Leptin's Effects Modulated by GABAergic Neurons

Paula G F Quaresma, Frederick Wasinski, Naira S Mansano, Isadora C Furigo, Pryscila D S Teixeira, Daniela O Gusmao, Renata Frazao, Jose Donato, Jr.
Endocrinology, Volume 162, Issue 11, November 2021, bqab168
https://doi.org/10.1210/endocr/bqab168

Abstract

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^+∕+ 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 α-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.

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