Fat metabolism and the control of food intake

Obesity and overweight are increasing at epidemic proportions in the US, Europe, and much of the world and the real culprit is a changing environment that promotes a sedentary lifestyle and overfeeding. Several animal, clinical, and epidemiological studies suggest that dietary fat plays a major role in the development of overfeeding and obesity. Therefore, it is imperative to understand the physiological mechanisms that control food intake and particularly mechanisms related to fat metabolism. Indeed, the subject of the present thesis was to extend our understanding of the role of fatty acid oxidation (FAO) in the control of food intake. The background of this thesis was provided by several lines of evidence indicating that peripheral fatty acid oxidation contributes to a metabolic control of feeding. Most important is that peripheral administration of FAO inhibitors stimulates feeding under many conditions in different species including humans. Yet, in contrast to the robust data demonstrating a feeding-stimulatory effect of reduced FAO, there is no evidence for a feeding-inhibitory potency of enhanced FAO. Therefore, the present thesis focused particularly on the feeding-inhibitory potency of increased FAO using the strategy of testing FAO's role in feeding when the supply of fatty acids from endogenous fat stores was enhanced. This was achieved both pharmacologically, by using specific ß3-adrenergic receptor agonists, and physiologically, by pre-test food deprivation. The role of FAO in the feeding response was tested by administration of the FAO inhibitor mercaptoacetate and disruption of the supposed nerval mediation - subdiaphragmatic vagal deafferentation.