2492-PUB: KCNK16 Deficiency Protects Mice against High-Fat Diet-Induced Weight Gain

Abstract

Potassium Channel, Two Pore Domain Subfamily K, Member 16 (TALK-1/KCNK16) is a K+ channel protein expressed in human and murine pancreas. Recent research by Vierra et al suggested a regulatory function of KCNK16 in mice for glucose-dependent β-cell second-phase insulin and δ-cell somatostatin secretion and a protective effect on fasting glycemia during 3 weeks high-fat diet (HFD). We tested the hypothesis, that deletion of KCNK16 affects body weight and glucose metabolism in vivo during prolonged HFD feeding. Therefore, we analyzed KCNK16-deficient knockout mice (KCNK16-/-) during HFD up to 21 weeks investigating body weight and composition, insulin sensitivity as well as insulin secretion. In HFD-fed KCNK16-/-, we observed a reduced body weight gain. Both, fat and lean mass were reduced and notably body-length was also significantly shorter. KCNK16-/- mice showed reduced food intake, an elevated oxygen consumption and energy expenditure. KCNK16-/- islets showed enhanced insulin secretion under glucose and GIP-1 simulation, but we did not reveal significant changes in fasting or fed plasma glucose or insulin. We found a moderate decrease in blood glucose during an ipITT. However, we did not observe an enhanced insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps nor a beneficial effect of KCNK16 deficiency on the modulation of in vivo insulin secretion during hyperglycemic clamps in HFD-fed mice. In conclusion, we observed a reduced body weight gain, but also shorter body-length in the KCNK16-deficient mouse model during prolonged HFD feeding. Notably, food intake was reduced while energy expenditure was increased. Disclosure S. Brachs: Employee; Spouse/Partner; Treamid Therapeutics GmbH. Research Support; Self; Sanofi-Aventis Deutschland GmbH. U. Schwahn: Employee; Self; Sanofi-Aventis Deutschland GmbH. K. Steinmeyer: Employee; Self; Sanofi-Aventis Deutschland GmbH. M. Schäfer: Employee; Self; Sanofi-Aventis Deutschland GmbH. J. Gassenhuber: Employee; Self; Sanofi-Aventis Deutschland GmbH. Employee; Spouse/Partner; Sanofi-Aventis Deutschland GmbH. J. Spranger: None. Funding Sanofi Aventis Deutschland GmbH