Abstract
AbstractPancreatic β cells secrete insulin in response to glucose elevation to maintain glucose homeostasis. A complex network of inter-organ communication operates to modulate insulin secretion and regulate glucose levels after a meal. Lipids obtained from diet or generated intracellularly are known to amplify glucose-stimulated insulin secretion, however, the underlying mechanisms are not completely understood. Here, we show that a Drosophila secretory lipase, Vaha (CG8093), is synthesized in the midgut and moves to the brain where it concentrates in the insulin-producing cells in a process requiring Lipid Transfer Particle, a lipoprotein originating in the fat body. In response to dietary fat, Vaha stimulates insulin-like peptide release (ILP), and Vaha deficiency results in reduced circulatory ILP and diabetic features including hyperglycemia and hyperlipidemia. Our findings suggest Vaha functions as a diacylglycerol lipase physiologically, by being a molecular link between dietary fat and lipid amplified insulin secretion in a gut-brain axis.
Funder
U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences
This study was funded by the Center for Cancer Research, National Cancer Institute, NIH, Division of Health and Human Services.
Publisher
Springer Science and Business Media LLC
Reference78 articles.
1. Newsholme, P. & Krause, M. Nutritional regulation of insulin secretion: implications for diabetes. Clin. Biochem Rev. 33, 35–47 (2012).
2. Newsholme, P., Cruzat, V., Arfuso, F. & Keane, K. Nutrient regulation of insulin secretion and action. J. Endocrinol. 221, 105–120 (2014).
3. Stein, D. T. et al. Essentiality of fatty acids for glucose-stimulated insulin secretion in the fasted rat. J. Clin. Invest. 97, 2728–2735 (1996).
4. Itoh, Y. et al. Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422, 173–176 (2003).
5. Yore, M. M. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159, 318–332 (2014).