Transgenic complementation of leptin-receptor deficiency: I. rescue of the obesity/diabetes phenotype of LEPR-null mice expressing a LEPR-B transgene

TJ Kowalski, SM Liu, RL Leibel, SC Chua Jr - Diabetes, 2001 - Am Diabetes Assoc
TJ Kowalski, SM Liu, RL Leibel, SC Chua Jr
Diabetes, 2001Am Diabetes Assoc
Mice homozygous for the Leprdb3J (db3J) 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 Leprdb (db) mutation (lacking the B isoform
only) have the same phenotype as db3J animals. To better understand the function (s) of the
LEPR isoforms in vivo, we generated db3J/db3J and db/db mice bearing a transgene
(neuron-specific enolase [NSE]-Rb) expressing the B isoform of LEPR, the isoform capable …
Mice homozygous for the Leprdb3J(db3J) 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 Leprdb (db) mutation (lacking the B isoform only)have the same phenotype as db3J animals. To better understand the function(s) of the LEPR isoforms in vivo, we generated db3J/db3J 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 db3J/db3J 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/dbmice) were similar to those of NSE-Rb db3J/db3Jmice, 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 neuroen-docrine system, and glucose metabolism.
Am Diabetes Assoc