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Adaptive thermogenesis is a vital physiological process for small endotherms. Female animals usually are more sensitive to cold temperature due to anatomical differences. Whether there is a sex difference at a molecular level is unclear. Stress granules (SGs) are dynamic organelles in which untranslated mRNAs reside during cellular stress. We hypothesize that the prompt response of SGs to cold stress can reveal the molecular difference between sexes. By analyzing the content in SGs of brown adipose tissue (BAT) at the early phase of cold stress for both sexes, we found more diverse mRNAs docked in the SGs in male mice and these mRNAs representing an extensive cellular reprogramming including apoptosis process and cold-induced thermogenesis. In female mice, the mRNAs in SGs dominantly were comprised of genes regulating ribonucleoprotein complex biogenesis. Conversely, the proteome in SGs was commonly characterized as structure molecules and RNA processing for both sexes. A spectrum of eukaryotic initiation factors (eIFs) was detected in the SGs of both female and male BAT, while those remained unchanged upon cold stress in male mice, various eIF3 and eIF4G isoforms were found reduced in female mice. Taken together, the unique features in SGs of male BAT reflected a prompt uncoupling protein-1 (UCP1) induction which was absent in female, and female, by contrast, were prepared for long-term transcriptional and translational adaptations. NEW & NOTEWORTHY: The proteome analysis reveals that stress granules are the predominant form of cytosolic messenger ribonucleoproteins of brown adipose tissue (BAT) at the early phase of cold exposure in mice for both sexes. The transcriptome of stress granules of BAT unveils a sex difference of molecular response in early phase of cold exposure in mice, and such difference prepares for a prompt response to cold stress in male mice while for long-term adaptation in female mice. [ABSTRACT FROM AUTHOR]

In the endocrine pancreas, growth hormone (GH) is known to promote pancreatic islet growth and insulin secretion. In this study, we show that GH receptor (GHR) loss in the germline and in adulthood impacts islet mass in general but more profoundly in male mice. GHR knockout (GHRKO) mice have enhanced insulin sensitivity and low circulating insulin. We show that the total cross-sectional area of isolated islets (estimated islet mass) was reduced by 72% in male but by only 29% in female GHRKO mice compared with wild-type controls. Also, islets from GHRKO mice secreted ∼50% less glucose-stimulated insulin compared with size-matched islets from wild-type mice. We next used mice with a floxed Ghr gene to knock down the GHR in adult mice at 6 mo of age (6mGHRKO) and examined the impact on glucose and islet metabolism. By 12 mo of age, female 6mGHRKO mice had increased body fat and reduced islet mass but had no change in glucose tolerance or insulin sensitivity. However, male 6mGHRKO mice had nearly twice as much body fat, substantially reduced islet mass, and enhanced insulin sensitivity, but no change in glucose tolerance. Despite large losses in islet mass, glucose-stimulated insulin secretion from isolated islets was not significantly different between male 6mGHRKO and controls, whereas isolated islets from female 6mGHRKO mice showed increased glucose-stimulated insulin release. Our findings demonstrate the importance of GH to islet mass throughout life and that unique sex-specific adaptations to the loss of GH signaling allow mice to maintain normal glucose metabolism. [ABSTRACT FROM AUTHOR]

While it has long been known that contraction robustly stimulates skeletal muscle glucose uptake, the molecular steps regulating this increase remain incompletely defined. The mammalian ortholog of Sir2, sirtuin 1 (SIRT1), is an NAD+-dependent protein deacetylase that is thought to link perturbations in energy flux associated with exercise to subsequent cellular adaptations. Nevertheless, its role in contraction-stimulated glucose uptake has not been described. The objective of this study was to determine the importance of SIRT1 to contraction-stimulated glucose uptake in mouse skeletal muscle. Using a radioactive 2-deoxyglucose uptake (2DOGU) approach, we measured ex vivo glucose uptake in unstimulated (rested) and electrically stimulated (100 Hz contraction every 15 s for 10 min; contracted) extensor digitorum longus (EDL) and soleus from ∼15-wk-old male and female mice with muscle-specific knockout of SIRT1 deacetylase activity and their wild-type littermates. Skeletal muscle force decreased over the contraction protocol, although there were no differences in the rate of fatigue between genotypes. In EDL and soleus, loss of SIRT1 deacetylase activity did not affect contraction-induced increase in glucose uptake in either sex. Interestingly, the absolute rate of contraction-stimulated 2DOGU was ∼1.4-fold higher in female compared with male mice, regardless of muscle type. Taken together, our findings demonstrate that SIRT1 is not required for contraction-stimulated glucose uptake in mouse skeletal muscle. Moreover, to our knowledge, this is the first demonstration of sex-based differences in contraction-stimulated glucose uptake in mouse skeletal muscle. [ABSTRACT FROM AUTHOR]

High-fat diet (HFD) feeding or leptin-deficient mice are extensively used as models resembling features of human nonalcoholic fatty liver disease (NAFLD). The concurrence of experimental factors as fat content and source or total caloric intake leads to prominent differences in the development of the hepatic steatosis and related disturbances. In this work, we characterized the hepatic lipid accumulation induced by HFD in wild-type (WT) and ob/ob mice with the purpose of differentiating adaptations to HFD from those specific of increased overfeeding due to leptin deficiency-associated hyperphagia. Given that most published works have been done in male models, we used female mice with the aim of increasing the body of evidence regarding NAFLD in female subjects. HFD promoted liver lipid accumulation only in the hyperphagic strain. Nevertheless, a decrease of lipid droplet-associated cholesteryl ester (CE) in both WT and obese animals was observed. These changes were accompanied by an improvement in the profile of lipoproteins that transport cholesterol and liver function markers in plasma from ob/ob mice and a lower hepatic index. Using primary hepatocytes from female mice, overaccumulation of CE induced by 0.4 mM oleic acid reversed in the presence of a specific Takeda G protein-coupled bile acid receptor agonist. Nevertheless, hepatocytes from male mice were not responsive. This study suggests that enterohepatic circulation of bile acids might be one of the factors that can affect sex dimorphism in NAFLD development, which underlines the importance of including female models in the NAFLD research field. NEW & NOTEWORTHY This work provides new insight into the use of high-fat diet as a model to induce nonalcoholic fatty liver disease in wild-type and ob/ob female mice. We show that high-fat diet induces steatosis only in ob/ob mice while, surprisingly, several health indicators improve. Noteworthy, experiments with primary hepatocytes from male and female mice show that they express Takeda G protein-coupled bile acid receptor and that it and bile acid enterohepatic circulation might be accountable for sex dimorphism in nonalcoholic fatty liver disease development. [ABSTRACT FROM AUTHOR]

Abnormal pulmonary vascular development is a critical factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Despite the well-established sex-specific differences in the incidence of BPD, the molecular mechanism(s) behind these are not completely understood. Exposure to a high concentration of oxygen (hyperoxia) contributes to BPD and creates a profibrotic environment in the lung. Our objective was to elucidate the sex-specific differences in neonatal human pulmonary microvascular endothelial cells (HPMECs) in normoxic and hyperoxic conditions, including the propensity for endothelial-to-mesenchymal transition. HPMECs (18- to 24-wk gestation donors, 6 male donors and 5 female donors) were subjected to hyperoxia (95% O2 and 5% CO2) or normoxia (air and 5% CO2) up to 72 h. We assessed cell migration and angiogenesis at baseline. Cell proliferation, viability, and expression of endothelial (CD31) and fibroblast markers (α-smooth muscle actin) were measured upon exposure to hyperoxia. Female HPMECs had significantly higher cell migration when assessed by the wound healing assay (40.99 ± 4.4%) compared with male HPMECs (14.76 ± 3.7%) and showed greater sprouting (1710 ± 962 βm in female cells vs. 789 ± 324 in male cells) compared with male endothelial cells in normoxia. Hyperoxia exposure decreased cell viability (by 9.8% at 48 h and 11.7% at 72 h) and proliferation (by 26.7% at 72 h) markedly in male HPMECs, whereas viability was sustained in female endothelial cells. There was greater expression of α-smooth muscle actin (2.5-fold) and decreased expression (5-fold) of CD31 in male HPMECs upon exposure to hyperoxia. The results indicate that cellular sex affects response in HPMECs in normoxia and hyperoxi. [ABSTRACT FROM AUTHOR]

00075.2018.--Bronchopulmonary dysplasia (BPD) is a chronic lung disease of the neonate characterized by impaired alveolarization and vascular growth. BPD is more common in premature male infants, but the reasons underlying sexually dimorphic outcomes are not known. It is thought that alterations in fibroblast phenotype in response to environmental stress such as hyperoxia contribute to BPD. Notch signaling creates a profibrotic environment in the lung. However, the role of hyperoxia on differential Notch pathway activation in male vs. female neonatal lung fibroblasts is not known. Primary murine lung fibroblasts from 10-day-old male and female mice were exposed to room air (21% O2, 5% CO2) or hyperoxia (95% O2, 5% CO2), and changes in cell proliferation, viability and expression of fibrosis-related genes and Notch pathway mediators were measured. Upon exposure to hyperoxia, cell proliferation was arrested in male and female fibroblasts, but cell viability was preserved. Increased Notch pathway activation was noted in male fibroblasts along with differential sexspecific modulation of key Notch pathway mediators in response to hyperoxia. α-Smooth muscle actin expression was increased in both male and female fibroblasts upon exposure to hyperoxia. Male and female fibroblasts further demonstrated distinct changes in expression of key fibrosis-related genes upon exposure to hyperoxia. Differential Notch pathway activation and distinct differences in the expression of key fibrosis-related genes might contribute to the sex-specific differences seen in hyperoxia-induced fibrosis and inhibition of lung development in BPD, with more severe implications in male neonates. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Even when patients survive the initial insult, there is significant morbidity and mortality secondary to subsequent pulmonary edema, acute lung injury (ALI), and nosocomial pneumonia. Whereas the relationship between TBI and secondary pulmonary complications is recognized, little is known about the mechanistic interplay of the two phenomena. Changes in mental status secondary to acute brain injury certainly impair airway- and lung-protective mechanisms. However, clinical and translational evidence suggests that more specific neuronal and cellular mechanisms contribute to impaired systemic and lung immunity that increases the risk of TBI-mediated lung injury and infection. To better understand the cellular mechanisms of that immune impairment, we review here the current clinical data that support TBI-induced impairment of systemic and lung immunity. Furthermore, we also review the animal models that attempt to reproduce human TBI. Additionally, we examine the possible role of damage-associated molecular patterns, the chlolinergic anti-inflammatory pathway, and sex dimorphism in post-TBI ALI. In the last part of the review, we discuss current treatments and future pharmacological therapies, including fever control, tracheostomy, and corticosteroids, aimed to prevent and treat pulmonary edema, ALI, and nosocomial pneumonia after TBI. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that endogenous brain Epo is a respiratory stimulant. Adult (3 mo) and newborn (10 days) male and female mice received an intracisternal (cisterna magna) injection of soluble Epo receptor (sEpoR; competes with EpoR to bind Epo; 50 µg/ml) or vehicle (0.1% BSA in PBS). Twenty-four hours after injection, we used whole body plethysmography to record minute ventilation (...E) tidal volume (VT), respiratory frequency (fR), O2 consumption (...O2), and CO2 production (...CO2) under normoxia and progressive exposure to hypoxia (12-10-6% O2; 10 min each). In adult male and female mice sEpoR decreased normoxic ...E (25%), due to a decrease of VT in males and fR in females. Moreover, sEpoR injection decreased the ventilatory response to 12% O2, assessed as ...E/...O2 or ...E/...CO2, in male but not in female mice. In newborn male and female mice sEpoR decreased ...E (-37% in males, -59% in females) and VT (-38% in males, -47% in females) in normoxia and fR in females. During hypoxia, sEpoR decreased ...E/...O2 and ...E/...CO2 in mice of both sexes. Upon extreme hypoxia (6% O2), the newborn mice treated with sEpoR showed respiratory depression, signs of asphyxia (gasping) and a high mortality rate in males and females. We concluded that endogenous brain Epo is a potent respiratory stimulant under normoxia and hypoxia in adult and newborn mice. Because sex-specific effects are different in newborn male and female, sex steroids secreted at different ages mice appear to modulate the effects of Epo on respiratory regulation in normoxia and in response to hypoxia. [ABSTRACT FROM AUTHOR]