Obesity hypothalamus

Proopiomelanocortin (POMC) is the precursor peptide of hormones and neuropeptides expressed in the pituitary and the hypothalamus (adrenocorticotropic hormone (ACTH), lipotropin, a-melanocyte-stimulating hormone (aMSH), yMSH, 3-endorphin, and others). The main clinical consequences of POMC deficiency are adrenal insufficiency (due to absence of ACTH), red hair pigmentation (due to absence of MSH) and severe early-onset obesity (due to the lack of aMSH). 

Obviously, regulation of food intake depends on many neurotransmitters and hormones but this final section will outline the role played by central 5-HT transmission in this process. It had been the belief for some time that increased 5-HT transmission in the brain reduces food intake (Blundell 1977) and this certainly explains the satiety in rats that follows infusion of 5-HT into the paraventricular nucleus (PVN) of the hypothalamus. However, recent studies using microdialysis have found that 5-HT efflux in the lateral hypothalamus is itself increased by food intake, suggesting the existence of a feedback control system. In fact, because the increase in 5-HT efflux is greater in genetically obese rats than in their lean counterparts, it has been proposed that there is a deficiency in the 5-HT inhibition of food intake in obesity. 

Neuropeptides play key roles in appetite regulation and obesity. Many genes for neuropeptides and neuropeptide receptors have been implicated in obesity and cachexia, anorexia and bulimia [34]. For example,NPY administration into the CNS causes overeating and obesity. A second peptide involved in obesity is leptin, a product of adipocytes and the stomach. The leptin gene is defective in the ob/ob mouse but in normal mice leptin binds to its receptor in the hypothalamus, causing a decrease in the synthesis and release of hypothalamic NPY. 

One of the classical obesity mntations in mice is termed ob, for obesity. Mice that are homozygous for the ob mutation (ob/ob mice) are grossly obese. Jeffrey Friedman at the Rockefeller University elucidated the defect in ob/ob mice in 1992. Specifically, the ob gene encodes a protein termed leptin.Leptin is prodnced in fat tissue and acts on the central nervous system at the hypothalamus. Basically, it reports nutritional information to this control center. 

Stanley, B.G., Kyrkouli, S.E., Lampert, S., et al. (1986) Neuropeptide Y chronically injected into the hypothalamus a powerful neurochemical inducer of hyperphagia and obesity. Peptides 7 1189— 1192. 

Flier, J.S. Maratos-Flier, E. (1998) Obesity and the hypothalamus novel peptides for new pathways. Cell 92, 437-440. 

Adults with GH deficiency tend to have generalized obesity, reduced muscle mass, asthenia, and reduced cardiac output. Adult-onset GH deficiency is usually found in the presence of other pituitary hormone deficiencies, and is usually due to damage to the hypothalamus or pituitary caused by tumor, infection, surgery, or radiation therapy. 

With the early application of stereotaxic surgery to neurological studies in experimental animals, Anand and Brobeck (1951) first reported that bilateral lesions of small nuclei in the hypothalamus could disrupt feeding behavior with medial hypothalamic lesions causing obesity and lateral lesions aphagia. In the latter syndrome, the lesioned animals would completely stop eating to the extent that if not maintained... 

AgRP, a powerful antagonist of the MC3R and MC4R melanocortin receptors in the hypothalamus. Obese patients have elevated plasma levels of AgRP, and over-expression of AgRP in animal models leads to obesity. 

Serotonin. Serotonin central receptors appear to play a major role in glucose homeostasis. Experiments in obese mice have demonstrated that small doses of a classical serotonin agonist, metachlorophenylpiperazine (mCPP), markedly lower plasma insulin levels and increase insulin sensitivity, without affecting food intake, body weight or fat mass. The downstream target of the involved serotonin receptor appears to be melanocortin-4 receptors, in the arcuate nucleus of the hypothalamus. 

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