frequently lead to poor long-term weight-loss results (90–95% of adults and children who lose weight gain it back) [1] , suggesting that attempts to alter body weight are opposed by systems of energy home- ostasis that upregulate food intake and decrease metabolic rate in order to maintain an indi- vidualized weight ‘set point’. Overcoming this defensive mechanism has become a major obsta- cle in the treatment of obesity and metabolic disease. In recent years, AMP-activated protein kinase (AMPK) has emerged as a potential pharmacological target to promote energy dis- sipation by regulating lipid metabolism. AMPK is an enzyme that serves as a ‘fuel gauge’ that monitors changes in the energy status of cells. When activated, AMPK upregulates catabolic processes to generate ATP (i.e., glucose uptake and fatty acid oxidation) and suppresses energy- consuming pathways (i.e., lipogenesis and pro- tein synthesis) that are not required for acute cell survival. Since obesity is characterized by excessive accumulation of fat, and stimulation of fatty acid (FA) oxidation is one of the major effects of AMPK in peripheral tissues, physio- logical activation of AMPK to promote fat oxi- dation has become of great therapeutic interest. This review is focused on the recent findings on the role of AMPK in regulating lipid metabolism in skeletal muscle, liver and adipose tissue, and the therapeutic importance of this energy sensor in the treatment of obesity and T2D. Structure & regulation of AMPK AMPK is a well-conserved heterotrimeric enzyme composed of a catalytic subunit ( α) and two regulatory subunits ( β and γ ). Multiple isoforms of each mammalian subunit exist (α1, α2, β1, β2 and γ1– γ 3) and are differentially expressed in various tissues. The existence of various isoforms of each subunit enables the potential formation of 12 heterotrimer com- binations that are thought to exhibit differ- ences in subcellular localization and signaling functions [2] . The N-terminus portion of the α-catalytic subunit has a serine/threonine pro- tein kinase domain, while the C-terminal region contains the β1-binding domain required for the formation of the heterotrimer complex [3] . The β-subunit serves as a scaffold that allows the assembly of the αβγ complex, and also contains the glycogen-binding domain (GBD), which is In recent years, AMP-activated protein kinase (AMPK) has emerged as a potential target for physiological and pharmacologic treatment of several metabolic disorders. AMPK is a heterotrimeric enzyme that has been proposed to function as a ‘fuel gauge’ that monitors changes in the energy status of cells. One pathway that is central to the integrated effects of AMPK in peripheral tissues is the stimulation of fatty acid oxidation and prevention of intracellular lipid accumulation, which could exert an important antilipotoxic effect and be of great relevance for the treatment of obesity and Type 2 diabetes. Here, we review the recent advances in the physiological role of AMPK in the regulation of lipid metabolism in peripheral tissues, and the molecular mechanisms involved in these processes. Furthermore, we focus on the relevance of AMPK activation in regulating lipid homeostasis in metabolic diseases, such as obesity and Type 2 diabetes. KEYWORDS: adipose tissue n AMPK n fatty acid oxidation n lipotoxicity n liver n obesity n skeletal muscle n Type 2 diabetes Mandeep Pinky Gaidhu 1 & Rolando Bacis Ceddia 1† † Author for correspondence: 1 School of Kinesiology & Health Science, York University, 4700 Keele St, Toronto, ON M3J 1P3, Canada Tel.: +1 416 736 2100 ext. 77204 Fax: +1 416 736 5774 roceddia@yorku.ca