title: Convergence of IPMK and LKB1-AMPK signaling pathways on metformin action.
abstract: Metformin is a biguanide drug that is widely prescribed for type 2 diabetes. Metformin suppresses hepatic gluconeogenesis and increases fatty acid oxidation. Although studies have suggested that metformin acts, at least in part, via activation of the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) pathway, the specific molecular mechanisms underlying metformin's regulation of glucose and lipid metabolism have not been well delineated. Recently, we have shown that inositol polyphosphate multikinase (IPMK) plays an important role in cellular energy metabolism and glucose-mediated AMPK regulation. Here we investigated the role of IPMK in metformin-induced AMPK activation. We observed that metformin-mediated activation of AMPK was impaired in the absence of IPMK. Overexpression of wild-type IPMK was sufficient to restore LKB1-AMPK activation by either metformin or AICAR in IPMK(-/-) murine embryonic fibroblast cells, suggesting that IPMK may act as an upstream regulator of LKB1-AMPK signaling in response to metformin. Moreover, this regulation was mediated by protein-protein interaction between IPMK and LKB1 as a dominant-negative peptide, which abrogates this interaction, attenuated metformin's ability to activate AMPK. Our data demonstrate that IPMK plays an important role in LKB1/AMPK signaling and may be targeted for treatment of metabolic diseases.
authors.affiliation: Department of Psychiatry and Pharmacology, Center for Neurobiology and Behavior (S.B., Y.C., S.F.K.); and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism and the Institute for Diabetes, Obesity, and Metabolism (R.S.A.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Sookhee
authors.initials: S
authors.lastname: Bang
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Rexford S
authors.initials: RS
authors.lastname: Ahima
authors.forename: Sangwon F
authors.initials: SF
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D055786:Gene Knockout Techniques; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology
chemical_list: D005227:Fatty Acids; D007004:Hypoglycemic Agents; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D017853:Phosphotransferases (Alcohol Group Acceptor); C434257:inositol polyphosphate multikinase; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D005947:Glucose