For more than two decades, there has been an exponential increase in the incidence of obesity around the world. This uncontrolled rise in obesity has been a concomitant increase in the diseases associated with obesity, such as type 2 diabetes, hypertension, and cardiovascular disease. Not surprisingly, we have also seen an unprecedented increase in the number of diagnosed cases of type 2 diabetes in children and adolescents.
Obesity is the result of an imbalance between food intake and disposal, and it is a consequence of the failure of one or more factors involved in any of the two processes. Once a primary cause of the failure is recognized, it is required that appropriate steps first be taken to try and correct the problem. A delicate balance between intake and expenditure of energy is required to maintain healthy weight. Perhaps for teleological reasons, the mechanisms that regulate energy homeostasis are biased in favor of net positive energy and are geared toward defense of weight loss rather than prevention of obesity. Spontaneous weight loss in the absence of disease is rare and the experience of progressive weight gain in free-living humans is common.
An elaborate network of central and peripheral neurohormonal signals has evolved to regulate feeding, one of the primal activities necessary for survival and selfpreservation. Current understanding indicates that energy homeostasis in health is predicated upon a balance between orexigenic and anorexigenic factors, both centrally and peripherally. Virtually all of the peripheral signals (e.g., insulin, PYY, leptin, CCK) are triggered by food ingestion and attenuated by fasting or starvation, indicating a response system that is tailored at satiety and meal termination. Ghrelin, the only peripheral signal activated preprandially, may be unique in its role as a rare peripheral signal for hunger and meal initiation.
The hypothalamus integrates diverse signals, including brain neurotransmitters, peripheral neurohumoral afferents, adipocyte-derived signals, gastrointestinal peptides, and other afferent inputs, to regulate energy homeostasis. The arcuate nucleus at the base of the hypothalamus expresses receptors for hormones and neuropeptides that regulate feeding. The paraventricular nucleus in the anterior hypothalamus, the major site of corticotropin releasing hormone and Thyroid Releasing Hormone secretion, receives rich projections from the ARC. Thus, the PVN integrates diverse paracrine and endocrine metabolic signals with classical neuroendocrine pathways mediated through the thyroid and hypothalamic-pituitary-adrenal axes.
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