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In both humans and mice, the adrenal gland is a sexually dimorphic organ, but the extent of this diversity throughout development remains unclear. Here, we analyzed the mouse adrenal gland transcriptome at postnatal days 0, 7, 15, 21, 28, 35, and 49 to uncover its transcriptomic trajectory. Sex‐dependent differences, indicated by the number of differentially expressed genes, gradually increase over time. Two Y‐linked genes are consistently expressed in male adrenal glands, suggesting that factors beyond sex hormones may contribute to adrenal sexual dimorphism. Genes involved in steroidogenesis, cholesterol synthesis, and catecholamine synthesis exhibit sex‐ and age‐dependent differential expression. Weighted gene co‐expression network analysis (WGCNA) identified many genes with known zone‐specific adrenal expression, including Akr1c18, Pik3c2g, Cyp2f2, Dhcr24, Thrb, and Spp1, clustering within the same module. FRZB, a WNT inhibitor, was also part of this module, exhibiting sex‐ and age‐dependent expression. Immunostaining confirmed that FRZB is specifically expressed in the inner cortex, aligning with other inner cortex markers. Additionally, heatmap analysis revealed that many WNT downstream genes show age‐dependent increases in expression in males, corresponding to progressively lower Frzb levels, suggesting a regulatory role for Frzb in adrenal sexual dimorphism. Furthermore, collagen‐related genes were highlighted in the clustered heatmap of all differentially expressed genes due to their gradual decrease in expression over time. These observations suggest that this comprehensive dataset not only enhances our understanding of adrenal development and sexual dimorphism, aids in identifying novel marker genes for specific adrenal cell types, but also holds potential for contributing to aging research. This comprehensive RNA‐seq dataset reveals the sex‐ and age‐dependent gene expression profile of the mouse adrenal gland. It helps identify novel marker genes of the adrenal inner cortex, offering new insights into the organ's development and aging process.

Melanocortin-2 receptor accessory protein 2 (MRAP2) is essential for the intricate regulation of energy balance. Although rare MRAP2 variants have been reported in obese individuals, their overall impact on human obesity risk remains uncertain because previous studies were small, heterogeneous, and often lacked systematic functional characterization. To address this gap, we conducted a comprehensive systematic review and cohort-level meta-analysis to quantify the association between rare coding variants in MRAP2 and obesity. We systematically searched five major databases (Embase, PubMed, Scopus, Google Scholar, and Web of Science) and identified five eligible publications comprising seven independent cohorts. In total, 27 rare coding MRAP2 variants were observed in 46 (1.01%) individuals with obesity and 18 (0.34%) individuals with normal weight, among 9771 individuals (5223 with normal weight and 4548 with obesity). Using inverse-variance–weighted random-effects models fitted with restricted maximum likelihood, carriers of rare coding MRAP2 variants had higher odds of obesity (OR = 2.61; 95% CI, 1.49–4.58; p = 8.0 × 10−4). Taken together, these findings, derived predominantly from European-ancestry cohorts, support MRAP2 as a biologically plausible susceptibility gene for human obesity and indicate that rare coding MRAP2 variants are associated with higher odds of obesity, providing a quantitative framework to guide future large-scale genetic and functional studies.

Steroid hormones are synthesized through enzymatic reactions using cholesterol as the substrate. In steroidogenic cells, the required cholesterol for steroidogenesis can be obtained from blood circulation or synthesized de novo from acetate. One of the key enzymes that control cholesterol synthesis is 24-dehydrocholesterol reductase (encoded by DHCR24). In humans and rats, DHCR24 is highly expressed in the adrenal gland, especially in the zona fasciculata. We recently reported that DHCR24 was expressed in the mouse adrenal gland’s inner cortex and also found that thyroid hormone treatment significantly upregulated the expression of Dhcr24 in the mouse adrenal gland. In the present study, we showed the cellular expression of DHCR24 in mouse adrenal glands in early postnatal stages. We found that the expression pattern of DHCR24 was similar to the X-zone marker gene 20αHSD in most developmental stages. This finding indicates that most steroidogenic adrenocortical cells in the mouse adrenal gland do not synthesize cholesterol locally. Unlike the 20αHSD-positive X-zone regresses during pregnancy, some DHCR24-positive cells remain present in parous females. Conditional knockout mice showed that the removal of Dhcr24 in steroidogenic cells did not affect the overall development of the adrenal gland or the secretion of corticosterone under acute stress. Whether DHCR24 plays a role in conditions where a continuous high amount of corticosterone production is needed requires further investigation.

The Sonic Hedgehog (Shh) gene expressed in the subcapsular cortical region of the adrenal gland has been found to play a role in adrenal gland development. The Shh(+) cell population at the fetal stages contributes to different cortical layers in the adrenal gland. However, the (1) capability of these cells after weaning and (2) how soon they can renew the adrenal cortex in the postnatal stages is not fully understood. Here, we conducted a lineage tracing experiment to track Shh(+) cells and cells descended from them in post-weaning mice to ultimately better understand the processes of adrenal cortex renewal and remodeling over time in young adult mice. This experiment used the NuTRAP; Shh-Cre-ERT2 mice as the Shh-reporter mouse model. This tamoxifen-inducible mouse model allows us to specifically target and label Shh-expressing cells and all descendant cells with green fluorescence. Tamoxifen was given at postnatal days (P) 22, P24, and P26 to enable the Cre recombinase activity driven by the Shh promoter. Adrenal glands were then analyzed after two and four months. This lineage tracing experiment found that Shh(+) cells and their descendant cells reached the margin of the Cyp2f2(+) cortical zone in 2 months and the cortical-medullary boundary in 4 months. This finding indicates that the Shh(+) cell population in post-weaning mice can proliferate, differentiate, and eventually renew the entire adrenal cortex over a four-month period of time. Understanding the adrenal cortex's renewal rate helps us design our follow-up study to test the capability of Shh(+) cells in adult mice at different ages and how their potency changes overtime at the 'omic' level. Because this NuTRAP;Shh-Cre-ERT2 mouse model also allows us to isolate cell-type-specific DNA/RNA, we can further decipher the underlying gene/pathways which control this progenitor cell population of the adrenal gland cortex. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 1:12 p.m. - 1:17 p.m.

The gender bias in adrenal diseases has been noticed for a long time. Mouse studies have shown that the adrenal gland is sexually dimorphic at different levels, such as transcriptome, histology, and cell renewal. However, the mechanism behind this sexual dimorphism is not fully understood. Here, we used RNA-seq to demonstrate how male and female adrenals respond differently to the same external cue, the thyroid hormone (T3) treatment, which directly elicits its function on the adrenal inner cortex by changing the cell fate of this population. Through the comparison of the adrenal gland transcriptomes from males and females with T3 or saline treatment, we found that more genes in female adrenals were responsive to the T3 treatment, whereas the fold change of the gene expressions was greater in male adrenals. Statistical analysis identified 104 sexually dimorphic T3-responsive genes. Immunostaining results showed that many of these genes were expressed in the adrenal gland inner cortex, which contains a unique cell population called X-zone (20-alpha-HSD positive). Previous studies showed that T3 treatment leads to the expansion of the 20αHSD-positive zone both in males and in females. Here we found that the top sexually dimorphic T3-responsive gene was expressed in the adrenal inner cortex partially colocalized with X-zone. Under T3 treatment, this unique cell population that surrounds the 20-alpha-HSD positive X-zone became obvious only in females but not in males. Our findings not only identified several novel marker genes for the adrenal inner cortex but also highlighted the sex-specific response of thyroid hormone action in the mouse adrenal gland.

Researchers have long known that dexamethasone causes cellular and functional changes in the adrenal gland. For example, long-term dexamethasone treatment leads to reversible adrenal cortex atrophy. In the adrenal medulla, dexamethasone treatment alters the maturation and function of the neural crest-derived chromaffin cells. Here we aim to study the acute transcriptional effect of dexamethasone on mouse adrenal gland at the transcriptome level. Our data suggested that a one-hour dexamethasone treatment had a cell type-specific effect on the adrenal transcriptome. There were 922 dexamethasone-induced genes and 853 dexamethasone-suppressed genes. GO analysis showed that the upregulated genes were primarily linked to neuronal cell function. Clustered heatmaps further showed that many genes involved in the catecholamine synthesis were upregulated by dexamethasone treatment, whereas most genes involved in the steroidogenesis pathway were downregulated. Interestingly, steroidogenic factor 1 (SF1, encoded by Nr5a1), the critical transcription factor that regulates steroidogenesis, had a >2-fold decrease under the one-hour dexamethasone treatment, suggesting a possible mechanism of the acute suppression of steroidogenic activity. Our findings indicate that the acute effects of dexamethasone stimulate catecholamine synthesis in the medulla, whereas steroidogenesis in the cortex is suppressed by dexamethasone.