Molecular pathways to obesity.
Obesity results from a chronic imbalance between energy intake and energy expenditure. Environmental factors, such as the increased availability of high caloric food or the decreased need for physical activity, contribute to its development and their influence is amplified by genetic predisposition. In recent years remarkable progress has been made in the understanding of the pathophysiology of obesity. Although most of the insights into the regulation of energy balance have been obtained in rodent models, the rare clinical cases of monogenic obesity provided evidence for the importance of several of these mechanisms in humans. The identification of leptin as a factor originating from adipose tissue and informing the brain about the status of energy reserves firmly established the concept of long-term regulation of body fat stores. The disappointing therapeutic results with leptin in obese patients could be explained by the fact that during evolution this hormone developed rather as a starvation signal than as an adiposity signal. It is conceivable that the pharmacological interference with mechanisms downstream of leptin, for example with the melanocortin pathway, might be therapeutically more promising. The discovery of new molecular mechanisms involved in the regulation of the differentiation and proliferation of adipocytes and the elucidation of their paracrine and endocrine functions have changed the traditional view of adipose tissue as an inert depot for triglycerides. The identification of new uncoupling proteins could modify the current concepts of the regulation of thermogenesis in humans. The remarkable progress in the identification of novel targets involved in the regualtion of energy balance should have a positive impact on the search for new antiobesity agents.
Hofbauer
K G
KG
Chair for Applied Pharmacology, Biozentrum/Pharmazentrum, University of Basel, Switzerland. karl.hofbauer@unibas.ch
D000818:Animals; D005075:Biological Evolution; D001921:Brain / Q000502:physiology; D004435:Eating; D004734:Energy Metabolism; D004777:Environment; D006706:Homeostasis; D006801:Humans; D020738:Leptin / Q000502:physiology; D009478:Neuropeptide Y / Q000502:physiology; D009765:Obesity / Q000209:etiology* / Q000235:genetics
D020738:Leptin; D009478:Neuropeptide Y