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Synergy Between Leptin Therapy and a Seemingly Negligible Amount of Voluntary Wheel Running Prevents Progression of Dietary Obesity in Leptin-Resistant Rats

¹ Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida
² Department of Veterans Affairs Medical Center, Gainesville, Florida
³ Department of Aging and Geriatrics, University of Florida College of Medicine, Gainesville, Florida
⁴ Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida

Address correspondence and reprint requests to Philip J. Scarpace, PhD, Department of Pharmacology and Therapeutics, Box 100267, University of Florida, Gainesville, Florida 32610. E-mail: scarpace{at}ufl.edu

Abbreviations: 11-β-HSD1, β-hydroxysteroid dehydrogenase type 1; EWAT, epididimal white adipose tissue; HSL, hormone-sensitive lipase; IL, interleukin; P-STAT3, STAT3 phosphorylation; PWAT, perirenal white adipose tissue; rAAV, adeno-associated virus–encoding leptin; RTWAT, retroperitoneal white adipose tissue; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription

OBJECTIVE—We examined whether chronic leptin treatment of diet-induced obese rats promotes or alleviates the susceptibility to continued high-fat feeding. Second, we examined if voluntary wheel running is beneficial in reducing the trajectory of weight gain in high-fat–raised leptin-resistant rats.

RESEARCH DESIGN AND METHODS—Sprague-Dawley rats were fed a standard diet or a high-fat diet for 5 months, and then hypothalamic leptin overexpression was induced through central administration of adeno-associated virus–encoding leptin while continuing either the standard or high-fat diet. Two weeks later, half of the rats in each group were provided access to running wheels for 38 days while being maintained on either a standard or high-fat diet.

RESULTS—In standard diet–raised rats, either wheel running or leptin reduced the trajectory of weight gain, and the combined effect of both treatments was additive. In high-fat–raised leptin-resistant rats, leptin overexpression first transiently reduced weight gain but then accelerated the weight gain twofold over controls. Wheel running in high-fat–raised rats was sixfold less than in standard diet–raised rats and did not affect weight gain. Surprisingly, wheel running plus leptin completely prevented weight gain. This synergy was associated with enhanced hypothalamic signal transducer and activator of transcription (STAT) 3 phosphorylation and suppressor of cytokine signaling 3 expression in wheel running plus leptin compared with leptin-treated sedentary high-fat counterparts. This enhanced STAT3 signaling associated with the combination treatment occurred only in high-fat–raised, leptin-resistant rats and not in standard diet–raised, leptin-responsive rats.

CONCLUSIONS—Chronic leptin treatment in diet-induced obese rats accelerates dietary obesity. However, leptin combined with wheel running prevents further dietary weight gain. Thus, this combination therapy may be a viable antiobesity treatment.

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