Genetic Analysis of Insulin and Insulin-like Growth Factor-1 Signaling in the Central Nervous System

Much of our understanding about insulin has been gained from murine knockouts of the insulin receptor (IR) gene in the whole body or restricted to individual tissues. Here, two novel inducible mouse models with IR inactivation in all tissues including brain (IRwb) or restricted to peripheral tissues (IRper) are described. Crucially, mouse models with inducible deletion later in life allow for the distinction between developmental and acute effects of insulin resistance. Compared to IRper mice, body wide deletion of IR has a more pronounced effect on reducing white adipose tissue mass (WAT), despite a similar reduction in IR expression in WAT of both models. The more pronounced lipodystrophy in IRwb mice points to a novel regulatory function of central insulin receptor signaling in control of lipogenesis which is substantiated by the ability of intracerebroventricularly applied insulin in C57BL/6 mice to slightly increase adipocyte size, fat mass and white adipose tissue lipoprotein lipase expression. Moreover, loss of insulin receptor signaling in adipocytes results in an increase in leptin secretion from the adipose tissue, indicating that insulin inhibits adipocyte-autonomous leptin secretion. In addition to the increase in leptin secretion, both strains display a dramatic upregulation of hepatic leptin receptor expression, while only IRper mice exhibit increased Stat-3 phosphorylation and IL-6 expression. IRwb mice, on the other hand, display a higher degree of impaired peripheral glucose metabolism, which is ameliorated by leptin administration along with Stat-3 phosphorylation. Furthermore, despite exhibiting largely reduced IR expression in pancreas, IRper mice still secrete insulin in response to an acute glucose challenge, whereas glucose-stimulated insulin secretion is abrogated in IRwb mice, but both mouse models respond to hyperglycemia with a significant increase in beta cell mass. In conclusion, these findings define CNS insulin action as a pivotal determinant of energy homeostasis and peripheral glucose metabolism in the adult mouse and support recent findings on the regulation of hepatic IL-6 mRNA by central insulin. Nevertheless, leptin-activated Stat-3 phosphorylation in liver may alternatively lead to improved glucose metabolism in IRwb mice. Furthermore, deletion of the insulin-like growth factor (IGF-) 1 receptor in the central nervous system reveals a significant role for IGF-1 receptor signaling in hippocampal learning and spatial memory acquisition and defines IGF-1R as a potential new therapeutic target in the treatment of conditions linked to anxiety-like behavior