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Differential Effects of Leptin in Regulation of Tissue Glucose Utilization in Vivo¹

Departments of Pharmacology and Pathology, Amgen, Inc., Thousand Oaks, California 91320

Address all correspondence and requests for reprints to: Zhi-Qing Shi, M.D., Ph.D., Department of Pharmacology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320. E-mail: jshi{at}amgen.com

We have recently shown that leptin enhances systemic insulin sensitivity and whole body glucose utilization in the rat. This study examines our hypothesis that leptin has differential effects in regulating glucose utilization among the tissues, i.e. stimulating glucose utilization in brown adipose tissue (BAT) and skeletal muscle but suppressing glucose utilization in white adipose tissue (WAT) in normal male rats (275–350 g BW). The rats were treated with sc infusion of recombinant murine leptin (4 mg/kg·day) or vehicle (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/day; 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 glucose levels, but raised ß-hydroxybutyrate levels. Glucose utilization by individual tissues was determined with an iv bolus of [1-¹⁴C]2-deoxyglucose (2-DG) after a 90-min hyperinsulinemic (2 mU/kg·min) euglycemic clamp. With leptin treatment, the 2-DG-determined glucose utilization in interscapular BAT 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 PF rats. Leptin increased 2-DG uptake by extensor digitorum longus muscle and soleus muscle compared with that in the V and PF groups. With leptin treatment, 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 and soleus muscle. Oxygen consumption was significantly increased (32.1 ± 7.4%) in BAT (139.0 ± 8.2 nmole O₂/30 min·10⁶ cells) of leptin-treated rats vs. that in V control rats (105.3 ± 6.7 nmole O₂/30 min·10⁶ cells). In conclusion, leptin has differential, tissue-specific effects on glucose and oxygen utilization, which contribute to the reduction in whole body adiposity by enhancing energy consumption in BAT and muscle while attenuating energy storage in WAT.

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