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Differential Mechanisms and Development of Leptin Resistance in A/J Versus C57BL/6J Mice during Diet-Induced Obesity

Pennington Biomedical Research Center (V.P., M.A.S., G.E.J., T.W.G.), Baton Rouge, Louisiana 70808; and Department of Medicine (P.M.W., I.C.F.), Medical University of South Carolina, Charleston, South Carolina 29425-2223

Address all correspondence and requests for reprints to: Thomas W. Gettys, Pennington Biomedical Research, 6400 Perkins Road, Baton Rouge, Louisiana 70808. E-mail: gettystw{at}pbrc.edu.

Changes in the biological efficacy of leptin were evaluated in obesity-resistant (A/J) and obesity-prone (C57BL/6J) mice at weaning and after consuming a high-fat (HF) diet for 4 and 8 wk. There was no evidence of leptin resistance in either strain at the start of the study, but after 4 and 8 wk on the HF diet, C57BL/6J mice became unresponsive to ip leptin. C57BL/6J mice responded to intracerebroventricular leptin at these time points but developed peripheral resistance to sympathetic stimulation of retroperitoneal white adipose tissue. In contrast, intracerebroventricular leptin was fully effective in A/J mice, reproducing the complete profile of responses observed in weanling mice. A/J mice were also partially responsive to ip leptin at both time points, increasing uncoupling protein 1 mRNA expression in brown adipose tissue and decreasing leptin mRNA in white adipose tissue. The findings indicate that retention of leptin responsiveness is an important component of the ability of A/J mice to mount a robust adaptive thermogenic response and resist diet-induced obesity.

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