Therapeutic effects of adropin on glucose tolerance and substrate utilization in diet-induced obese mice with insulin resistance

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dc.contributor.authorGao, Suen
dc.contributor.authorMcMillan, Ryan P.en
dc.contributor.authorZhu, Qingzhangen
dc.contributor.authorLopaschuk, Gary D.en
dc.contributor.authorHulver, Matthew W.en
dc.contributor.authorButler, Andrew A.en
dc.contributor.departmentHuman Nutrition, Foods, and Exerciseen
dc.date.accessioned2017-10-12T15:12:51Zen
dc.date.available2017-10-12T15:12:51Zen
dc.date.issued2015-01-17en
dc.description.abstractObjective: The peptide hormone adropin regulates fuel selection preferences in skeletal muscle under fed and fasted conditions. Here, we investigated whether adropin treatment can ameliorate the dysregulation of fuel substrate metabolism, and improve aspects of glucose homeostasis in diet-induced obesity (DIO) with insulin resistance. Methods: DIO C57BL/6 mice maintained on a 60% kcal fat diet received five intraperitoneal (i.p.) injections of the bioactive peptide adropin³⁴⁻⁷⁶(450 nmol/kg/i.p.). Following treatment, glucose tolerance and whole body insulin sensitivity were assessed and indirect calorimetry was employed to analyze whole body substrate oxidation preferences. Biochemical assays performed in skeletal muscle samples analyzed insulin signaling action and substrate oxidation. Results: Adropin treatment improved glucose tolerance, enhanced insulin action and augmented metabolic flexibility towards glucose utilization. In muscle, adropin treatment increased insulin-induced Akt phosphorylation and cell-surface expression of GLUT4 suggesting sensitization of insulin signaling pathways. Reduced incomplete fatty acid oxidation and increased CoA/acetyl-CoA ratio suggested improved mitochondrial function. The underlying mechanisms appear to involve suppressions of carnitine palmitoyltransferase-1B (CPT-1B) and CD36, two key enzymes in fatty acid utilization. Adropin treatment activated pyruvate dehydrogenase (PDH), a rate-limiting enzyme in glucose oxidation, and downregulated PDH kinase-4 (PDK-4) that inhibits PDH. Along with these changes, adropin treatment downregulated peroxisome proliferator-activated receptor-gamma coactivator-1∝ that regulates expression of Cpt1b, Cd36 and Pdk4. Conclusions: Adropin treatment of DIO mice enhances glucose tolerance, ameliorates insulin resistance and promotes preferential use of carbohydrate over fat in fuel selection. Skeletal muscle is a key organ in mediating adropin’s whole-body effects, sensitizing insulin signaling pathways and altering fuel selection preference to favor glucose while suppressing fat oxidation.en
dc.description.sponsorshipThis work was supported by a Proof of Principle Award from Novo Nordisk’s Diabetes Innovation Award Program (to A.A.B.), the National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-078765 to M.W.H), the American Diabetes Association (1-13-CE-16 to M.W.H. and 7-08-RA-16 to A.A.B.) and a grant from the Canadian Diabetes Association (to G.D.L.).en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1016/j.molmet.2015.01.005en
dc.identifier.issue4en
dc.identifier.urihttp://hdl.handle.net/10919/79626en
dc.identifier.volume4en
dc.language.isoenen
dc.publisherElsevieren
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectadropinen
dc.subjectglucose metabolismen
dc.subjectfatty acid metabolismen
dc.subjectinsulin actionen
dc.subjectmetabolic flexibilityen
dc.subjectmitochondrial functionen
dc.titleTherapeutic effects of adropin on glucose tolerance and substrate utilization in diet-induced obese mice with insulin resistanceen
dc.title.serialMolecular Metabolismen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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Scholarly Works, Human Nutrition, Foods, and Exercise