Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes

Abstract

We have generated mice that carry a neuron-specific leptin receptor (LEPR) transgene whose expression is driven by the rat synapsin I promoter synapsin-LEPR B (SYN-LEPR-B). We have also generated mice that are compound hemizygotes for the transgenes SYN-LEPR-B and neuron-specific enolase-LEPR B (NSE-LEPR-B). We observed a degree of correction in db/db mice that are hemizygous (Syn db/db) and homozygous (Syn/Syn db/db) for the SYN-LEPR-B transgene similar to that previously reported for the NSE-LEPR-B transgene. We also show complete correction of the obesity and related phenotypes of db/db mice that are hemizygous for both NSE-LEPR-B and SYN-LEPR-B transgenes (Nse+Syn db/db). Body composition, insulin sensitivity, and cold tolerance were completely normalized in Nse+Syn db/db mice at 12 weeks of age compared with lean controls. In situ hybridization for LEPR B isoform expression in Nse+Syn db/db mice showed robust expression in the energy homeostasis-relevant regions of the hypothalamus. Expression of 3 neuropeptide genes, agouti-related peptide (Agrp), neuropeptide Y (Npy), and proopiomelanocortin (Pomc), was fully normalized in dual transgenic db/db mice. The 2 transgenes in concert conferred normal fertility to male and female db/db mice. Male mice with partial peripheral deletion of Lepr, induced in the periweaning phase, did not show alterations in body composition or mass. In summary, we show that brain-specific leptin signaling is sufficient to reverse the obesity, diabetes, and infertility of db/db mice.

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

“…LR is also expressed in gonads (47), but most of leptin's effects on the reproductive axis are relayed by the brain (48)(49)(50). One potential candidate is the AgRP neuronal population, due to its role in leptin's function and the disrupted expression of AgRP mRNA and peptide of LR Δα mice (51-53).…”

Astrocytic leptin-receptor knockout mice show partial rescue of leptin resistance in diet-induced obesity

“…By contrast, mice with neuronal ObR knockout show prominent obesity with gains in weight and fat. This is observed in knockout mice generated by neuronal excision of either the entire ObR with a floxed ObR line flanking exon 1 of the gene (4) or the cytoplasmic signaling tails of ObR with a floxed ObR line flanking exon 17, resulting in a mutant but membrane-bound receptor (5,15). Nonetheless, a small number of neural progenitor cells also use the GFAP promoter, and there can be variability in the efficiency and regional difference of expression (2).…”

“…They have hyperleptinemia, hyperinsulinemia, hypercorticosteronemia, infertility, and cold intolerance. Neuronal-specific mutation of ObR impairs hypothalamic functions and mimics the obese phenotype observed in db/db mice (4,5,15). The metabolic phenotype of astrocytic ObR mutation, however, has not yet been reported.…”

Serum leptin level and cognition in the elderly: Findings from the Health ABC Study

“…However, in vivo studies have shown that leptin improves insulin sensitivity (Ebihara et al, 2001;Lin et al, 2002;Ogawa et al, 1999;Yamauchi et al, 2001) and normalize glucose metabolism in rodents (Chinookoswong et al, 1999;Masuzaki et al, 1999). Transgenic expression of neuron-specific leptin receptor in receptor-deficient mice leads to amelioration of diabetes (de Luca et al, 2005). Additionally, leptin has been shown to have an antidiabetic function through control of intracellular fatty acid metabolism, maintenance of glucose sensitivity, and prevention of islet lipotoxicity (Shimabukuro et al, 1997;Shimokawa and Higami, 2001;Unger, 2005).…”