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The upregulation of plasma inflammatory biomarkers in individuals with metabolic syndrome implies that activation of the innate immune response contributes to the pathogenesis of type 2 diabetes (1). Today, a large array of studies has demonstrated that activation of inflammatory pathways underlies obesity-associated insulin resistance at the liver and fat (2–4). However, little is known regarding whether obesity induces inflammation in the brain thereby disrupting the ability of insulin to control glucose homeostasis. Hotamisligil et al. (5) first established a link between obesity and the increased production of inflammatory molecules by demonstrating that tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, is overexpressed in the adipose tissue of obese mice. This finding was confirmed in humans with obesity and insulin resistance (6,7). TNF-α induces peripheral insulin resistance in rodents (8,9) and alters insulin sensitivity and glucose homeostasis in humans (10,11). In fact, subjects with chronic inflammatory disease who are treated with TNF inhibitor show a 60% reduction in diabetes rates (12). Downstream of the inflammatory process lies the inhibitor of κB kinase (IKK-β) complex and its target, nuclear factor-ĸB (NF-ĸB), a transcription factor that regulates the expression of inflammatory genes (2–4) and mediates peripheral insulin resistance associated with overnutrition (2–4). In parallel, the c-Jun amino-terminal kinase (JNK), which can be activated in response to TNF-α or other stressors, is also implicated in insulin resistance of diabetic mice (2–4). NF-ĸB–mediated gene expression is regulated in part through the Toll-like receptors (TLRs), which serve to activate proinflammatory signaling cascades upon recognition of pathogen-associated molecular patterns (2–4 …

Last year marked the ninetieth anniversary of the discovery of insulin by Nobel Laureates Frederick Banting and John Macleod, as well as Charles Best and James Bertram Collip. The initial success of insulin’s ability to lower glucose levels in type 1 diabetes is now shadowed by the urgent need to characterize insulin resistance and secretion defects in type 2 diabetes and obesity. Insulin triggers signaling pathways in liver, muscle, and fat that inhibit glucose production and increase glucose uptake (1). However, it has only been in recent years that the brain has received attention for being an insulin-sensitive organ that regulates food intake (2) and glucose (3) and lipid (4) homeostasis in animals (Fig. 1). FIG. 1. A working hypothesis for insulin action in the brain. Insulin triggers signaling cascades in the brain to regulate food intake and modulate the reward-related hedonic food response. In addition, brain insulin action alters glucose and lipid metabolism. The hypothalamus (blue) is the main effector of the metabolic changes induced by insulin and can coordinate the prefrontal cortex (green) to regulate the hedonic assessment of appetite. WAT, white adipose tissue. Circulating insulin crosses the blood-brain barrier and acts on its receptor in the hypothalamus to lower food intake and body weight (2). Infusion of insulin into the central nervous system (CNS) lowers food intake in rats (5), mice (6), and baboons (7), whereas hyperphagia is detected in neuronal insulin receptor knockout mice (8). Further, high-fat feeding induces hypothalamic insulin resistance in rodents (9). Although these animal studies expand the role of insulin to regulate appetite and suggest that characterizing insulin signaling pathways may reveal novel targets that reverse brain insulin resistance in obesity, a central question remains, Is …