CHRONIC LEPTIN TREATMENT DOES NOT PREVENT THE DEVELOPMENT OF OBESITY IN TRANSGENIC MICE WITH BROWN FAT DEFICIENCY

0With the exception of ob/ob mice, circulating plasma leptin is elevat ed in all other obese rodents as well as in obese humans, suggesting t hat leptin resistance rather than leptin deficiency is a characteristi c feature of obesity. The exact molecular mechanisms leading to leptin resistance and the applicability of exogenous leptin to overcome resi stance to the anorectic effect of the hormone, are insufficiently char acterized. The aim of this study was to investigate whether chronic le ptin administration could prevent the development of obesity and its a ssociated disorders in transgenic mice with toxigene mediated ablation of brown adipose tissue (BAT). Daily injections of leptin were starte d at the age of 6 weeks, when body weight, food intake and plasma lept in levels of transgenics were not different from control mice. Over th e next 6 weeks, leptin treated transgenics showed the same excessive b ody weight gain as transgenic mice injected with saline. Leptin treatm ent was furthermore not able to prevent the development of hyperphagia , hyperglycaemia, hyperinsulinaemia and hyperlipidaemia in transgenic mice. In contrast, control mice injected with leptin had significantly lower body weight, food intake and plasma triglycerides than those tr eated with saline. In summary, leptin treatment was not able to preven t the development of obesity and its associated abnormalities in trans genic mice with BAT deficiency. This data suggests that intact BAT fun ction is of critical importance for leptin's effect on food intake and energy expenditure, and that primary dysfunction of BAT is associated with leptin resistance, even when hyperleptinaemia is not yet present .