Downregulation of uncoupling protein 2 mRNA in white adipose tissue and uncoupling protein 3 mRNA in skeletal muscle during the early stages of leptin treatment

The mechanisms underlying the increase in energy expenditure during leptin treatment are not clear We recently showed that a S-h intravenous or intracerebroventricular infusion of leptin elevated basal glucose uptake in skeletal muscle (SM) and brown adipose tissue and increased whole-body glucose turnover in C57Bl/6J mice (Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ: Acute stimulation of glucose metabolism in mice by leptin treatment, Nature 389:374-377, 1997). We extended the previous study by measuring steady-state levels of uncoupling protein (UCP)-2 mRNA and UCP-3 mRNA in white adipose tissue (WAT) and SM. Leptin by intravenous or intracerebroventricular infusion for 5 h was associated with a decrease in UCP-2 mRNA in WAT (47-52%) and UCP-3 mRNA in SM (33-37%). Because overexpression of UCP-8 or UCP-3 can depolarize the inner mitochondrial membrane? suppression of UCP-2 mRNA and UCP-3 mRNA may in fact lower respiratory demands in WAT and SM. This IS consistent with the parallel suppression of cytochrome oxidase subunit TT (COX-IV) mRNA in WAT (35-39%) after leptin infusion, COX-IV mRNA in SM did not respond to acute leptin treatment, Mitochondrial inorganic phosphate carrier (PII)mRNA was also suppressed in WAT (33-35%) by either method of leptin infusion,but only intravenous infusion of leptin reduced PIC mRNA in SM (40%). Denervation suppressed mRNA levels for UCP-2 (49%), UCP-3 (36%), and COS-IV (59%) and eliminated the acute response to leptin in SM. The comparable response to leptin under int-ravenous or intracerebroventricular infusion and the loss of responsiveness after denervation strongly suggest that the acute effects of leptin involve central signaling pathways.