Leptin Interacts with Ghrelin and Insulin

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It is commonly assumed that the effects of leptin and ghrelin on metabolism, including food intake, are exactly opposite. Ghrelin is considered to be a hunger hormone, whereas leptin is a satiety signal [47]. Rising ghrelin levels in concert with falling leptin levels may serve as a critical signal to induce hunger during fasting [48]. It has been observed that leptin exerts a restraint on the orex-igenic effects of ghrelin in two ways, centrally by counteracting its appetite-promoting effects at the level of neuropeptide Y (NPY) signalling in the hypothalamus and peripherally by attenuating gastric ghrelin secretion [49]. Moreover, there is evidence suggesting that leptin and ghrelin may also work via the hindbrain [42].

Leptin and insulin interact with each other. Insulin plays a major role in the regulation of lep-tin production, stimulating the transcriptional activity of the leptin promoter, increasing leptin gene expression and elevating leptin circulating concentrations. These effects are all mediated by actions of insulin to promote glucose uptake and oxidative metabolism in adipocytes [50].

On the other hand, leptin can down-modulate insulin signalling in adipocytes in two different ways. Leptin may modulate the pancreatic insulin and glucose homeostasis acting in the hypothalamus throughout the activation of neuronal circuits and the autonomic nervous system [49], but it also exerts a direct effect on the adipocytes. In animals with elevated serum leptin concentrations, leptin inhibits insulin signalling, impairing insulin receptor autophosphorylation. This modulation of adipocyte insulin signalling could be relevant in physiological situations of hyperlepti-naemia and central leptin resistance, such as ageing and obesity [51]. In addition, leptin exerts a tonic restraint to the adipocytes for the secretion of adiponectin, a hormone implicated in insulin resistance [49].

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