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Neuronal deletion of Lepr elicits diabesity in mice without affecting cold tolerance or fertility

¹Department of Pediatrics, Division of Molecular Genetics, Columbia University College of Physicians and Surgeons, New York, New York; ²Department of Physiology, University of Tennessee, Memphis, Tennessee; ³Department of Anatomy and Cell Biology, ⁴Institute for Cancer Genetics, and ⁵Institute of Human Nutrition, and ⁶St. Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, New York

Submitted 3 November 2004 ; accepted in final form 28 April 2005

Leptin signaling in the brain regulates energy intake and expenditure. To test the degree of functional neuronal leptin signaling required for the maintenance of body composition, fertility, and cold tolerance, transgenic mice expressing Cre in neurons (CaMKII-Cre) were crossed to mice carrying a floxed leptin receptor (Lepr) allele to generate mice with neuron-specific deletion of Lepr in 50% (C F/F mice) and 75% (C 17/F mice) of hypothalamic neurons. Leptin receptor (LEPR)-deficient mice (17/17) with heat-shock-Cre-mediated global Lepr deletion served as obese controls. At 16 wk, male C F/F, C 17/F, and 17/17 mice were 13.2 (P < 0.05), 45.0, and 55.9% (P < 0.001) heavier, respectively, than lean controls, whereas females showed 31.6, 68.8, and 160.7% increases in body mass (P < 0.001). Significant increases in total fat mass (C F/F: P < 0.01; C 17/F and 17/17:P < 0.001 vs. sex-matched, lean controls), and serum leptin concentrations (P < 0.001 vs. controls) were present in proportion to Lepr deletion. Male C 17/F mice had significant elevations in basal serum insulin concentrations (P < 0.001 vs. controls) and were glucose intolerant, as measured by glucose tolerance test (AUC P < 0.01 vs. controls). In contrast with previous observations in mice null for LEPR signaling, C F/F and C 17/F mice were fertile and cold tolerant. These findings support the hypothesis that body weight, adiposity, serum leptin concentrations, and glucose intolerance are proportional to hypothalamic LEPR deficiency. However, fertility and cold tolerance remain intact unless hypothalamic LEPR deficiency is complete.

leptin receptor; Cre recombinase

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