Speaker Abstract: S-09
The Battle Between Homeostatic and Non-homeostatic Factors in the Control of Body Weight
Hans-Rudolf Berthoud, Ph.D., Professor of Neurobiology, Neurobiology of Nutrition Laboratory, Pennington Biomedical Research Center, Louisiana State University
A leptin-sensitive peptidergic neural network in the hypothalamus has been identified as the homeostatic control system for the regulation of adiposity and body weight. This system is remarkably powerful in guaranteeing a sufficient supply of energy, as demonstrated by genetic models with deficiencies in signaling at the leptin receptor or further downstream. Although often portrayed as a simple reflex circuit involving the arcuate nucleus of the hypothalamus and the nucleus of the solitary tract, this system actually impinges on most of the brain through widely projecting neurons located mainly in the lateral hypothalamus. In addition, leptin receptors are not only located in the hypothalamus but also in the nucleus accumbens, many cortical areas, thalamus, caudal brainstem, taste receptor cells, and sensory ganglia. Therefore, the leptin-deficient brain is powerfully driven towards food and conservation of energy stores, and this response-pattern is completely stopped with leptin treatment.
Many investigators automatically assumed that leptin treatment would also work to prevent or reverse obesity. However, leptin's power to stimulate food intake at low circulating levels is not reciprocated by curbing appetite at high circulating levels. This is probably because leptin and the other satiety hormones such as cholecystokinin (CCK), polypeptide YY (PYY), glucagons-like peptide-1 (GLP-1), amylin, and insulin were never "designed" to prevent obesity, and strong satiety mechanisms were actually counterproductive in the restrictive environment during which most of vertebrate evolution took place. Thus, in many obese individuals there is nothing wrong with the homeostatic control system, it is simply overpowered by environmental influences associated with the modern lifestyle.
The extensive neural systems for processing appetitive and rewarding aspects of food intake are constantly attacked by sophisticated signals from the highly commercialized environment, ultimately resulting in increased energy intake. Combined with a decrease in energy expenditure associated with the sedentary lifestyle, there is a net energy surplus that in many genetically predisposed individuals is too much for the homeostatic control system to handle. This dominant effect of external over internal metabolic signals has recently been demonstrated in animal experiments. Identification of the neural pathways that mediate this dominance of cortico-limbic processes over the homeostatic regulatory circuits in the hypothalamus and brainstem will be important for the development of behavioral strategies and pharmacological therapies. Some of the prime candidate pathways are reciprocal connections between the nucleus accumbens, ventral pallidum, orbitofrontal cortex, and amygdala with areas of the hypothalamus containing "feeding" peptides.
2004 FDA Science Forum | FDA Chapter, Sigma Xi | CFSAN | FDA
Last updated on 2004-MAY-28 by frf