The insulin receptor (IR) is expressed widely throughout the brain (1); however, unlike insulin in peripheral tissues whose major function is regulation of glucose metabolism, the actions of insulin in the brain are less glucocentric. Glucose enters neurons and glia of the brain primarily through the facilitative glucose transporters GLUT1 and GLUT3 (2), which are not insulin dependent. Despite being dispensable for glucose entry into the brain, early work by Woods et al.(3) and others (reviewed in ref. 1) demonstrated that intracerebroventricular (ICV) delivery of insulin into the brain could produce a multitude of effects, including suppression of feeding behavior and hepatic glucose production, activation of thermogenesis in brown adipose tissue, and stimulation of lipogenesis in white adipose tissue, all without significantly altering systemic insulin levels. Using a conditional knockout of the IR in the brain, Brüning and colleagues (4, 5) demonstrated that the actions of insulin in the brain require IRs and can produce a range of phenotypes including mild obesity, decreased counterregulatory responsiveness to hypoglycemia, and hypothalamic hypogonadism. This has been confirmed and refined by region-specific IR knockouts and knockdowns of the IR using antisense technology (6, 7). Studies using animal models and in vitro systems have uncovered many other roles for brain insulin signaling, including insulin-dependent uptake of glucose in the hippocampus for memory formation (8), stimulation of brain cholesterol synthesis (9), and increased astrocyte glycogen storage (10), to name a few.

In normal physiology, a major function of insulin is to suppress hepatic gluconeogenesis while stimulating hepatic cholesterol and triglyceride synthesis (Fig. 1A) and glucose uptake into muscle and fat. Mice with hepatic insulin resistance created by knockout of the IR in the liver (LIRKO mice) demonstrate increased hepatic gluconeogenesis and decreased hepatic lipogenesis, consistent with insulin resistance in both pathways (11). In type 2