Rab4b controls hepatic glucose production during fasting through glycophagy.

Hepatic glucose production, essential for maintaining glycemia, is often altered in metabolic-associated fatty liver and glycogen storage diseases. Therefore, understanding the mechanisms that regulate the glucose production by hepatocyte is pivotal. Recent studies have identified endocytic trafficking as a key modulator of liver glucose production. Particularly, its role in directing protein trafficking toward lysosomal degradation influences gluconeogenesis. However, the contribution of endocytic recycling to liver glucose production remains yet poorly understood. Here, we demonstrate that hepatocyte-specific disruption of endocytic recycling, achieved through Rab4b knockout in male, leads to fasting hyperglycemia. Mechanistically, hepatocytes lacking Rab4b exhibit an increased capacity to produce glucose independently of gluconeogenesis by depleting their glycogen stores. This is driven by enhanced glycophagy, leading to excessive glucose release and fasting hyperglycemia. Notably, liver Rab4b expression also correlates with glycemia in both mice and human, highlighting a critical role of Rab4b-dependent endocytic recycling in regulating blood glucose homeostasis during fasting.