[649] Metabolic Homeostasis

Metabolic homeostasis is ensured by complex interactions between the Central Nervous System (CNS) and peripheral tissues. The CNS controls the periphery by regulating the fraction of energy which enters the organism (food intake) and that which leaves the organism (thermogenesis). To be able to exert this role, the CNS receives signals from peripheral organs which convey information on the extent of body energy stores. When this information is integrated, the CNS responds via efferent regulatory signals channeled mostly via the endocrine and the autonomic nervous system. Amongst the several feedback signals arising from peripheral tissues, leptin and ghrelin are important ones.

Leptin is a hormone that is synthesized in adipose tissue. Once secreted into the blood and reaching the CNS, leptin acts as a satiety factor upon binding to its long hypothalamic receptor isoform. Ghrelin is a hormone synthesized in the stomach. It is the endogenous ligand for the growth-hormone secretagogue receptor, but it also stimulates food intake.

At the level of the hypothalamus, leptin and ghrelin regulate several neuropeptides having effects on both food intake and energy dissipation. Anorectic neuropeptides, such as corticotropin-releasing hormone (CRH), "Cocaine-and- Amphetamine-Regulated Transcript" (CART), the melanocortin system comprising "Proopiomelanocortin" (POMC), the "a-Melanocyte- Stimulating Hormone" (α-MSH), and the MC3-MC4 types of receptors, are stimulated by leptin, thereby decreasing food intake. In contrast, orexigenic neuropeptides, such as neuropeptide Y (NPY), "Melanin-Concentrating Hormone" (MCH), the "Agouti-Related Peptide" (AgRP) and orexins, are inhibited by leptin, but stimulated by ghrelin, resulting in a decrease, or an increase in food intake, respectively.

In addition to their effects on food intake and thermogenesis, hypothalamic neuropeptides and feedback hormones influence peripheral metabolism, modulating utilization and storage of nutriments. This is the aspect that our group is presently investigating, with emphasis on the study of carbohydrate and lipid metabolism. Such projects aim at a better understanding of the physiology of metabolic regulations, and of the alterations that ultimately lead to pathological conditions, such as obesity and insulin resistance. Our group is also interested in the mechanisms by which glucocorticoids influence metabolic homeostasis, and in the question as to why, when glucocorticoids are in excess, they produce an obesity syndrome associated with insulin resistance. Finally, our group is studying the metabolic effects of other hormones (such as the adipose-tissue derived hormone, resistin), attempting to understand whether their effects are strictly peripheral ones, or whether they are partly elicited within the Central Nervous System.

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