Appetite Regulatory Peptides and Insulin Resistance

Abstract

In addition to leptin and insulin, receptors for ghrelin are also located on arcuate AgRP/NPY neurons, which are activated by central ghrelin administration. Furthermore, peripheral ghrelin administration activates neurons in the ARC and AgRP and NPY have been demonstrated to be requisite mediators of the hyperphagia induced by systemic ghrelin [11]. So, meal-generated satiety signals from the GI tract do interact with longer-term adiposity signals, such as insulin and leptin in energy balance [8].NPY is one of the most abundant peptides of the hypothalamus and one of the most potent orexigenic factors. The majority of neurons expressing NPY in the hypothalamus are found within the ARC and most co-express AgRP [14]. Synthesis and release of NPY are both regulated by leptin binding to its hypothalamic receptor. NPY links afferents reflecting the nutritional status of the organism from endocrine, gastrointestinal, and central and peripheral nervous systems to effectors of energy intake and expenditure [15]. NPY stimulates appetite inducing hyperphagia, increase of fat depots, decrease of thermogenesis, and suppression of sympathetic activity. NPY is known to be involved in other physiological functions, such as cardiovascular regulation, affective disorder, memory retention, neuroendocrine control. When leptin levels increase after food intake, the latter binds to its receptors in the hypothalamus which leads to discontinuation of NPY secretion [5,16]. The decrease of NPY concentration in obesity probably plays a role of a counterregulatory factor intended to prevent further weight gain. Thus, NPY becomes one of the main regulators of food intake, body weight and energy expenditure.Ghrelin is a fast-acting hormone, seemingly playing a role in meal initiation. Secreted predominantly from the stomach, ghrelin is the natural ligand for the growth hormone secretagogue-receptor (GHS-R) in the pituitary gland, thus fulfilling the criteria of a brain- gut peptide [5,6]. Although the majority of ghrelin is produced peripherally, there are ghrelin immunoreactive neurons within the hypothalamus that have terminals on hypothalamic NPY/AgRP, POMC and corticotropin releasing hormone (CRH) neurons [17], as well as orexin fibres in the LHA [18]. It was found that ghrelin acts to promote appetite in two ways-directly, by depolarizing the orexigenic NPY/AgRP neurons, and indirectly, by increasing the tonic inhibition exerted by the NPY/AgRP neurons over the anorexigenic POMC/CART neurons. Both of these ultimately enhance appetite [4,17,18]. The ability of ghrelin to increase food intake and body weight is mediated through the stimulation of NPY production in the hypothalamic ARC, where it antagonizes the inhibitory effect on NPY secretion displayed by leptin and insulin [19].The purpose of this chapter is to provide background information on the relationship between the main appetite regulatory peptides NPY and ghrelin, and insulin resistance. The role of NPY and ghrelin in food intake and body weight control in humans, and their ...