Sex Difference in Corticosterone-Induced Insulin Resistance in Mice

Prolonged exposure to glucocorticoids (GCs) causes various metabolic derangements. These include obesity and insulin resistance, as inhibiting glucose utilization in adipose tissues is a major function of GCs. Although adipose tissue distribution and glucose homeostasis are sexdependently regulated, it has not been evaluated whether GCs affect glucose metabolism and adipose tissue functions in a sex-dependent manner. In this study, high-dose corticosterone (rodent GC) treatment in C57BU6J mice resulted in nonfasting hyperglycemia in male mice only, whereas both sexes displayed hyperinsulinemia with normal fasting glucose levels, indicative of insulin resistance. Metabolic testing using stable isotope-labeled glucose techniques revealed a sex-specific corticosterone-driven glucose intolerance. Corticosterone treatment increased adipose tissue mass in both sexes, which was reflected by elevated serum leptin levels. However, female mice showed more metabolically protective adaptations of adipose tissues than did male mice, demonstrated by higher serum total and high-molecular-weight adiponectin levels, more hyperplastic morphological changes, and a stronger increase in mRNA expression of adipogenic differentiation markers. Subsequently, in vitro studies in 3T3-L1 (white) and T37i (brown) adipocytes suggest that the increased leptin and adiponectin levels were mainly driven by the elevated insulin levels. In summary, this study demonstrates that GC-induced insulin resistance is more severe in male mice than in female mice, which can be partially explained by a sex-dependent adaptation of adipose tissues.</p

Sex difference in thermal preference of adult mice does not depend on presence of the gonads

Background: The thermoneutral zone (TNZ) is a species-specific range of ambient temperature (T a), at which mammals can maintain a constant body temperature with the lowest metabolic rate. The TNZ for an adult mouse is between 26 and 34 °C. Interestingly, female mice prefer a higher T a than male mice although the underlying mechanism for this sex difference is unknown. Here, we tested whether gonadal hormones are dominant factors controlling temperature preference in male and female mice. Methods: We performed a temperature preference test in which 10-week-old gonadectomized and sham-operated male and female C57BL/6J mice were allowed to choose to reside at the thermoneutral cage of 29 °C or an experimental cage of 26, 29, or 32 °C. Results: All mice preferred a T a higher than 26 °C, especially in the inactive phase. Choosing between 29 and 32 °C, female mice resided more at 32 °C while male mice had no preference between the temperatures. Hence, the preferred T a for female mice was significantly higher (0.9 ± 0.2 °C) than that for male mice. However, gonadectomy did not

Estrogens increase expression of bone morphogenetic protein 8b in brown adipose tissue of mice

Background: In mammals, white adipose tissue (WAT) stores fat and brown adipose tissue (BAT) dissipates fat to produce heat. Several studies showed that females have more active BAT. Members of the bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) families are expressed in BAT and are involved in BAT activity. We hypothesized that differential expression of BMPs and FGFs might contribute to sex differences in BAT activity. Methods: We investigated the expression of BMPs and FGFs in BAT of male and female C57BL/6J mice upon gonadectomy, cold exposure, and exposure to sex steroids. Results: Of the FGF family, BAT Fgf1, Fgf9, Fgf18, and Fgf21 expression was induced upon cold exposure, but only Fgf1 expression was obviously different between the sexes: females had 2.5-fold lower BAT Fgf1 than males. Cold exposure induced BAT Bmp4 and Bmp8b expression, but only Bmp8b differed between the sexes: females had 35-fold higher BAT Bmp8b than males. Ovariectomy almost completely blunted BAT Bmp8b expression, while orchidectomy had no effect. Male mice and ovariectomized female mice treated with diethylstilbestrol (DES) had approximately 350-fold and approximately 36-fold higher BAT Bmp8b expression, respectively. Ninety-day and 7-day treatment of female mice with dihydrotestosterone (DHT) decreased BAT Bmp8b expression by approximately fivefold and approximately fourfold, respectively. Finally, treatment of primary murine brown adipocytes with DES did not result in changes in Bmp8b expression. Conclusions: BAT Bmp8b expression in mice is positively regulated by presence of ovaries and estrogens such as DES

Sex difference in cold perception and shivering onset upon gradual cold exposure

To maintain a thermal balance when experiencing cold, humans reduce heat loss and enhance heat production. A potent and rapid mechanism for heat generation is shivering. Research has shown that women prefer a warmer environment and feel less comfortable than men in the same thermal condition. Using the Blanketrol® III, a temperature management device commonly used to study brown adipose tissue activity, we tested whether the experimental temperature (_TE_) at which men and women start to shiver differs. Twenty male and 23 female volunteers underwent a cooling protocol, starting at 24 °C and gradually decreasing by 1–2 °C every 5 min until an electromyogram detected the shivering or the temperature reached 9 °C. Women started shivering at a higher _TE_ than men (11.3 ± 1.8 °C for women _vs_ 9.6 ± 1.8 °C for men, _P_ = 0.003). In addition, women felt cool, scored by a visual analogue scale, at a higher _TE_ than men (18.3 ± 3.0 °C for women _vs_ 14.6 ± 2.6 °C for men, _P_ < 0.001). This study demonstrate

Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

Steroid receptors are pleiotropic transcription factors that coordinate adaptation to different physiological states. An important target organ is the brain, but even though their effects are well studied in specific regions, brain-wide steroid receptor targets and mediators remain largely unknown due to the complexity of the brain. Here, we tested the idea that novel aspects of steroid action can be identified through spatial correlation of steroid receptors with genome-wide mRNA expression across different regions in the mouse brain. First, we observed significant coexpression of six nuclear receptors (NRs) [androgen receptor (Ar), estrogen receptor alpha (Esr1), estrogen receptor beta (Esr2), glucocorticoid receptor (Gr), mineralocorticoid receptor (Mr), and progesterone recep

Sex Differences in Brown Adipose Tissue Function: Sex Hormones, Glucocorticoids, and Their Crosstalk

Excessive fat accumulation in the body causes overweight and obesity. To date, research has confirmed that there are two types of adipose tissue with opposing functions: lipid-storing white adipose tissue (WAT) and lipid-burning brown adipose tissue (BAT). After the rediscovery of the presence of metabolically active BAT in adults, BAT has received increasing attention especially since activation of BAT is considered a promising way to combat obesity and associated comorbidities. It has become clear that energy homeostasis differs between the sexes, which has a significant impact on the development of pathological conditions such as type 2 diabetes. Sex differences in BAT activity may contribute to this and, therefore, it is important to address the underlying mechanisms that contribute to sex differences in BAT activity. In this review, we discuss the role of sex hormones in the regulation of BAT activity under physiological and some pathological conditions. Given the increasing number of studies suggesting a crosstalk between sex hormones and the hypothalamic-pituitary-adrenal axis in metabolism, we also discuss this crosstalk in relation to sex differences in BAT activity

Sex difference in the mouse BAT transcriptome reveals a role of progesterone

Brown adipose tissue (BAT) is a metabolically active organ that exhibits sex-differential features, that is, being generally more abundant and active in females than in males. Although sex steroids, particularly estrogens, have been shown to regulate BAT thermogenic function, the underlying molecular mechanisms contributing to sexual dimorphism in basal BAT activity have not been elucidated. Therefore, we assessed the transcriptome of interscapular BAT of male and female C57BL/6J mice by RNA sequencing and identified 295 genes showing ≥2-fold differential expression (adjusted P < 0.05). In silico functional annotation clustering suggested an enrichment of genes encoding proteins involved in cell-cell contact, interaction, and adhesion. Ovariectomy reduced the expression of these genes in female BAT toward a male pattern whereas orchiectomy had marginal effects on the transcriptional pattern, indicating a prominent role of female gonadal hormones in this sex-differential expression pattern. Progesterone was identified as a possible upstream regulator of the sex-differentially expressed genes. Studying the direct effects of progesterone in vitro in primary adipocytes showed that progesterone significantly altered the transcription of several of the identified genes, possibly via the glucocorticoid receptor. In conclusion, this study reveals a sexually dimorphic transcription profile in murine BAT at general housing conditions and demonstrates a role for progesterone in the regulation of the interscapular BAT transcriptome

Sex difference in the mouse BAT transcriptome reveals a role of progesterone in BAT function: Supplementary data

Supplementary table: Selected genes from the significant functional annotation clusters and their functional descriptio

Pharmacological LXR activation reduces presence of SR-B1 in liver membranes contributing to LXR-mediated induction of HDL-cholesterol

Objective: Pharmacological LXR activation has anti-atherosclerotic actions in animal models. Part of these beneficial effects may be explained by accelerated reverse cholesterol transport since both plasma high density lipoprotein (HDL) cholesterol and fecal neutral sterol secretion are higher upon LXR activation. Mechanisms underlying these LXR-mediated effects have not been fully elucidated. Methods: We investigated the roles of the isoforms LXRα and LXRβ and the HDL cholesterol uptake receptor SR-B1 in modulation of cholesterol metabolism upon treatment of mice with the LXR ligand T0901317. Results: HDL cholesterol was maximally 60% increased in a time-dependent fashion due to appearance of more and larger HDL particles. Fecal neutral sterol secretion was maximally induced after 1. week treatment. T0901317 treatment induced fecal neutral sterol secretion by ∼300% in wild-type but not in Lxrα deficient mice. Surprisingly, LXR activation reduced SR-B1 protein amount in hepatic membranes, suggesting that this might contribute to elevated HDL cholesterol. However, T0901317 still elevated plasma HDL cholesterol in Sr-b1 deficient mice, suggesting that SR-B1 is not the only step involved in LXR-mediated induction of plasma HDL cholesterol. In addition, SR-B1 is not essential for LXR-induced cholesterol removal from the body. Conclusion: Induction of fecal neutral sterol secretion by T0901317 critically depends on LXRα but not on LXRβ. LXR activation reduces SR-B1 in hepatic membranes, probably partly contributing to elevated HDL cholesterol. SR-B1 is not required to enhance fecal neutral sterol secretion