American journal of physiology. Endocrinology and metabolism最新文献

Diabetic complications are linked to oxidative stress, which hampers the cyclic guanosine monophosphate production by inhibiting nitric oxide/soluble guanylate cyclase (sGC) signaling. This study aimed to determine whether the administration of a novel sGC activator avenciguat alone or in combination with an SGLT2 inhibitor could slow the progression of renal and liver fibrosis in the type 2 diabetic and uninephrectomized db/db mouse model. Experiment groups included normal controls, untreated db/db mice terminated at 12 and 18 wk of age, and db/db mice treated with either one of two doses of avenciguat alone, empagliflozin (Empa) alone, or a combination of both from weeks 12 to 18 of age. Untreated db/db mice exhibited obesity, hyperglycemia, elevated levels of HbA1c and triglycerides (TG), and developed progressive albuminuria, glomerulosclerosis, fatty liver, and liver fibrosis between weeks 12 and 18 of age, accompanied by increased renal and liver production of fibronectin, type-IV collagen, laminin, and increased oxidative stress markers. Avenciguat had no effect on body weight but reduced both blood HbA1c and TG levels, whereas Empa reduced HbA1c but not TG levels as compared with untreated db/db. Both avenciguat and Empa alone effectively slowed the progression of diabetes-associated glomerulosclerosis and liver fibrosis. Importantly, avenciguat, especially at high doses in combination with Empa, further lowered these progression markers compared with baseline measurements. These results suggested that either avenciguat alone or in combination with Empa is therapeutic. Avenciguat in combination with Empa shows promise in halting the progression of diabetic complications.NEW & NOTEWORTHY Whether combining an sGC activator with an SGLT2 inhibitor could better control diabetes-associated oxidative stress and NO-cGMP signal deficiency has not yet been explored. Using the type 2 diabetic db/db mouse model, this study underscores the sGC activator avenciguat as a novel therapy for diabetic nephropathy and liver injury beyond sGLT2 inhibitors. It also highlights the need for further investigation into the combined effects of these two treatments in managing diabetic complications.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones. Lack of GLP-1 receptor signaling has been reported to be compensated for by increased GIP secretion and action. Conversely, GLP-1 sensitivity has been reported to be increased in GIP receptor knockout (Gipr^-/-) mice. This suggests a compensatory adaptation to the loss of incretin signaling via increased action/secretion of the remaining incretin hormone. We assessed glucose-stimulated GIP and GLP-1 secretion during oral glucose tolerance tests (OGTTs) and in isolated perfused intestines of GLP-1 receptor knockout (Glp-1r^-/-) mice and their wild-type littermates (Glp-1r^+/+) and in Gipr^-/- mice and their wild-type littermates (Gipr^+/+). Sensitivity to GIP and GLP-1 was assessed in isolated perfused pancreases of Glp-1r^-/- and Glp-1r^+/+ mice and Gipr^-/- and Gipr^+/+ mice, respectively. We found similar GIP responses in Glp-1r^-/- and Glp-1r^+/+ mice and similar GLP-1 responses in Gipr^-/- and Gipr^+/+ mice during the OGTTs and in the isolated perfused intestines. Insulin responses to GIP and GLP-1 were similar in Glp-1r^-/- and Glp-1r^+/+ mice and in Gipr^-/- and Gipr^+/+ mice, respectively. Our results do not support the existence of a compensatory adaptation to the loss of single incretin signaling via increased glucose-stimulated secretion of, or sensitivity to, the remaining incretin hormone.NEW & NOTEWORTHY We show that mice lacking the GLP-1 receptor do not compensate by increased glucose-stimulated GIP secretion or sensitivity, nor do mice lacking the GIP receptor compensate by increased glucose-stimulated GLP-1 secretion or sensitivity. The notion of a compensatory adaptation to the loss of single incretin signaling via increased action/secretion of the remaining incretin hormone was thus not supported using single incretin receptor knockout mice.

Vacuolar protein sorting-associated protein 41 (VPS41) has been established as a requirement for normal insulin secretory function in pancreatic β cells. Genetic deletion of VPS41 in mouse pancreatic β cells results in diabetes, although the mechanisms are not understood. Presently, we show that VPS41 deletion results in rapid mature insulin degradation and downregulation of β-cell identity. This phenotype is observed in vivo, with VPS41KO mice displaying progressive loss of insulin content and β-cell function with age. In acute VPS41 depletion in vitro, the loss of insulin is associated with increased degradative pathway activity, increased Adapter Protein 3 complex colocalization with lysosomes, increased nuclear localization of transcription factor E3, and downregulation of PDX1 and INS mRNA expression. Inhibition of lysosomal degradation rescues the rapidly depleted insulin content. These data evidence a VPS41-dependent mechanism for both insulin content degradation and loss of β-cell identity in β cells.NEW & NOTEWORTHY In this study, we show that acute VPS41 deletion results in rapid degradation of insulin, whereas chronic VPS41 deletion results in downregulation of β-cell identity. In acute VPS41 depletion in vitro, the loss of insulin is associated with increased degradative pathway activity, increased Adapter Protein 3 complex colocalization with lysosomes, increased nuclear localization of transcription factor E3, and downregulation of PDX1 and INS mRNA expression. Inhibition of lysosomal degradation rescues the rapidly depleted insulin content.

Fetal development in an adverse in utero environment significantly increases the risk of developing metabolic diseases in later life, including dyslipidemia, nonalcoholic fatty liver diseases, and diabetes. The aim of this study was to determine whether improving the in utero fetal growth environment with a placental nanoparticle gene therapy would ameliorate fetal growth restriction (FGR)-associated dysregulation of fetal hepatic lipid and glucose metabolism-related signaling pathways. Using the guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, placenta efficiency and fetal weight were significantly improved following three administrations of a nonviral polymer-based nanoparticle gene therapy to the placenta from mid-pregnancy (gestational day 35) until gestational day 52. The nanoparticle gene therapy transiently increased expression of human insulin-like growth factor 1 (hIGF1) in placenta trophoblast. Fetal liver tissue was collected near-term at gestational day 60. Fetal sex-specific differences in liver gene and protein expression of profibrosis and glucose metabolism-related factors were demonstrated in sham-treated FGR fetuses but not observed in FGR fetuses who received placental hIGF1 nanoparticle treatment. Increased plasma bilirubin, an indirect measure of hepatic activity, was also demonstrated with placental hIGF1 nanoparticle treatment. We speculate that the changes in liver gene and protein expression and increased liver activity that result in similar expression profiles to appropriately growing control fetuses might confer protection against increased susceptibility to aberrant liver physiology in later life. Overall, this work opens avenues for future research assessing the translational prospect of mitigating FGR-induced metabolic derangements.NEW & NOTEWORTHY A placenta-specific nonviral polymer-based nanoparticle gene therapy that improves placenta nutrient transport and near-term fetal weight ameliorates growth restriction-associated changes to fetal liver activity, and cholesterol and glucose/nutrient homeostasis genes/proteins that might confer protection against increased susceptibility to aberrant liver physiology in later life. This knowledge may have implications toward removing predispositions that increase the risk of metabolic diseases, including diabetes, dyslipidemia, and nonalcoholic fatty liver disease in later life.

The respiratory exchange ratio (RER), which is the ratio of total carbon dioxide produced over total oxygen consumed, serves as a qualitative measure to determine the substrate usage of a particular organism on the whole body level. Quantification of RER by its direct conversion into %glucose- (%G_ox) and %lipid oxidation (%L_ox) at a given timepoint can be done by utilizing nonprotein respiratory quotient tables. These tables, however, are limited to specific increments, and intermediate RER values are not covered by these tables. RER data are mostly continuous, which requires faithful interpolation, which we aimed for here. We first determined, statistically and schematically, that linear interpolation would lead to incorrect values. Therefore, we constructed a new mathematical model as an interpolating strategy to translate continuous RER values into correct values of %G_ox and %L_ox. We validated our new mathematical model against the original table by Péronnet and Massicotte (Can J Sport Sci 16: 23-29, 1991), against a linear interpolation of these data, as well as against a model based on an exponential approach using a dataset of a nutritional intervention study in mice. This showed that our model outperforms the other methods, providing more accurate data. We conclude that applying our mathematical model will lead to an increase in data quality and offer a very simple, straightforward approach to obtain the best %G_ox and %L_ox levels from continuous RER values.NEW & NOTEWORTHY With the here proposed mathematical model, we provide a new tool to convert continuous RER data into more accurate estimations of %G_ox and %L_ox. It circumvents the use of nonprotein respiratory quotient tables and thereby aids and simplifies by automating the conversions. The model can further be implemented into software commonly used for indirect calorimetry measurements and thereby provides %G_ox and %L_ox data in real-time during a running experiment.

In this study, we examined the effect of GPR180, a G protein-coupled receptor (GPCR) family member, on lipid metabolism of adipose tissue. We used adeno-associated virus overexpression of Gpr180 in subcutaneous adipose tissue, adipocyte-specific Gpr180 knockout mice and stromal vascular fraction (SVF) cells to explore the role and mechanism of GPR180 in lipid metabolism in adipocytes. Levels of Gpr180 mRNA in subcutaneous and epididymal adipose tissues were significantly reduced in mice fed high-fat diet (HFD). Overexpression of Gpr180 in subcutaneous white adipose tissue (sWAT) improved lipid metabolism and protected mice from HFD-induced obesity. Conversely, adipocyte-specific knockout of Gpr180 exacerbated lipid metabolism disorders induced by HFD. In cultured adipocytes differentiated from SVF cells, GPR180 inhibited lipogenesis and fatty acid (FA) uptake. Collectively, our study reveals that GPR180 functions to suppress lipid accumulation in adipocytes.NEW & NOTEWORTHY This study identifies GPR180 as a novel regulator of lipid metabolism and energy homeostasis. It demonstrates that GPR180 influences adipose tissue function, mitigates high-fat diet-induced obesity, and inhibits lipogenesis. Unique expression patterns and GWAS data linking GPR180 to lipid regulation highlight its systemic role. These findings establish GPR180 as a promising therapeutic target for metabolic disorders, warranting further research to uncover its molecular mechanisms and clinical applications.

Maternal obesity decreases infant energy expenditure, subsequently predisposing infants to greater adiposity and weight gain. Conversely, some findings suggest that maternal exercise may increase infant energy expenditure; however, the impact of maternal exercise mode (i.e., aerobic or resistance exercise) on infant energy expenditure is not known. The purpose of this study was to investigate whether supervised maternal exercise [aerobic, resistance, and combination (aerobic + resistance)] affects infant energy expenditure. When weight-adjusted resting energy expenditure was determined at 1 mo of age, infants exposed to resistance exercise in utero had >35% higher energy expenditure compared with infants exposed to aerobic exercise or no exercise. In addition, infant energy expenditure and lean mass were associated with maternal blood lipids independent of exercise mode. The increase in infant resting energy expenditure with the addition of any resistance exercise during gestation resulted in a discrepancy between measured and estimated energy expenditure using common estimation equations. These results implicate maternal metabolic health in determining infant metabolic rate, and maternal resistance exercise during pregnancy as a lifestyle intervention to increase infant energy expenditure potentially decreasing the subsequent infant adiposity gain. ClinicalTrials.gov Identifier: NCT03838146 and NCT04805502.NEW & NOTEWORTHY Maternal resistance exercise increases infant energy expenditure. This increase creates a gap between the measured and estimated energy expenditure when using standard estimation equations. These findings suggest that maternal resistance exercise can serve as a nonpharmacological method to enhance an infant's daily caloric expenditure.

Regenerating islet-derived protein 3 gamma (Reg3g), a gut peptide has been implicated in host defense and various physiological functions including metabolic regulation. Emerging evidence has demonstrated that peripheral administration of Reg3g results in improved glucose regulation as a gut hormone. In this study, we explored the therapeutic potential of Reg3g through intraduodenal infusion in mouse models of metabolic disorders. The objective of this study was to test the hypothesis that administered Reg3g into the intestinal lumen contributes to metabolic improvements by enhancing gut barrier function. Our mouse studies revealed that duodenal infusion of Reg3g reduces gut permeability and systemic endotoxemia. Studies with intestinal organoids supported the role of Reg3g in preserving cellular integrity and antioxidant gene expression under fructose-induced stress. Although Reg3g treatment results in little change to body weight, food intake, or glucose tolerance, Reg3g-treated mice exhibited reduced hepatic lipid accumulation along with the downregulation of lipogenic pathway genes. These data point toward the positive impact of Reg3g administration through intraduodenal infusion to regulate the intricate cross talk between gut barrier function and hepatic steatosis with the gut-liver axis.NEW & NOTEWORTHY This study shows that intraduodenal administration of the gut peptide, regenerating islet-derived protein 3 g (Reg3g), reduces hepatic lipid accumulation, improves gut barrier function, and lowers systemic endotoxemia in mouse models of metabolic disorders. These findings elucidate the therapeutic benefits of Reg3g administration into the gut.

Human neonates are predisposed to an increased risk of mortality from infection due to fundamental differences in the framework of innate and adaptive immune responses relative to those in the adult population. As one key difference in neonates, an increase in the immunosuppressive cytokine, IL-27, is responsible for poor outcomes in a murine neonatal model of bacterial sepsis. In our model, the absence of IL-27 signaling during infection is associated with improved maintenance of body mass, increased bacterial clearance with reduced systemic inflammation, and decreased mortality rates that correlate to preservation of glucose homeostasis and insulin production. To further elucidate the mechanisms associated with IL-27 signaling and metabolic fitness, we analyzed global transcriptomes from spleen, liver, pancreas, and hindlimb muscle during Escherichia coli-induced sepsis in wild-type (WT) and IL-27Rα-deficient (KO) mice. Metabolically important tissues such as the liver, pancreas, and hindlimb muscle exhibit a shift in differential gene expression of pathways involved in oxidative phosphorylation, glycolysis, gluconeogenesis, lipid metabolism, and fatty acid β oxidation. The hindlimb muscle of KO pups demonstrated a significant reduction in all of these pathways during infection. The KO liver showed a significant down-regulation in gluconeogenesis and glycolytic pathways. Collectively, these findings suggest a negative influence of IL-27 on the metabolic profile during early-life infection. This is an important consideration for antagonization of IL-27 as a potential host-directed therapeutic opportunity as our findings point to an overall improvement in infectious disease parameters and metabolic fitness.NEW & NOTEWORTHY IL-27 has been linked with immune regulation during infection, but this is the first report of a combined influence of IL-27 on complete host response during systemic infection with metabolic fitness in a neonate. Novel findings demonstrate improved glucose homeostasis and insulin response supported by a reduced expression of genes involved in gluconeogenesis in the absence of IL-27 signaling. An increased expression of genes integral to cholesterol biosynthesis further supports a protective response during sepsis.

Metabolic disease is rising along with both global industrialization and the use of new commercial, agricultural, and industrial chemicals and food additives. Exposure to these compounds may contribute to aspects of metabolic diseases such as obesity, diabetes, and fatty liver disease. Ingesting compounds in the food supply is a key route of human exposure, resulting in the interaction between toxicants or additives and the intestinal microbiota. Toxicants can influence the composition and function of the gut microbiota, and these microbes can metabolize and transform toxicants and food additives. Microbe-toxicant interactions in the intestine can alter host mucosal barrier function, immunity, and metabolism, which may contribute to the risk or severity of metabolic disease development. Targeting the connection between toxicants, food, and immunity in the gut using strategies such as fermentable fiber (i.e., inulin) may mitigate some of the effects of these compounds on host metabolism. Understanding causative factors in the microbe-host relationship that promote toxicant-induced dysmetabolism is an important goal. This review highlights the role of common toxicants (i.e., persistent organic pollutants, pesticides, and fungicides) and food additives (emulsifiers and artificial sweeteners) found in our food supply that alter the gut microbiota and promote metabolic disease development.