title: TRPM2 Ca2+ channel regulates energy balance and glucose metabolism.
abstract: TRPM2 Ca(2+)-permeable cation channel is widely expressed and activated by markers of cellular stress. Since inflammation and stress play a major role in insulin resistance, we examined the role of TRPM2 Ca(2+) channel in glucose metabolism. A 2-h hyperinsulinemic euglycemic clamp was performed in TRPM2-deficient (KO) and wild-type mice to assess insulin sensitivity. To examine the effects of diet-induced obesity, mice were fed a high-fat diet for 4-10 mo, and metabolic cage and clamp studies were conducted in conscious mice. TRPM2-KO mice were more insulin sensitive partly because of increased glucose metabolism in peripheral organs. After 4 mo of high-fat feeding, TRPM2-KO mice were resistant to diet-induced obesity, and this was associated with increased energy expenditure and elevated expressions of PGC-1α, PGC-1β, PPARα, ERRα, TFAM, and MCAD in white adipose tissue. Hyperinsulinemic euglycemic clamps showed that TRPM2-KO mice were more insulin sensitive, with increased Akt and GSK-3β phosphorylation in heart. Obesity-mediated inflammation in adipose tissue and liver was attenuated in TRPM2-KO mice. Overall, TRPM2 deletion protected mice from developing diet-induced obesity and insulin resistance. Our findings identify a novel role of TRPM2 Ca(2+) channel in the regulation of energy expenditure, inflammation, and insulin resistance.
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, USA.
authors.forename: Zhiyou
authors.initials: Z
authors.lastname: Zhang
authors.forename: Wenyi
authors.initials: W
authors.lastname: Zhang
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Jung
authors.forename: Hwi Jin
authors.initials: HJ
authors.lastname: Ko
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Lee
authors.forename: Randall H
authors.initials: RH
authors.lastname: Friedline
authors.forename: Eunjung
authors.initials: E
authors.lastname: Lee
authors.forename: John
authors.initials: J
authors.lastname: Jun
authors.forename: Zhexi
authors.initials: Z
authors.lastname: Ma
authors.forename: Francis
authors.initials: F
authors.lastname: Kim
authors.forename: Nicholas
authors.initials: N
authors.lastname: Tsitsilianos
authors.forename: Kathryn
authors.initials: K
authors.lastname: Chapman
authors.forename: Alastair
authors.initials: A
authors.lastname: Morrison
authors.forename: Marcus P
authors.initials: MP
authors.lastname: Cooper
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Miller
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001823:Body Composition / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D002147:Calmodulin / Q000378:metabolism; D002153:Calorimetry, Indirect; D004041:Dietary Fats / Q000494:pharmacology; D004734:Energy Metabolism / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D047468:Immunoprecipitation; D007249:Inflammation / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology; D010766:Phosphorylation; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism; D050053:TRPM Cation Channels / Q000502:physiology*
chemical_list: D002147:Calmodulin; D004041:Dietary Fats; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D012313:RNA; D013482:Superoxide Dismutase; D005947:Glucose