Differential effects of leptin in regulation of tissue glucose utilizationin vivo

We have recently shown that leptin enhances systemic insulin sensitivity an d whole body glucose utilization in the rat. This study examines our hypoth esis that leptin has differential effects in regulating glucose utilization among the tissues, i.e. stimulating glucose utilization in brown adipose t issue (BAT) and skeletal muscle but suppressing glucose utilization in whit e adipose tissue (WAT) in normal male rats (275-350 g BW). The rats were tr eated with sc infusion of recombinant murine leptin (4 mg/kg day) or vehicl e (V) with Alzet osmotic pumps or with Vehicle and pair-feeding (PF) for 7 days. Leptin significantly decreased food intake (leptin, 11.5 +/- 0.4 g/da y; V, 16.8 +/- 1.5 g/day; P < 0.05) and body weight (maximum change, 5.0 +/ - 0.2%; P < 0.05 vs. V) and lowered plasma triglyceride, insulin, and gluco se levels, but raised P-hydroxybutyrate levels. Glucose utilization by indi vidual tissues was determined with an iv bolus of [1-C-14]2-deoxyglucose (2 -DG) after a 90-min hyperinsulinemic (2 mU/kg min) euglycemic clamp. With l eptin treatment, the e-DG-determined glucose utilization in interscapular B AT was almost 3-fold that in V-treated rats and 70% greater than that in PF rats. In contrast, in the epididymal WAT, glucose utilization was reduced by leptin treatment to only 34% that in V-treated rats and 45% that in PP r ats. Leptin increased 2-DG uptake by extensor digitorum longus muscle and s oleus muscle compared with that in the V and PF groups. With leptin treatme nt, the GLUT4 glucose transporter mRNA and protein levels were increased in BAT, but decreased in WAT (both P < 0.05). There was no significant change in GLUT4 mRNA and protein expression in extensor digitorum longus muscle a nd soleus muscle. Oxygen consumption was significantly increased (32.1 +/- 7.4%) in BAT (139.0 +/- 8.2 nmole O-2/30 min 10(6) cells) of leptin-treated rats us. that in V control rats (105.3 +/- 6.7 nmole O-2/30 min 10(6) cell s). In conclusion, leptin has differential, tissue-specific effects on gluc ose and oxygen utilization, which contribute to the reduction in whole body adiposity by enhancing energy consumption in BAT and muscle while attenuat ing energy storage in WAT.