Where Does Insulin Resistance Start?

Abstract

During the last two decades, many studies have focused on the pivotal role of the hypothalamus in the control of energy metabolism (1). Hypothalamic nuclei, particularly the arcuate and the ventromedial, receive numerous peripheral inputs from adipokines (leptin, adiponectin, and resistin) and free fatty acids. These signals of “nutrient abundance” lead to the activation of multiple hypothalamic pathways that overlap and generate a plethora of central and peripheral responses (2). In this context, the central neuronal signals generated by insulin have been the most extensively studied (3). The pivotal experiment performed by Woods et al. (4) in the late 1970s showed that intracerebral infusion of insulin in baboons reduced food intake and body weight and paved the way for intense scientific investigation over subsequent years by highlighting the key role of insulin at the central nervous system (CNS) level. Insulin receptors (5) and components of the insulin signaling pathway (6) are widely distributed in the brain. Insulin interacts with its binding sites by crossing the blood-brain barrier through a receptor-mediated and saturable transport mechanism (7), although it has been hypothesized that insulin is also synthesized in the brain (7). Considerable evidence has been generated to indicate that insulin can modulate the expression of neuropeptides involved in the regulation of food intake within the CNS (8) and also can influence glucoregulation via CNS connections that regulate hepatic glucose production (9), glycogen synthesis in the skeletal muscle (10), and fat metabolism in adipocytes (11). By activating its receptors, insulin directly suppresses prepro-NPY mRNA transcription in the arcuate nucleus, leading to a reduction in NPY and a decrease in food intake (12), whereas intracerebroventricular delivery of insulin increases the expression of pro-opiomelanocortin (POMC) (13) (Fig. 1). This hypothalamic mode of insulin action resembles the well-known effect of leptin, suggesting that these …