Journal
DIABETES
Volume 50, Issue 2, Pages 425-435Publisher
AMER DIABETES ASSOC
DOI: 10.2337/diabetes.50.2.425
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Funding
- NIDDK NIH HHS [DK26687, DK52431] Funding Source: Medline
- NINDS NIH HHS [NS10675] Funding Source: Medline
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Mice homozygous for the Lepr(db3J) (db(3J)) mutation are null for all known isoforms of the leptin receptor (LEPR). These animals are obese, hyperphagic, cold intolerant, insulin resistant, and infertile. Mice homozygous for the Lepr(db) (db) mutation (lacking the B isoform only) have the same phenotype as db(3J) animals. To better understand the function(s) of the LEPR isoforms in vivo, we generated db(3J)/db(3J) and db/db mice bearing a transgene (neuron-specific enolase [NSE]Rb) expressing the B isoform of LEPR, the isoform capable of activating the signal transducer and activator of transcription (STAT) pathway, under the control of the neuron-specific enolase enhancer/promoter. The NSE-Rb transgene was expressed in the brain, with low levels of expression in adrenals, testis, and white adipose tissue. LEPR-B transgene expression in NSE-Rb db(3J)/db(3J) mice partially corrected the increased fat mass, hyperphagia, and glucose intolerance while restoring fertility in males and rescuing the cold intolerance in both sexes. The body weights of NSE-Rb transgenic mice that possessed the full complement of short LEPR isoforms (NSE-Rb db/db mice) were similar to those of NSE-Rb db(3J)/db(3J) mice, suggesting that the short LEPR isoforms play little role in body weight regulation. Based on quantitative analysis of hypothalamic neuropeptide gene expression in the transgenic animals, we infer full restoration of leptin sensitivity to proopiomelanocortin (POMC) neurons, partial correction of leptin sensitivity in agouti gene-related protein (AGRP)/neuropeptide Y (NPY) neurons, and a lack of effect on leptin sensitivity of melanin concentrating hormone neurons. Thus, hypothalamic POMC and AGRP/NPY neurons are primary candidates as the mediators of the effects of the NSE-Rb transgene on energy homeostasis, ingestive behavior, the neuroendocrine system, and glucose metabolism.
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