TRPM2 Ca2+ channel regulates energy balance and glucose metabolism

• Published in: American journal of physiology: endocrinology and metabolism Vol. 302; no. 7; pp. E807 - E816
• Main Authors: Zhang, Zhiyou, Zhang, Wenyi, Jung, Dae Young, Ko, Hwi Jin, Lee, Yongjin, Friedline, Randall H, Lee, Eunjung, Jun, John, Ma, Zhexi, Kim, Francis, Tsitsilianos, Nicholas, Chapman, Kathryn, Morrison, Alastair, Cooper, Marcus P, Miller, Barbara A, Kim, Jason K
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.04.2012
• Subjects: Animals; Blotting, Western; Body Composition - physiology; Body Weight - physiology; Calmodulin - metabolism; Calorimetry, Indirect; Dietary Fats - pharmacology; Energy Metabolism - physiology; Glucose - metabolism; Glucose Clamp Technique; Glucose Tolerance Test; Immunoprecipitation; Inflammation - metabolism; Insulin Receptor Substrate Proteins - metabolism; Insulin Resistance - physiology; Mice; Mice, Knockout; Myocardium - enzymology; Myocardium - metabolism; Oxygen Consumption - physiology; Phosphorylation; RNA - biosynthesis; RNA - genetics; Superoxide Dismutase - metabolism; TRPM Cation Channels - physiology
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00239.2011

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.