Spatial regulation of glucose and lipid metabolism by hepatic insulin signaling.

Hepatic insulin sensitivity is critical for systemic glucose and lipid homeostasis. The liver is spatially organized into zones in which hepatocytes express distinct metabolic enzymes; however, the functional significance of this zonation to metabolic dysregulation caused by insulin resistance is undetermined. Here, we used CreER mice to selectively disrupt insulin signaling in periportal (PP) and pericentral (PC) hepatocytes. PP-insulin resistance has been suggested to drive combined hyperglycemia and excess lipogenesis in individuals with type 2 diabetes. However, PP-insulin resistance in mice impaired lipogenesis and suppressed high-fat diet (HFD)-induced hepatosteatosis, despite elevated gluconeogenesis and insulin. In contrast, PC-insulin resistance reduced HFD-induced PC steatosis while preserving normal glucose homeostasis, in part by shifting glycolytic metabolism from the liver to the muscle. These results demonstrate distinct roles of insulin in PP versus PC hepatocytes and suggest that PC-insulin resistance might be therapeutically useful to combat hepatosteatosis without compromising glucose homeostasis.