A New Role for GPR103b in the Peripheral Regulation of Adipogenesis

Abstract

The activation of G protein-coupled receptor 103 (GPR103) by its endogenous peptidic ligands, QRFPs, is involved in the central regulation of feeding by increasing food intake, body weight, and fat mass after intracerebroventricular injection in mice. However, the role of GPR103 in regulating peripheral metabolic pathways has not yet been explored. The present study aimed to investigate the role of GPR103 in adipogenesis and lipid metabolism using 3T3-L1 adipocyte cells. Our results show that differentiated 3T3-L1 cells expressed the GPR103b subtype mRNA and protein, as well as QRFP mRNA. QRFP-43 and 26 induced an increase in triglyceride accumulation of 50 and 41%, respectively, and elicited a dose-dependent increase in fatty acid uptake, by up to approximately 60% at the highest concentration, in 3T3-L1-differentiated cells. QRFP-43 and 26 inhibited isoproterenol (ISO)-induced lipolysis in a dose-dependent manner, with IC50s of 2.3 1.2 and 1.1 1.0 nM, respectively. The expression of genes involved in lipid uptake (FATP1, CD36, LPL, ACSL1, PPAR, and C/EBP), was increased by 2to 3-fold following treatment with QRFP. The effects of QRFP on ISO-induced lipolysis and fatty acid uptake were abolished when GPR103b was silenced. In a mouse model of diet-induced obesity, the expression of GPR103b in epididymal fat pads was elevated by 16-fold whereas that of QRFP was reduced by 46% compared to lean mice. Furthermore, QRFP was bioactive in omental adipocytes from obese individuals, inhibiting ISO-induced lipolysis in these cells. Our results suggest that GPR103b and QRFP work in an autocrine/paracrine manner to regulate adipogenesis. Foxa1 and Foxa2 Maintain the Metabolic and Secretory Features of the Mature -Cell Nan Gao, John Le Lay, Wei Qin, Nicolai Doliba, Jonathan Schug, Alan J. Fox, Olga Smirnova, Franz M. Matschinsky, and Klaus H. Kaestner (Mol Endocrinol, published June 9, 2010, 10.1210/me.2009-0513) ABSTRACT Foxa1 and Foxa2 play both redundant and distinct roles in early pancreas development. We demonstrate here that inducible ablation of both transcription factors in mature mouse -cells leads to impaired glucose homeostasis and insulin secretion. The defects in both glucose-stimulated insulin secretion and intracellular calcium oscillation are more pronounced than those in -cells lacking only Foxa2. Unexpectedly, in contrast to the severe reduction of -cell-enriched factors contributing to metabolic and secretory pathways, expression of a large number of genes that are involved in neural differentiation and function is significantly elevated. We further demonstrate that expression of carbohydrate response element-binding protein (ChREBP or Mlxipl), an important transcriptional regulator of carbohydrate metabolism, is significantly affected in compound Foxa1/a2 mutant -cells. ChREBP expression is directly controlled by Foxa1 and Foxa2 in both the fetal endocrine pancreas as well as mature islets. These data demonstrate that Foxa1 and Foxa2 play crucial roles in the development and maintenance of -cell-specific secretory and metabolic pathways. 3564 Abstracts Translational Highlights from MOLECULAR ENDOCRINOLOGY J Clin Endocrinol Metab, July 2010, 95(7):3563–3564Foxa1 and Foxa2 play both redundant and distinct roles in early pancreas development. We demonstrate here that inducible ablation of both transcription factors in mature mouse -cells leads to impaired glucose homeostasis and insulin secretion. The defects in both glucose-stimulated insulin secretion and intracellular calcium oscillation are more pronounced than those in -cells lacking only Foxa2. Unexpectedly, in contrast to the severe reduction of -cell-enriched factors contributing to metabolic and secretory pathways, expression of a large number of genes that are involved in neural differentiation and function is significantly elevated. We further demonstrate that expression of carbohydrate response element-binding protein (ChREBP or Mlxipl), an important transcriptional regulator of carbohydrate metabolism, is significantly affected in compound Foxa1/a2 mutant -cells. ChREBP expression is directly controlled by Foxa1 and Foxa2 in both the fetal endocrine pancreas as well as mature islets. These data demonstrate that Foxa1 and Foxa2 play crucial roles in the development and maintenance of -cell-specific secretory and metabolic pathways. 3564 Abstracts Translational Highlights from MOLECULAR ENDOCRINOLOGY J Clin Endocrinol Metab, July 2010, 95(7):3563–3564