Central insulin action regulates peripheral glucose and fat metabolism in mice

Abstract

Insulin resistance is a hallmark of type 2 diabetes, and many insights into the functions of insulin have been gained through the study of mice lacking the IR. To gain a better understanding of the role of insulin action in the brain versus peripheral tissues, we created 2 mouse models with inducible IR inactivation, 1 in all tissues including brain (IR Δwb ), and 1 restricted to peripheral tissues (IR Δper ). While downregulation of IR expression resulted in severe hyperinsulinemia in both models, hyperglycemia was more pronounced in IR Δwb mice. Both strains displayed a dramatic upregulation of hepatic leptin receptor expression, while only IR Δper mice displayed increased hepatic Stat3 phosphorylation and Il6 expression. Despite a similar reduction in IR expression in white adipose tissue (WAT) mass in both models, IR Δwb mice had a more pronounced reduction in WAT mass and severe hypoleptinemia. Leptin replacement restored hepatic Stat3 phosphorylation and normalized glucose metabolism in these mice, indicating that alterations in glucose metabolism occur largely as a consequence of lipoathrophy upon body-wide IR deletion. Moreover, chronic intracerebroventricular insulin treatment of control mice increased fat mass, fat cell size, and adipose tissue lipoprotein lipase expression, indicating that CNS insulin action promotes lipogenesis. These studies demonstrate that central insulin action plays an important role in regulating WAT mass and glucose metabolism via hepatic Stat3 activation.

Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions

“…This enhancement may occur mainly in the classical insulinsensitive tissues liver [6], adipocytes [7] and muscle [8], as suggested by animal studies.…”

“…Thus insulindependent hepatic glucose production [6], fat metabolism in adipocytes [7] and muscle glycogen synthesis [8] are all influenced by central actions of insulin.…”

Evidence for Central Regulation of Glucose Metabolism

“…Mice with brain insulin receptor inactivation had worse hyperglycemia and failed to increase hepatic STAT3 phosphorylation or up-regulate IL-6 expression. Furthermore, control mice given chronic ICV insulin had increased fat mass and adipose tissue lipoprotein lipase expression (30). This work highlights the importance of central insulin in regulating peripheral glucose and lipid metabolism via hepatic STAT3 activation.…”

“…ICV insulin infusion also failed to increase hepatic STAT3 phosphorylation in mice lacking IL-6 (28), suggesting that central insulin may function via IL-6-mediated hepatic STAT3 activation to suppress EGP. The importance of hepatic STAT3 was further shown in mice with inducible insulin receptor inactivation, either in the whole body or in peripheral tissues only (30). Mice with brain insulin receptor inactivation had worse hyperglycemia and failed to increase hepatic STAT3 phosphorylation or up-regulate IL-6 expression.…”

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

“…Whether leptin's actions on brain neurons can robustly improve hyperglycemia (and other metabolic imbalances) in the context of insulin deficiency has not been tested. Recently, however, exciting results have indicated that overt hyperglycemia and death caused by insulin signaling deficiency can be reversed by leptin therapy alone (25,26), thus suggesting that insulin is dispensable for the glycemia-lowering actions of leptin. Nevertheless, the mechanism(s) by which leptin monotherapy improves T1D is unknown.…”