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Glucocorticoid and Mineralocorticoid Receptor Signaling have Sex-dependent and Independent Effects in Mouse Hippocampus

ABSTRACT: Many stress-related neuropsychiatric disorders display pronounced sex differences in their frequency and clinical symptoms. Glucocorticoids are primary stress hormones that have been implicated in the development of these disorders but whether they contribute to the observed sex bias is poorly understood. Glucocorticoids signal through two closely related nuclear receptors, the glucocorticoid (GR) and mineralocorticoid receptor (MR), that are both expressed at high levels in the hippocampus. To investigate the sex-dependent and independent actions of glucocorticoids in the hippocampus, we developed knockout mice lacking hippocampal GR (GREmx1-cre), MR (MREmx1-cre), or both GR and MR (GRMREmx1-cre). Genome-wide microarrays were performed on RNA isolated from the hippocampus of male and female flox control and knockout mice in order to 1) identify genes dysregulated in a sex-dependent and independent manner by a deficiency in GR, MR, or both GR and MR signaling and 2) identify the genes responsible for the sex-dependent and independent phenotypes observed in these mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE240873 | GEO | 2023/12/05

REPOSITORIES: GEO

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Project description:Increased visceral adiposity and hyperglycemia, two characteristics of metabolic syndrome, are also present in conditions of excess glucocorticoids (GCs). GCs are hormones thought to act primarily via the glucocorticoid receptor (GR). GCs are commonly prescribed for inflammatory disorders, yet their use is limited due to many adverse metabolic side effects. In addition to GR, GCs also bind the mineralocorticoid receptor (MR), but there are many conflicting studies as to the exact role of MR in metabolic disease. Using MR knockout mice (MRKO), we find that both white and brown adipose depots form normally when compared to wild-type mice at P5. We created mice with adipocyte-specific deletion of MR (FMRKO) to better understand the role of MR in metabolic dysfunction. Treatment of mice with excess GCs for 4 weeks, via corticosterone in drinking water, induced increased fat mass and glucose intolerance to similar levels in FMRKO and floxed-control mice. Separately, when fed a high-fat diet for 16 weeks, FMRKO mice had reduced body weight, fat mass, and hepatic steatosis, relative to floxed-control mice. Decreased adiposity likely resulted from increased energy expenditure since food intake was not different. RNA sequencing analysis revealed decreased enrichment of genes associated with adipogenesis in inguinal white adipose of FMRKO mice. Differentiation of mouse embryonic fibroblasts (MEFs), showed modestly impaired adipogenesis in MRKO MEFs compared to wild-type, but this was rescued upon the addition of peroxisome proliferator-activated receptor gamma (PPARγ) agonist or PPARγ overexpression. Collectively, these studies provide further evidence supporting the potential value of MR as a therapeutic target for conditions associated with metabolic syndrome. Method (Chow): At six weeks of age mice were maintained on a chow diet (PicoLab® Rodent Diet 20 5053* [20% protein]) for 16 weeks Method (High Fat Diet): 6 week-old mice were fed ab libitum with Teklad TD.88137 (21.2% fat [42% kcal fat], 48.5% carbohydrate [34% sucrose by weight], 17.3% protein, and 0.2% cholesterol by weight) for 16 weeks Method (Corticosterone): 10-11-week-old mice were administered corticosterone via drinking water (100 μg/mL) for 4 weeks, while maintained on a chow diet

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Glucocorticoid and Mineralocorticoid Receptor Signaling have Sex-dependent and Independent Effects in Mouse Hippocampus

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