Leptin Receptor Expression in GABAergic Cells is Not Sufficient to Normalize Metabolism and Reproduction in Mice

Previous studies indicate that leptin receptor (LepR) expression in GABAergic neurons is necessary for the biological effects of leptin. However, it is not clear whether LepR expression only in GABAergic neurons is sufficient to prevent the metabolic and neuroendocrine imbalances caused by LepR deficiency. In the present study, we produced mice that express the LepR exclusively in GABAergic cells (LepR(VGAT) mice) and compared them with wild-type (LepR(+/+)) and LepR-deficient (LepR(Null/Null)) mice. Although LepR(VGAT) mice showed a pronounced reduction in body weight and fat mass, as compared with LepR(Null/Null) mice, male and female LepR(VGAT) mice exhibited an obese phenotype relative to LepR+ 4 mice. Food intake was normalized in LepR(VGAT) mice ; however, LepR(VGAT) mice still exhibited lower energy expenditure in both sexes and reduced ambulatory activity in the females, compared with LepR(+/+) mice. The acute anorexigenic effect of leptin and hedonic feeding were normalized in LepR(VGAT) mice despite the hyperleptinemia they present. Although LepR(VGAT) mice showed improved glucose homeostasis compared with LepR(Null/Null) mice, both male and female LepR(VGAT) mice exhibited insulin resistance. In contrast, LepR expression only in GABAergic cells was sufficient to normalize the density of agouti-related peptide (AgRP) and alpha-MSH immunoreactive fibers in the paraventricular nucleus of the hypothalamus. However, LepR(VGAT) mice exhibited reproductive dysfunctions, including subfertility in males and alterations in the estrous cycle of females.Taken together, our findings indicate that LepR expression in GABAergic cells, although critical to the physiology of leptin, is insufficient to normalize several metabolic aspects and the reproductive function in mice.

Automated summary

The expression of LepR in GABAergic cells is critical for the physiological effects of leptin, but it is insufficient to normalize several metabolic aspects and reproductive function in mice.