Deficiency of ZnT8 Promotes Adiposity and Metabolic Dysfunction by Increasing Peripheral Serotonin Production

• DOI: 10.2337/db18-1321
• Publication Date: 2019-04-02T01:35:19Z
• Authors: Zhuo Mao; Hui Lin; Wen Su; Jinghui Li; Minsi Zhou; Zhuoran Li; Beibei Zhou; Qing Yang; Mingyan Zhou; Ke Pan; Jinhan He; Weizhen Zhang
• Keywords: Mice, Knockout; 2. Zero hunger; 0301 basic medicine; Serotonin; Somatostatin-Secreting Cells; Colon; Enteroendocrine Cells; Zinc Transporter 8; Tryptophan Hydroxylase; Cell Line; Gastrointestinal Microbiome; Mice; 03 medical and health sciences; Diabetes Mellitus, Type 2; Enterochromaffin Cells; Animals; Humans; Energy Metabolism; Gastrointestinal Motility; Adiposity

ZnT8 is a zinc transporter enriched in pancreatic β-cells, and its polymorphism is associated with increased susceptibility to type 2 diabetes. However, the exact role of ZnT8 in systemic energy metabolism remains elusive. In this study, we found that ZnT8 knockout mice displayed increased adiposity without obvious weight gain. We also observed that the intestinal tract morphology, motility, and gut microbiota were changed in ZnT8 knockout mice. Further study demonstrated that ZnT8 was expressed in enteroendocrine cells, especially in 5-hydroxytryptamine (5-HT)–positive enterochromaffin cells. Lack of ZnT8 resulted in an elevated circulating 5-HT level owing to enhanced expression of tryptophan hydroxylase 1. Blocking 5-HT synthesis in ZnT8-deficient mice restored adiposity, high-fat diet–induced obesity, and glucose intolerance. Moreover, overexpression of human ZnT8 diabetes high-risk allele R325W increased 5-HT levels relative to the low-risk allele in RIN14B cells. Our study revealed an unexpected role of ZnT8 in regulating peripheral 5-HT biogenesis and intestinal microenvironment, which might contribute to the increased risk of obesity and type 2 diabetes.