Hypothalamic Leptin Action
The cloning of leptin, the product of the ob (obese) gene, in the early 1990s has renewed the interest in the relationship between brain and control of energy balance and metabolism. Although the notion that the hypothalamus is a major control center for energy homeostasis was previously well established, the discovery that leptin acts in the hypothalamus to regulate food intake and energy expenditure has greatly advanced our understanding of the neuroendocrine control of energy metabolism. A major target of leptin action in the hypothalamus is the modulation of hypothalamic neuropeptidergic neurons. Leptin can reduce food intake and increase energy expenditure by simultaneously downregulating “orexic” peptides [that promote food intake and energy efficiency, such as neuropeptide Y (NPY), melanocyte-concentrating hormone, MCH, and orexins] and increasing the expression of anorectic peptides (such as the α-melanocyte-stimulating hormone, α-MSH, and corticotrophin releasing hormone, CRH). Two populations of neurons in the arcuate nucleus of the hypothalamus are highly responsive to leptin (Fig. 6.2b).
One of these populations responds to leptin by increasing the expression of proopiomelanocortin (POMC), the precursor of α-MSH. The other population of neurons responds to leptin by markedly decreasing the expression of NPY and the agouti-related protein (AgRP). The latter is a natural antagonist of the melanocortin pathway acting on the MC4 (and MC3) receptors. The peptide α-MSH is the natural ligand for the CNS melanocortin receptors (MC3 and MC4). The MC4 receptor is expressed in the hypothalamus and has been convincingly implicated in the regulation of energy homeostasis. In particular, genetic knockout of the MC4 receptor gene and ICV administration of agonists and antagonists for this receptor result in dramatic effects on feeding behavior and energy balance. Since obesity is tightly associated with insulin resistance, hypothalamic leptin action plays a major role in carbohydrate metabolism and insulin action. For example, rodents with a genetic deficiency of leptin function, such as the ob/ob and db/db mice, and the Zucker fa/fa rats, are markedly resistant to insulin action and develop diabetes mellitus later in life.
Prolonged leptin administration in leptin-deficient ob/ob mice markedly decreases both plasma insulin and glucose concentration. Administration of leptin to ob/ob mice at doses insufficient to induce weight loss rapidly normalizes blood glucose levels, suggesting that leptin has insulin-sensitizing effects independent of its anorectic action. Leptin was also shown to regulate glucose tolerance, insulin signaling/action, and lipid metabolism independently of its anorectic effects. Leptin regulates food intake and body adiposity partly via activation of melanocortin receptors in the hypothalamus and in other areas within the central nervous system.
Bidirectional modulation of central melanocortin action leads to significant changes in peripheral insulin action. On the other hand, the prolonged administration of either leptin or melanocortin agonists or antagonists also impacts on the distribution of body adiposity and on lipid homeostasis. The loss of adiposity is likely to influence insulin action, since it is well established that changes in fat mass and/or fat distribution similar to those associated with long-term treatment with either leptin or melanocortin agonists can alter insulin action, particularly in insulin-resistant and obese animals.
Thus, short-term administration studies, in the absence of changes in fat mass, might provide a glimpse on the direct role of hypothalamic leptin in the modulation of glucose metabolism. Leptin appears to exert its pleiotropic behavioral, metabolic, and neuroendocrine actions via multiple neural pathways. What pathways are responsible for the action of CNS leptin on glucose metabolism? Leptin activates central melanocortin receptors mainly via increased biosynthesis of the physiological ligand α-MSH and via decreased biosynthesis of an antagonist agouti-related protein (AgRP) at the level of the hypothalamus. The activation of the central melanocortin pathway mediates in great part leptin action on food intake, energy expenditure, sympathetic nervous system, insulin secretion, and body fat distribution. The acute central activation of melanocortin receptors stimulates the expression of gluconeogenic enzymes within the liver, markedly increases the rate of gluconeogenesis, and decreases the suppressive effect of insulin on glucose production.
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