Work

SAT-130 Glucocorticoid Receptor Signaling in GABAergic, But Not Kisspeptin, Neurons Modulates AgRP Expression and Pubertal Timing in Male and Female Mice

Year: 2024

Type: article

Abstract: S.A. Pereira: None. A.N. Fontes: None. L. Arvizu-Sanchez: None. C.G. Meireles: None. R.S. Carroll: None. V.M. Navarro: None. U.B. Kaiser: None. Background and Objectives: Reproduction is tightly regulated by nutritional status and stress. Glucocorticoid (GC) secretion induced by metabolic stress due to negative energy balance can delay pubertal transition by inhibiting GnRH and LH release. Kisspeptin (Kiss1) neurons are the GnRH and LH pulse generator and key regulators of puberty and are proposed to play a role in mediating the effects of GC on reproduction. While the precise mechanisms by which nutritional deprivation affects regulation of Kiss1 neurons remain to be fully characterized, it is known that Kiss1 neurons are subject to regulation by multiple neural networks, among which GABAergic neurons appear to play a determinant role. Of note, a large proportion of GABAergic and Kiss1 neurons express glucocorticoid receptors (GR). Therefore, in this study we aimed to investigate whether the actions of GCs on puberty occur through GR-expressing GABAergic neurons and/or through GR-expressing Kiss1 neurons. Methods and Results: We generated mice with conditional deletion of GR in GABAergic or Kiss1 neurons using VgatCre or Kiss1Cre mice crossed with GRlox/lox mice to generate GABAGRKO or KISS1GRKO mice, respectively. The pubertal phenotypes of GABAGRKO and KISS1GRKO mice and their littermate controls (GRlox/lox) were characterized under ad libitum (AD) diet or during 50% caloric restriction (CR) after postnatal day 25 (PND25). While male and female KISS1GRKO mice had normal pubertal timing on AD diet, GABAGRKO mice of both sexes on AD diet had earlier puberty onset compared to controls. CR delayed puberty onset in both male and female control and KISS1GRKO mice, but not in GABAGRKO mice. Male and female GABAGRKO mice were euthanized at PND30 while on AD diet and their mediobasal hypothalami (MBH) were collected for mRNA measurement by RT-qPCR of genes known to be related to pubertal development, including Kiss1, Tac2, Pdyn, Agrp and Pomc. Kiss1 and Pdyn expression were higher in the MBH of GABAGRKO males compared to controls; in contrast, Pdyn expression was lower in the MBH of GABAGRKO females and Kiss1 expression was unchanged compared to controls. Agrp expression was lower in the MBH of both GABAGRKO male and female mice compared to controls. No differences were observed in Tac2 and Pomc expression. CR led to an increase of Agrp mRNA levels in the MBH of male and female control mice, but not in the MBH of male and female GABAGRKO mice at PND35. Conclusions: GR signaling in Kiss1 neurons does not affect pubertal timing under AD diet. In contrast, the absence of GR in GABAergic neurons results in early puberty onset in AD conditions as well as in resistance to CR-induced delayed puberty, associated with downregulation of Agrp expression in male and female GABAGRKO mice. These findings suggest a role of GCs acting on GR in GABA/AgRP neurons upstream of Kiss1 neurons to modulate puberty development. Saturday, June 1, 2024

Source: Journal of the Endocrine Society

DOI: 10.1210/jendso/bvae163.2414