Sex differences in somatotrope response to fasting: biphasic responses in male mice.
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ABSTRACT:
SUBMITTER: Miles TK
PROVIDER: S-EPMC7673470 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The glucose-6-phosphatase catalytic 2 (G6PC2) gene is expressed specifically in pancreatic islet beta cells. Genome-wide association studies have shown that single nucleotide polymorphisms in the G6PC2 gene are associated with variations in fasting blood glucose (FBG) but not fasting plasma insulin. Molecular analyses examining the functional effects of these single nucleotide polymorphisms demonstrate that elevated G6PC2 expression is associated with elevated FBG. Studies in mice complement these genome-wide association data and show that deletion of the G6pc2 gene lowers FBG without affecting fasting plasma insulin. This suggests that, together with glucokinase, G6PC2 forms a substrate cycle that determines the glucose sensitivity of insulin secretion. Because genome-wide association studies and mouse studies demonstrate that elevated G6PC2 expression raises FBG and because chronically elevated FBG is detrimental to human health, increasing the risk of type 2 diabetes, it is unclear why G6PC2 evolved. We show here that the synthetic glucocorticoid dexamethasone strongly induces human G6PC2 promoter activity and endogenous G6PC2 expression in isolated human islets. Acute treatment with dexamethasone selectively induces endogenous G6pc2 expression in 129SvEv but not C57BL/6J mouse pancreas and isolated islets. The difference is due to a single nucleotide polymorphism in the C57BL/6J G6pc2 promoter that abolishes glucocorticoid receptor binding. In 6-hour fasted, nonstressed 129SvEv mice, deletion of G6pc2 lowers FBG. In response to the stress of repeated physical restraint, which is associated with elevated plasma glucocorticoid levels, G6pc2 gene expression is induced and the difference in FBG between wild-type and knockout mice is enhanced. These data suggest that G6PC2 may have evolved to modulate FBG in response to stress.
| S-EPMC4967123 | biostudies-other
Project description:BackgroundThe gut is a major energy consumer, but a comprehensive overview of the adaptive response to fasting is lacking. Gene-expression profiling, pathway analysis, and immunohistochemistry were therefore carried out on mouse small intestine after 0, 12, 24, and 72 hours of fasting.ResultsIntestinal weight declined to 50% of control, but this loss of tissue mass was distributed proportionally among the gut's structural components, so that the microarrays' tissue base remained unaffected. Unsupervised hierarchical clustering of the microarrays revealed that the successive time points separated into distinct branches. Pathway analysis depicted a pronounced, but transient early response that peaked at 12 hours, and a late response that became progressively more pronounced with continued fasting. Early changes in gene expression were compatible with a cellular deficiency in glutamine, and metabolic adaptations directed at glutamine conservation, inhibition of pyruvate oxidation, stimulation of glutamate catabolism via aspartate and phosphoenolpyruvate to lactate, and enhanced fatty-acid oxidation and ketone-body synthesis. In addition, the expression of key genes involved in cell cycling and apoptosis was suppressed. At 24 hours of fasting, many of the early adaptive changes abated. Major changes upon continued fasting implied the production of glucose rather than lactate from carbohydrate backbones, a downregulation of fatty-acid oxidation and a very strong downregulation of the electron-transport chain. Cell cycling and apoptosis remained suppressed.ConclusionThe changes in gene expression indicate that the small intestine rapidly looses mass during fasting to generate lactate or glucose and ketone bodies. Meanwhile, intestinal architecture is maintained by downregulation of cell turnover.
| S-EPMC2148066 | biostudies-literature
Project description:The adaptive fasting response is invoked as a promising cardiometabolic and neurodegenerative therapeutic pathway. We and others have defined the carbohydrate transporter glucose transporter 8 (GLUT8) as a critical regulator of hepatic and whole-organism metabolic homeostasis in the overfed and diabetic states. However, the functions of this critical transporter in the physiological fasting response remain poorly understood. Here, we tested the hypothesis that GLUT8 modulates the adaptive hepatic fasting response. We demonstrate that mice with targeted Slc2a8 disruption exhibit enhanced thermogenesis, ketogenesis, and peripheral lipid mobilization during fasting. These metabolic enhancements were observed in the context of mildly impaired hepatic mitochondrial oxidative metabolism in vivo and in vitro. Mechanistically, we show that hepatic peroxisome proliferator-activated receptor α (PPARα) and its transcriptional fasting response target hepatokine, fibroblast growth factor (FGF)21, are cell-autonomously hyperactivated in GLUT8-deficient liver and in isolated primary murine hepatocytes during nutrient depletion. Hepatic PPARα knockdown in GLUT8-deficient mice normalized the enhanced ketogenic and FGF21 secretory responses and decreased mitochondrial respiratory function without altering the hyperthermic response to fasting. Our data demonstrate that hepatocyte GLUT8 regulates adaptive fasting in part through regulation of the PPARα signaling cascade. Moreover, the ketotic and thermic responses to fasting are differentially encoded within the GLUT8-PPARα communication axis. GLUT8 therefore represents a therapeutic target that can be leveraged against cardiometabolic disease.
| S-EPMC6366533 | biostudies-literature
Project description:Within the mammalian olfactory sensory epithelium, experience-dependent changes in the rate of neuronal turnover can alter the relative abundance of neurons expressing specific chemoreceptors. Here we investigate how the mouse olfactory sensory receptor repertoire changes as a function of exposure to odors emitted from members of the opposite sex, which are highly complex and sexually dimorphic. Upon housing mice either sex-separated or sex-combined until six months of age, we find that sex-separated mice exhibit significantly more numerous differentially expressed genes within their olfactory epithelia. A subset of these chemoreceptors exhibit altered expression frequencies following both sex-separation and olfactory deprivation. We show that several of these receptors detect either male- or female-specific odors. We conclude that the distinct odor experiences of sex-separated male and female mice induce sex-specific differences in the abundance of neurons that detect sexually dimorphic odors.
| S-EPMC6279840 | biostudies-other
Project description:IntroductionHuman studies suggest that smoking behavior in men may depend more on the pharmacological effects of nicotine, whereas in women, this behavior may rely more on nonpharmacological factors associated with smoking. Investigation of these parameters in mice may also reveal sex differences.MethodsMale and female C57Bl/6:129SvEv hybrid mice were exposed to increasing concentrations of nicotine in a voluntary oral nicotine consumption paradigm in which we measured fluid consumption over time and dose. Separate cohorts of mice were exposed to nicotine in a place-conditioning paradigm, and preference was determined. These behavioral models were used to examine sex differences in mice as they rely on pharmacological as well as nonpharmacological factors. Mice exposed to nicotine or saline also were tested for sex differences in locomotor-activating effects of nicotine and in analgesia using standard activity monitoring and hot-plate tests.ResultsFemales responded more to the conditioned rewarding effects of nicotine compared with males. Males, however, seemed more responsive to the pharmacological aspects of nicotine by reducing nicotine drinking at higher concentrations; females maintained consistent levels of intake over several doses of nicotine. Male and female mice demonstrated similar locomotor and antinociceptive responses to nicotine.DiscussionThese data suggest that place-conditioning and two-bottle choice paradigms may be more sensitive measures of sexual dimorphism in the C57BL/6:129SvEv hybrid mouse than are locomotor or nociception assays.
| S-EPMC2699930 | biostudies-literature
Project description:Maternal low-protein (MLP) diet can lead to hepatic steatosis, which only develops with ageing. It is still unclear whether the young offspring show any signs of past exposure to prenatal adverse conditions. We hypothesized that early nutritional insult would first affect the dynamic responsiveness to nutritional challenges rather than the static state. We analyzed the transcriptome and metabolome profiles of the hepatic response to fasting/refeeding in young male mice offspring to identify changes induced by early gestational MLP diet. Restricted MLP exposure strictly to early gestation was achieved by the embryo transfer method. As a result, the fasting-induced upregulation of genes related to long-chain fatty acid metabolism and of stress response genes related to protein folding were significantly diminished in MLP pups. Lipid profiling after fasting showed that the hepatic signature of triacylglycerols was shifted to longer acyl-chains and higher saturation by the MLP diet. Bioinformatic analyses suggested that these phenomenological changes may be partially linked to the peroxisome proliferator activated receptor α (PPARα) pathway. Taken together, early gestational MLP diet affected the hepatic dynamic response to nutritional stress in seemingly healthy young offspring, accompanied with partial deterioration of PPARα action.
| S-EPMC5575317 | biostudies-literature
Project description:We have previously reported that the mouse gut microbiome contributes to pulmonary responses to ozone, a common asthma trigger, and that short-chain fatty acids, end products of bacterial fermentation, likely contribute to this role of the microbiome. A growing body of evidence indicates that there are sex-related differences in gut microbiota and these differences can have important functional consequences. The purpose of this study was to determine whether there are sex-related differences in the impact of the gut microbiota on pulmonary responses to ozone. After acute exposure to ozone, male mice developed greater airway hyperresponsiveness than female mice. This difference was abolished after antibiotic ablation of the gut microbiome. Moreover, weanling female pups housed in cages conditioned by adult male mice developed greater ozone-induced airway hyperresponsiveness than weanling female pups raised in cages conditioned by adult females. Finally, ad libitum oral administration via drinking water of the short-chain fatty acid propionate resulted in augmented ozone-induced airway hyperresponsiveness in male, but not female, mice. Overall, these data are consistent with the hypothesis that the microbiome contributes to sex differences in ozone-induced airway hyperresponsiveness, likely as a result of sex differences in the response to short-chain fatty acids.
| S-EPMC6376411 | biostudies-literature
Project description:Background The gut is a major energy consumer, but a comprehensive overview of the adaptive response to fasting is lacking. Gene-expression profiling, pathway analysis, and immunohistochemistry were therefore carried out on mouse small intestine after 0, 12, 24, and 72 hours of fasting. Results Intestinal weight declined to 50% of control, but this loss of tissue mass was distributed proportionally among the gut’s structural components, so that the microarrays’ tissue base remained unaffected. Unsupervised hierarchical clustering of the microarrays revealed that the successive time points separated into distinct branches. Pathway analysis depicted a pronounced, but transient early response that peaked at 12 hours, and a late response that became progressively more pronounced with continued fasting. Early changes in gene expression were compatible with a cellular deficiency in glutamine and metabolic adaptations directed at glutamine conservation, inhibition of pyruvate oxidation, stimulation of glutamate catabolism via aspartate and phosphoenolpyruvate to lactate, and enhanced fatty-acid oxidation and ketone-body synthesis. In addition, the expression of key genes involved in cell cycling and apoptosis was suppressed. At 24 hours of fasting, many of the early adaptive changes abated. Major changes upon continued fasting implied the production of glucose rather than lactate from carbohydrate backbones, a downregulation of fatty-acid oxidation and a very strong downregulation of the electron-transport chain. Cell cycling and apoptosis remained suppressed. Conclusion The changes in gene expression indicate that the small intestine rapidly looses mass during fasting to generate lactate or glucose and ketone bodies. Meanwhile, intestinal architecture is maintained by downregulation of cell turnover. Keywords: fasting response, time course
2007-11-12 | GSE8019 | GEO
Project description:Nickel nanoparticles (NiNPs) are increasingly used in nanotechnology applications, yet information on sex differences in NiNP-induced lung disease is lacking. The goal of this study was to explore mechanisms of susceptibility between male and female mice after acute or subchronic pulmonary exposure to NiNPs. For acute exposure, male and female mice received a single dose of NiNPs with or without LPS by oropharyngeal aspiration and were necropsied 24 h later. For subchronic exposure, mice received NiNPs with or without LPS six times over 3 weeks prior to necropsy. After acute exposure to NiNPs and LPS, male mice had elevated cytokines (CXCL1 and IL-6) and more neutrophils in bronchoalveolar lavage fluid (BALF), along with greater STAT3 phosphorylation in lung tissue. After subchronic exposure to NiNPs and LPS, male mice exhibited increased monocytes in BALF. Moreover, subchronic exposure of male mice to NiNP only induced higher CXCL1 and CCL2 in BALF along with increased alveolar infiltrates and CCL2 in lung tissue. STAT1 in lung tissue was induced by subchronic exposure to NiNPs in females but not males. Males had a greater induction of IL-6 mRNA in liver after acute exposure to NiNPs and LPS, and greater CCL2 mRNA in liver after subchronic NiNP exposure. These data indicate that susceptibility of males to acute lung inflammation involves enhanced neutrophilia with increased CXCL1 and IL-6/STAT3 signaling, whereas susceptibility to subchronic lung inflammation involves enhanced monocytic infiltration with increased CXCL1 and CCL2. STAT transcription factors appear to play a role in these sex differences. This study demonstrates sex differences in the lung inflammatory response of mice to NiNPs that has implications for human disease.
| S-EPMC8011295 | biostudies-literature
Project description:IntroductionThe problem of antibiotic resistance is a global one, involving many industries and entailing huge financial outlays. Therefore, the search for alternative methods to combat drug-resistant bacteria has a priority status. Great potential is seen in bacteriophages which have the natural ability to kill bacterial cells. Bacteriophages also have several advantages over antibiotics. Firstly, they are considered ecologically safe (harmless to humans, plants and animals). Secondly, bacteriophages preparations are readily producible and easy to apply. However, before bacteriophages can be authorized for medical and veterinary use, they must be accurately characterized in vitro and in vivo to determinate safety.MethodsTherefore, the aim of this study was to verify for the first time the behavioral and immunological responses of both male and female mice (C57BL/6J) to bacteriophage cocktail, composed of two bacteriophages, and to two commonly used antibiotics, enrofloxacin and tetracycline. Animal behavior, the percentage of lymphocyte populations and subpopulations, cytokine concentrations, blood hematological parameters, gastrointestinal microbiome analysis and the size of internal organs, were evaluated.ResultsUnexpectedly, we observed a sex-dependent, negative effect of antibiotic therapy, which not only involved the functioning of the immune system, but could also significantly impaired the activity of the central nervous system, as manifested by disruption of the behavioral pattern, especially exacerbated in females. In contrast to antibiotics, complex behavioral and immunological analyses confirmed the lack of adverse effects during the bacteriophage cocktail administration.DiscussionThe mechanism of the differences between males and females in appearance of adverse effects, related to the behavioral and immune functions, in the response to antibiotic treatment remains to be elucidated. One might imagine that differences in hormones and/or different permeability of the blood-brain barrier can be important factors, however, extensive studies are required to find the real reason(s).
| S-EPMC10247983 | biostudies-literature