Regulation of ANGPTL8 in Liver and Adipose Tissue by Nutritional and Hormonal Signals and its Effect on Glucose Homeostasis in Mice.

Objective: The angiopoietin-like protein (ANGPTL) family represents a promising therapeutic target for dyslipidemia, which is a feature of obesity and type 2 diabetes (T2DM). The aim of the present study was to determine the metabolic role of ANGPTL8 and to investigate its nutritional, hormonal and molecular regulation in key metabolic tissues. Methods: The regulation of Angptl8 gene expression by insulin and glucose was quantified using a combination of in vivo insulin clamp experiments in mice and in vitro experiments in primary and cultured hepatocytes and adipocytes. The role of AMPK signaling was examined, and the transcriptional control of Angptl8 was determined using bioinformatic and luciferase reporter approaches. The metabolism of Angptl8 knockout mice (ANGPTL8-/- ) was examined in mice following chow and high-fat diets (HFD). Results: Insulin acutely increased Angptl8 expression in liver and adipose tissue, which involved the C/EBPβ transcription factor. In insulin clamp experiments, glucose further enhanced Angptl8 expression in the presence of insulin in adipose tissue. The activation of AMPK signaling antagonized the effect of insulin on Angptl8 expression in hepatocytes and adipocytes. The ANGPTL8-/- mice had improved glucose tolerance and displayed reduced fed and fasted plasma triglycerides. However, there was no change in bodyweight or steatosis in ANGPTL8-/- mice after the HFD. Conclusion: These data show that ANGPTL8 plays important metabolic roles in mice that extend beyond triglyceride metabolism. The finding that insulin, glucose and AMPK signaling regulate Angptl8 expression may provide important clues about the distinct function of ANGPTL8 in these tissues.