Ablation of MARK4, an AMPK-related Kinase, Leads to Insulin Hypersensitivity and Resistance to Diet-induced Obesity

MARK4, also known as Par-1d/ MarkL1, is a member of the AMPK-related family of kinases which are implicated in the regulation of dynamic biological functions, including glucose and energy homeostasis. However, the physiological function of MARK4 in mammals remains elusive. Here we investigated a role of MARK4 in regulating energy homeostasis by generating mice with targeted inactivation of the MARK4 gene. We show that MARK4 deficiency in mice caused hyperphagia, hyperactivity, and hypermetabolism, leading to a protection from diet-induced obesity and its related metabolic complications through up-regulation of brown-fat activity. Consequently, MARK4 deficiency mitigates insulin resistance associated with diet-induced obesity by dramatically enhancing insulin-stimulated AKT phosphorylation in major metabolic tissues. Ablation of MARK4 also significantly improved glucose homeostasis by upregulating the activity and expression of AMPK kinase in key metabolic tissues. Taken together, these data identified a key role of MARK4 in energy metabolism, implicating the kinase as a novel drug target for the treatment of obesity and type 2 diabetes. INTRODUCTION The microtubule affinity regulatory kinases (MARKs), which represent the mammalian homologs of nematode Par-1, were originally identified by their ability to phosphorylate microtubule-associated proteins (MAPs), thus to regulate microtubule stability in cultured cells (1). Par-1 is an evolutionarily conserved protein kinase required for polarity in worms, flies, frogs and mammals (2-4). The mammalian Par-1 family consists of four members (Par-1c/Mark1, Par1b/Mark2/Emk, Par-1a/Mark3/C-TAK1, and Par-1d /MARK4/KarkL1), each encoded by a distinct gene that is selectively expressed in multiple tissues (5). Physiological functions of the MARK2 and MARK3 kinase have recently been studied using targeted gene knockout approaches in mice (5,6). Two independently derived mouse lines null for MARK2 have implicated this protein kinase in diverse physiological processes, including fertility (7), immune system homeostasis (8), learning and memory (9), glucose homeostasis, and energy metabolism (6). In addition to MARK2, most information regarding the cell biological functions of the Par-1 kinase comes from studies of MARK3. Specifically, MARK3 has been implicated in pancreatic (10) and hepatocarcinogenesis (11), as well as colorectal tumors (12). Loss of MARK3 also leads to reduced adiposity, resistance to hepatic steatosis, and defective gluconeogenesis. However, the functional roles of MARK1 and MARK4 remain elusive. MARK kinases are members of AMPK-related family of kinases. AMPK is a key regulator of energy homeostasis, and is activated in response to an increase http://www.jbc.org/cgi/doi/10.1074/jbc.M112.388934 The latest version is at JBC Papers in Press. Published on September 19, 2012 as Manuscript M112.388934 Copyright 2012 by The American Society for Biochemistry and Molecular Biology, Inc. by gest on N ovem er 7, 2017 hp://w w w .jb.org/ D ow nladed from