HDAC5 in β‐Cells Contributes to the Improvement of Glucose Metabolism Induced by Alternate Day Fasting

ABSTRACT Alternate day fasting (ADF) improves glucose metabolism, but the underlying mechanism remains unclear. In this study, we demonstrate that ADF upregulates HDAC5 in pancreatic β‐cells, which in turn suppresses RASA3 expression, leading to subsequent suppression of β‐cell proliferation, increase of insulin secretion, and improvement of glucose metabolism. Under both normal chow and high‐fat dietary feedings, ADF reduced islet mass, enhanced insulin secretion induced by glucose, and improved glucose tolerance. ADF significantly increased HDAC5 expression in islets. HDAC5 deficiency abrogated the metabolic benefits of ADF, resulting in increased islet area, reduced insulin secretion, and impaired glucose tolerance. Transcriptomic sequencing identified RASA3 as a key downstream molecule. HDAC5 negatively regulated RASA3 in cultured MIN6 cells. Overexpression of RASA3 promoted β‐cell proliferation and reversed the effects of HDAC5. Collectively, this study demonstrates that HDAC5 contributes to the effects of ADF in the improvement of glucose metabolism and provides an alternative strategy for drug targeting that mimics the effects of fasting.