American journal of physiology. Endocrinology and metabolism最新文献

Fetal development in an adverse in utero environment significantly increases the risk of developing metabolic diseases in later life, including dyslipidemia, non-alcoholic 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 was significantly improved following three administrations of a non-viral 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 pro-fibrosis 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.

Diabetic complications are linked to oxidative stress, which hampers the cyclic guanosine monophosphate production by inhibiting nitric oxide /soluble guanylate cyclase (sGC) signalling. This study aimed to determine whether administration of a novel sGC activator avenciguat alone or in combination with a 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 weeks 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, while Empa reduced HbA1c but not TG levels as compared to untreated db/db. Both avenciguat and Empa alone effectively slowed the progression of diabetes-associated glomerulosclerosis and liver fibrosis. Importantly, avenciguat, especially at high dose in combination with Empa, further lowered these progression markers compared to 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.

Intermittent hypoxemia (IH), a pathophysiologic consequence of obstructive sleep apnea (OSA), adversely affects insulin sensitivity, insulin secretion, and glucose tolerance. Nifedipine, an L-type calcium channel blocker frequently used for the treatment of hypertension, can also impair insulin sensitivity and secretion. However, the cumulative and interactive repercussions of IH and nifedipine on glucose homeostasis have not been previously investigated. Adult male C57BL6/J mice were exposed to either nifedipine or vehicle concurrently with IH or intermittent air (IA) over 5 days. IH exposure entailed cycling fractional-inspired oxygen levels between 0.21 and 0.055 at a rate of 60 events/h. Nifedipine (20 mg/kg/day) or vehicle was administered via subcutaneous osmotic pumps resulting in four groups of mice: IA-vehicle (control), IA-nifedipine, IH-vehicle, and IH-nifedipine. Compared with IA (control), IH increased fasting glucose (mean Δ: 33.0 mg/dL; P < 0.001) and insulin (mean Δ: 0.53 ng/mL; P < 0.001) with nifedipine having no independent effect. Furthermore, glucose tolerance was worse with nifedipine alone, and IH further exacerbated the impairment in glucose disposal (P = 0.013 for interaction). Nifedipine also decreased glucose-stimulated insulin secretion and the insulinogenic index, with addition of IH attenuating those measures further. There were no discernible alterations in insulin biosynthesis/processing, insulin content, or islet morphology. These findings underscore the detrimental impact of IH on insulin sensitivity and glucose tolerance while highlighting that nifedipine exacerbates these disturbances through impaired β-cell function. Consequently, cautious use of L-type calcium channel blockers is warranted in patients with OSA, particularly in those at risk for type 2 diabetes.NEW & NOTEWORTHY The results of this study demonstrate the interaction between intermittent hypoxemia (IH) and nifedipine in a murine model. IH raises fasting glucose and insulin levels, with nifedipine exacerbating these disturbances. Glucose tolerance worsens when nifedipine is administered alone, and IH magnifies the impairment in glucose disposal. These findings raise the possibility of potential deleterious effects of L-type calcium channel blockers in patients with obstructive sleep apnea (OSA).

Exogenous glucose oxidation is reduced 55% during aerobic exercise after 3 days of complete starvation. Whether energy deficits more commonly experienced by athletes and military personnel similarly affect exogenous glucose oxidation and what impact this has on physical performance remains undetermined. This randomized, longitudinal parallel study aimed to assess the effects of varying magnitudes of energy deficit (DEF) on exogenous glucose oxidation and physical performance compared with energy balance (BAL). Participants consumed a 4-day BAL diet, followed by a 6-day 20% (n = 10), 40% (n = 10), or 60% (n = 10) DEF diet. At the end of each energy phase, participants performed 90-min of steady-state cycle ergometry (56 ± 3% V̇o_2peak) while consuming a glucose drink (80 g), followed by a time to exhaustion (TTE) performance test. Substrate oxidation (g/min) was determined by indirect calorimetry and ¹³C-glucose. Muscle glycogen (mmol/kg dry wt) and transcript accumulation were assessed in rested fasted muscle collected before exercise in each phase. Muscle glycogen was lower (P = 0.002) during DEF (365 ± 179) than BAL (456 ± 125), regardless of group. Transcriptional regulation of glucose uptake (GLUT4 and IRS2) and glycogenolysis (HKII and PKM) were lower (P < 0.05) during DEF than BAL, independent of group. Regardless of group, exogenous glucose oxidation was 10% lower (P < 0.001) during DEF (0.38 ± 0.08) than BAL (0.42 ± 0.08). There was no evidence of a difference in TTE between BAL and DEF or between groups. In conclusion, despite modest reduction in exogenous glucose oxidative capacity during energy deficit, physical performance was similar compared with balance.NEW & NOTEWORTHY Short-term (6-day) energy deficit reduced exogenous glucose oxidation during exercise. Though less exogenous glucose was used for fuel, young healthy individuals appear to have a metabolic resilience to short-term periods of low energy availability, with no observed differences in the ability to take up and oxidize exogenous glucose between minimal (20%), moderate (40%), and severe (60%) energy deficits. Similar metabolic responses to carbohydrate supplementation independent of deficit severity likely contributed to sustainment of physical performance.

Maternal obesity puts the offspring at high risk of developing obesity and cardiometabolic diseases in adulthood. Here, we utilized a mouse model of maternal high-fat diet (HFD)-induced obesity that recapitulates metabolic perturbations seen in humans. We show increased adiposity in the offspring of HFD-fed mothers (Off-HFD) when compared with the offspring of regular diet-fed mothers (Off-RD). We have previously reported significant immune perturbations in the bone marrow of newly weaned Off-HFD. Here, we hypothesized that lipid metabolism is altered in the bone marrow of Off-HFD versus Off-RD. To test this hypothesis, we investigated the lipidomic profile of bone marrow cells collected from 3-week-old Off-RD and Off-HFD. Diacylglycerols (DAGs), triacylglycerols (TAGs), sphingolipids, and phospholipids were remarkably different between the groups, independent of fetal sex. Levels of cholesteryl esters were significantly decreased in Off-HFD, suggesting reduced delivery of cholesterol. These were accompanied by age-dependent progression of mitochondrial dysfunction in bone marrow cells. We subsequently isolated CD11b+ myeloid cells from 3-wk-old mice and conducted metabolomic, lipidomic, and transcriptomic analyses. The lipidomic profiles of myeloid cells were similar to those of bone marrow cells and included increases in DAGs and decreased TAGs. Transcriptomics revealed altered expression of genes related to immune pathways, including macrophage alternative activation, B-cell receptors, and transforming growth factor-β signaling. All told, this study revealed lipidomic, metabolomic, and gene expression abnormalities in bone marrow cells broadly, and in bone marrow myeloid cells particularly, in the newly weaned offspring of mothers with obesity, which might at least partially explain the progression of metabolic and cardiovascular diseases in their adulthood.NEW & NOTEWORTHY Our data revealed significant immunometabolic perturbations in the bone marrow and myeloid cells in the newly weaned offspring born to mothers with obesity. Adaptation to an adverse maternal intrauterine environment affects bone marrow metabolism at a very young age and might affect responses to immune challenges that appear later in life, for example, infections or cancer.

Erythropoietin (EPO) is pivotal in regulating red blood cell (erythrocyte) concentrations and is primarily synthesized in the kidney. Recent research has unveiled a possible link between elevated circulating concentrations of ketone bodies (KB) and circulating EPO concentrations; however, it is not known whether nutritionally induced endogenous ketogenesis can be a stimulus to induce EPO in humans. Therefore, this study aimed to assess whether acute and chronic intake of medium-chain fatty acid-containing triacylglycerol (MCT), which rapidly enhances endogenous circulating KB, would elevate circulating EPO concentrations in humans, as indicated by prior work with exogenous KB administration. The study followed a crossover design involving 16 young men undergoing two 8-day MCT or energy-matched long-chain fatty acid-containing triacylglycerol (LCT) interventions in a randomized order. Five-hour test days were performed before and after each intervention, in which circulating KB and EPO concentrations as well as hematological parameters were assessed. Acute intake of MCT yielded a 222% sustained 5-h elevation in KB concentrations compared with LCT-with notable peak values of 0.7 ± 0.1 mmol·L^-1 (312% above basal values). Remarkably, within just 8 days of daily MCT intake an impressive 38% increase in basal, fasting plasma EPO concentrations (7.19 ± 1.14 to 9.91 ± 1.25 mIU·mL^-1) was demonstrated. In conclusion, this study unveils a novel physiological stimulus of circulating EPO concentrations in humans, potentially offering a new dietary approach to counter anemia in cardiovascular diseases.NEW & NOTEWORTHY This study is the first to assess the effects of nutritionally induced ketogenesis by acute and subchronic intake of medium-chain fatty acids on plasma erythropoietin concentrations. Medium-chain fatty acid intake increases postprandial ketone body concentrations and within only 8 days of daily intake substantially enhances basal plasma erythropoietin concentrations in young men. We therefore reveal a dietary stimulus of endogenous circulating erythropoietin concentrations in humans, with the potential to counter anemia in cardiovascular diseases.

Neuroimmunometabolism describes how neuroimmune cells, such as microglia, adapt their intracellular metabolic pathways to alter their immune functions in the central nervous system (CNS). Emerging evidence indicates that neurons also orchestrate the microglia-mediated immune response through neuro-immune cross talk, perhaps through metabolic signaling. However, little is known about how the brain's metabolic microenvironment and microglial intracellular metabolism orchestrate the neuroimmune response in healthy and diseased brains. This review addresses the balance of immunometabolic substrates in healthy and diseased brains, their metabolism by brain-resident microglia, and the potential impact of metabolic dysregulation of these substrates on the neuroimmune response and pathophysiology of psychiatric disorders. This review also suggests metabolic reprogramming of microglia as a preventive strategy for the management of neuroinflammation-related brain disorders, including psychiatric diseases.

Diabetic kidney disease (DKD) is a severe diabetic microvascular complication featured by chronic low-grade inflammation. Roux-en-Y gastric bypass (RYGB) surgery has gained importance as a safe and effective surgery to treat DKD. Bile acids significantly change after RYGB, which brings a series of metabolic benefits, but the relationship with the improvement of DKD is unclear. Therefore, this study performed RYGB surgery on db/db mice to observe the beneficial effects of the surgery on the kidneys and performed bile acid-targeted metabolomics analysis to explore bile acid changes. We found that RYGB significantly reduced albuminuria in db/db mice, improved renal function, reversed renal structural lesions, and attenuated podocyte injury and inflammation. Notably, bile acid metabolomic analysis revealed taurolithocholic acid (TLCA) as the most significantly altered bile acid after RYGB. Furthermore, in vitro and in vivo validation experiments revealed that TLCA supplementation improved renal function and reduced renal inflammatory damage in db/db mice. In addition, TLCA inhibited high glucose-induced inflammatory damage in MPC-5 cells, and its mechanism of action may be related to activating Takeda G protein-coupled receptor 5 (TGR5), inhibiting NF-κB phosphorylation, and thus inhibiting inflammatory response. In conclusion, RYGB may play a protective role in the kidneys of diabetic mice by activating the TLCA/TGR5 pathway.NEW & NOTEWORTHY This study determined that the renal protective effect of Roux-en-Y gastric bypass (RYGB) in db/db mice was associated with elevated serum TLCA. Notably, TLCA supplementation improved renal function and alleviated podocyte inflammatory injury in db/db mice, which was associated with the TGR5/NF-κB pathway.

The recovery from muscle atrophy is impaired with aging as characterized by improper muscle remodeling and sustained functional deficits. Age-related deficits in muscle regrowth are tightly linked with the loss of early pro-inflammatory macrophage responses and subsequent cellular dysregulation within the skeletal muscle niche. Macrophage inflammatory phenotype is regulated at the metabolic level, highlighting immunometabolism as an emerging strategy to enhance macrophage responses and restore functional muscle regrowth. Accordingly, metabolic targets with an emphasis on glycolytic, hypoxia, and redox-related pathways stand out for their role in promoting macrophage inflammation and enhancing muscle regrowth in aging. Here we highlight promising immuno-metabolic targets that could be leveraged to restore optimal pro-inflammatory macrophage function in aging and enhance muscle regrowth following muscular atrophy.