title: Inactivation of MARK4, an AMP-activated protein kinase (AMPK)-related kinase, leads to insulin hypersensitivity and resistance to diet-induced obesity.
abstract: MARK4, also known as Par-1d/MarkL1, is a member of the AMP-activated protein kinase (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 for 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 protection from diet-induced obesity and its related metabolic complications through up-regulation of brown fat activity. Consequently, MARK4 deficiency mitigated 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 up-regulating the activity and expression of AMPK kinase in key metabolic tissues. Taken together, these data identify 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.
authors.affiliation: College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Sun
authors.forename: Liang
authors.initials: L
authors.lastname: Tian
authors.forename: Jia
authors.initials: J
authors.lastname: Nie
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000201:enzymology / Q000235:genetics; D004041:Dietary Fats / Q000009:adverse effects; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D006963:Hyperphagia / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000201:enzymology / Q000209:etiology / Q000235:genetics*; D010101:Oxygen Consumption / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; C482979:MARK4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D005947:Glucose