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 intrac erebroventricular infusion of leptin elevated basal glucose uptake in skele tal muscle (SM) and brown adipose tissue and increased whole-body glucose t urnover in C57Bl/6J mice (Kamohara S, Burcelin R, Halaas JL, Friedman JM, C harron MJ: Acute stimulation of glucose metabolism in mice by leptin treatm ent, 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 w hite adipose tissue (WAT) and SM. Leptin by intravenous or intracerebrovent ricular infusion for 5 h was associated with a decrease in UCP-2 mRNA in WA T (47-52%) and UCP-3 mRNA in SM (33-37%). Because overexpression of UCP-8 o r 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 sub unit 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 phos phate carrier (PII)mRNA was also suppressed in WAT (33-35%) by either metho d of leptin infusion,but only intravenous infusion of leptin reduced PIC mR NA 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. T he comparable response to leptin under int-ravenous or intracerebroventricu lar infusion and the loss of responsiveness after denervation strongly sugg est that the acute effects of leptin involve central signaling pathways.