Transgenic Mice Overexpressing Nuclear SREBP-1c in Pancreatic β-Cells

Transgenic Mice Overexpressing Nuclear SREBP-1c in Pancreatic β-Cells Akimitsu Takahashi 1 , Kaori Motomura 1 , Toyonori Kato 1 , Tomohiro Yoshikawa 1 , Yoshimi Nakagawa 1 2 , Naoya Yahagi 2 , Hirohito Sone 1 , Hiroaki Suzuki 1 , Hideo Toyoshima 1 , Nobuhiro Yamada 1 and Hitoshi Shimano 1 2 1 Department of Internal Medicine (Metabolism and Endocrinology), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan 2 Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan Address correspondence and reprint requests to Hitoshi Shimano, MD, PhD, Department of Internal Medicine, Institute of Clinical Medicine and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tennodai, Tsukuba, Ibaraki 305-8575, Japan. E-mail: shimano-tky{at}umin.ac.jp Abstract Influx of excess fatty acids and the resultant accumulation of intracellular triglycerides are linked to impaired insulin secretion and action in the pathogenesis of type 2 diabetes. Sterol regulatory element-binding protein (SREBP)-1c is a transcription factor that controls cellular synthesis of fatty acids and triglycerides. SREBP-1c is highly expressed in high-energy and insulin-resistant states. To investigate effects of this synthetic lipid regulator on insulin secretion, we generated transgenic mice overexpressing nuclear SREBP-1c under the insulin promoter. β-Cell-specific expression of SREBP-1c caused reduction in islet mass and impaired glucose-stimulated insulin secretion and was associated with accumulation of triglycerides, suppression of pancreas duodenal homeobox-1, and upregulation of uncoupling protein 2 gene expression. The mice presented with impaired glucose tolerance that was exacerbated by a high-energy diet. Taken together with enhanced insulin secretion from SREBP-1-null islets, these data suggest that SREBP-1c and endogenous lipogenesis could be involved in β-cell dysfunction and diabetes. CPT, carnitine palmitoyltransferase FAS, fatty acid synthase FFA, free fatty acid GSIS, glucose-stimulated insulin secretion HFHS, high fat/high sucrose IGT, impaired glucose tolerance IRS, insulin receptor substrate KRBH, Krebs-Ringer bicarbonate buffer with 10 mmol/l HEPES Nkx6.1, NK6 transcription factor related, locus 1 Pdx, pancreas duodenal homeobox RIP, rat insulin I promoter SCD, stealyl CoA desaturase SREBP, sterol regulatory element-binding protein UCP, uncoupling protein Footnotes A.T.