American journal of physiology. Endocrinology and metabolism最新文献

Resting and maximal exercise respiratory rates (V̇o₂) decline in aging. Those losses have been attributed to impaired mitochondrial function, but the data are inconsistent with healthy aging. To interrogate the hypothesis of mitochondrial dysregulation in aging, we studied hind limb skeletal muscles from young and older, male and female, NIA C57BL/6JN mice. We observed no age-associated changes in coupling efficiency (ADP:O) of mitochondrial reticulum preparations, but respiratory control (RCR) was decreased in older mice. In addition, older skeletal muscle exhibited subtle yet significant reductions in the expression of proteins functionally related to substrate uptake and oxidation (mMCT1, mPC1, CPT1b, and HADH). Although there were no differences in mitochondrial contents per mg of muscle in older mice, there were significant losses of muscle, and hence, mitochondrial mass and proteins associated with membrane dynamics (Drp1, Fis1, and Mfn2). Furthermore, two-dimensional and three-dimensional, cross- and longitudinal muscle sections showed alterations in mitochondrial reticulum organization in muscles of older mice. Therefore, aging is associated with subtle but significant changes in the organization and functioning of muscle mitochondrial reticulum.NEW & NOTEWORTHY We interrogated numerous structural and functional aspects of the mitochondrial reticulum using a standard mouse model of aging. We observed no age-associated changes in the coupling efficiency of mitochondrial preparations, but respiratory control decreased, and there were numerous subtle changes in mitochondrial morphology in aging mouse muscles. Overall mitochondrial functioning is well preserved in aging, indicating the performance decrements are related to loss of muscle mass and cardiovascular function.

Metabolic dysfunction-associated steatohepatitis (MASH) continues to be a major health crisis worldwide due to increases in obesity and insulin resistance. The role of the extracellular matrix regulator reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in metabolic liver disease is poorly understood. We previously reported that RECK gain-of-function, specifically in hepatocytes, protects against diet-induced MASH. Here, we hypothesized that hepatocyte-specific RECK loss-of-function exacerbates liver injury in a preclinical model of diet-induced MASH. Using two novel mouse models of hepatocyte-specific RECK depletion, we demonstrate that RECK gene deletion significantly increased inflammation, ballooning, and fibrosis in the liver. Transcriptomic and proteomic analysis supported these findings, revealing gene/protein networks associated with inflammation and fibrosis. Targeted assessment revealed that RECK depletion results in elevated hepatic mRNA levels of several genes associated with inflammation, extracellular matrix remodeling, and fibrogenesis. Furthermore, levels of phosphorylated epidermal growth factor receptor (EGFR) and its ligand amphiregulin (AREG) were also increased with RECK germline deletion, suggesting a potential link between RECK and EGFR activity. These studies reveal RECK as a critical regulator of hepatic inflammation and fibrosis and highlight its potential as a novel therapeutic in MASH.NEW & NOTEWORTHY Deletion of the RECK gene in hepatocytes induced hepatic injury in preclinical models of diet-induced MASH. Transcriptomic and proteomic analysis revealed enrichment of pathways involved in liver inflammation and fibrotic remodeling. Targeted assessment validated multi-omic findings, showing an increase in genes associated with inflammation, extracellular matrix remodeling, and fibrosis with loss of RECK. These studies reveal RECK as a critical regulator of hepatic inflammation and fibrosis and underscore its potential as novel therapeutic in MASH.

Atrial natriuretic peptide (ANP) is secreted from the heart and the circulating concentrations increases during an acute bout of exercise. ANP is suggested to stimulate lipolysis, which has been demonstrated administering supraphysiological doses of ANP to humans. However, it is not known whether an acute increase in circulating ANP within the physiological range affects lipolysis in healthy humans, and thereby play a role in mobilization of energy in healthy humans. To determine the effects of physiological doses of ANP on lipolysis, ketogenesis, and glucose metabolism in resting, healthy men. Ten healthy men were randomized to a 1-h infusion of ANP vs. placebo in a crossover design while infused with the stable isotopes: [1,1,2,3,3-D₅]-glycerol, potassium-¹³C₁₆]-palmitate, sodium-D-β-[2,4-¹³C₂]-hydroxybutyrate, and [6,6-D₂]-glucose to determine changes in rate of appearance and disappearance of glycerol, palmitate, β-hydroxybutyrate, and glucose. Plasma ANP concentration increased from 2.8 pmol/L to a peak of 11.1 pmol/L with ANP infusion. This was compiled by an increase in the plasma concentration of the secondary messenger, 3',5'-cyclic guanosine monophosphate (cGMP), from 6.5 nmol/L to 12.5 nmol/L. No effects of ANP infusion were observed in the rate of appearance and rate of disappearance of glycerol, palmitate, β-hydroxybutyrate, or glucose. The blood volume and blood pressure remained unaffected during the study. In the present study, physiological doses of ANP had no effect on lipolysis, ketogenesis, and glucose metabolism in healthy men. The lipid turn-over does, therefore, not seem to be regulated by ANP in healthy individuals.NEW & NOTEWORTHY Atrial natriuretic peptide (ANP) is suggested to stimulate lipolysis, which has been demonstrated using supraphysiological doses of ANP. We explored the effects of physiological doses of ANP, as observed during an acute exercise bout, on lipolysis, ketogenesis, and glucose metabolism. Ten healthy men was randomized to infusion of ANP vs. placebo using stable isotope labeled tracers. The present study indicates that lipid metabolism does not seem to be regulated by ANP in men.

The mitochondrial tRNA-derived fragment mt-tRF-Leu^TAA couples mitochondrial metabolism to insulin secretion. While its role in pancreatic β-cell function is well established, its broader impact on multiorgan glucose homeostasis remains unclear. In insulin target tissues, the presence, regulation, and mechanism of action of mt-tRF-Leu^TAA are entirely unexplored. This study addresses this gap by investigating the impact of diet, nutritional status, and diabetes on mt-tRF-Leu^TAA regulation and by assessing its role in insulin sensitivity. We examined mt-tRF-Leu^TAA levels in different insulin target tissues, including skeletal muscle, liver, and epididymal white adipose tissue, of rodents under physiological and pathological conditions. In skeletal muscle myotubes, we combined subcellular fractionation, antisense oligonucleotide-mediated knockdown, and glucose uptake assays to determine mt-tRF-Leu^TAA's mitochondrial localization and its influence on insulin sensitivity. mt-tRF-Leu^TAA levels in mouse skeletal muscle decreased twofold in response to fasting. In myotubes, this tRNA fragment was enriched in mitochondria, and its downregulation enhanced glucose uptake. While the levels of mt-tRF-Leu^TAA remained unchanged in insulin target tissues of diabetic mice, we observed a skeletal muscle-specific downregulation of mt-tRF-Leu^TAA in young adult rats exhibiting insulin hypersensitivity. This study identifies mt-tRF-Leu^TAA as a candidate regulator of skeletal muscle insulin response. By modulating both insulin secretion and action, mt-tRF-Leu^TAA appears to play a notable role in systemic metabolic control and may represent a promising target for diabetes treatment.NEW & NOTEWORTHY Fasting downregulates levels of mt-tRF-Leu^TAA in skeletal muscle. While this small RNA fragment is enriched in the mitochondria of myotubes, inhibition of mt-tRF-Leu^TAA in myotubes enhances insulin-mediated glucose uptake. Consistently, mt-tRF-Leu^TAA is also downregulated in the skeletal muscle of insulin-hypersensitive rats. Together, these findings highlight mt-tRF-Leu^TAA as a key metabolic regulator influencing both insulin secretion and action.

Although white adipose tissue (WAT) serves as a dynamic storage organ that regulates overall metabolism, the molecular impacts of resistance training (RT) on WAT are still not fully understood. Considering that training variables influence RT outcomes, understanding the relationship between exercise volume and WAT remodeling is crucial for elucidating adaptive mechanisms. The hypothesis posits that a higher volume of RT, specifically 8 wk of climbing a vertical ladder for eight sets (RT-8), will lead to more significant positive adaptations in WAT remodeling than a lower volume of four sets (RT-4). The investigation combined histological, molecular (proteomic), and biochemical analyses (electron paramagnetic resonance, zymography, and enzyme-linked immunosorbent assay) with bioinformatics tools. By high-throughput mass spectrometry-based proteomics, we quantified 4,434 proteins in WAT of male rats and revealed that the RT-8 group displayed increased protein abundance associated with lipid transport, fatty acid unsaturation, and lipolysis compared with RT-4. In addition, compared with sedentary controls, RT-8 showed enhanced antioxidant capacity through phase II antioxidant enzymes (thioredoxins, peroxiredoxins, glutathione transferases, and ferritin). In contrast, the RT-4 group did not significantly alter the redox proteome, but selectively upregulated first-line antioxidant defense via the α-Klotho/superoxide dismutase/catalase axis. RT-4 was also associated with a reduction in reactive oxygen species production (superoxide ion and hydrogen peroxide), matrix metalloproteinase-2 activity, and adipocyte cross-sectional area to a similar extent as RT-8, without disrupting redox balance, ubiquitin ligase complex activity, or inflammatory pathways. Our findings contribute to the growing body of literature, suggesting that RT volume is a key determinant of the WAT proteomic signature, with training volume eliciting distinct molecular adaptations.NEW & NOTEWORTHY This study is the first to analyze how resistance training (RT) volume modulates white adipose tissue (WAT) remodeling. RT decreases adiposity index and adipocyte size regardless of exercise volume. Higher-volume RT shows greater abundance linked to phase II antioxidant enzymes and lipolysis pathways. However, inflammatory mediators and redox imbalance may be related to increased volume. Conversely, lower volume induces first-line antioxidant defense through α-Klotho upregulation, revealing that each volume dictates distinct regulatory mechanisms in WAT.

The oral glucose tolerance test (OGTT) promotes transient increases in peripheral blood flow via humoral mechanisms, including insulin. Polycystic ovary syndrome (PCOS) is associated with insulin resistance and vascular dysfunction, even in nonobese females. We therefore tested the hypothesis that OGTT-stimulated increases in femoral blood flow (FBF) would be impaired in females with PCOS. In the overnight postabsorptive state, plasma glucose, insulin, and FBF (duplex ultrasound and superficial femoral artery) were measured pre-OGTT and at 0, 15, 30, 60, 90, and 120 min following a 75-g glucose bolus. We recruited females with PCOS [n = 10, age: 27 ± 5 yr, body mass index (BMI): 23.8 ± 3.1 kg/m²] and age- and BMI-matched females without PCOS (CTRL; n = 10, age: 27 ± 4 yr, BMI: 23.7 ± 2.0 kg/m²). Pre-OGTT glucose concentrations were not different between PCOS and CTRL (4.7 ± 0.4 vs. 4.7 ± 0.4 mmol/L, P = 0.74), nor were insulin concentrations (41.7 ± 12.0 vs. 32.4 ± 11.2 pmol/L, P = 0.11). However, OGTT glucose area under the curve (AUC; 938 ± 124 vs. 762 ± 113 mmol/L × 120 min, P = 0.01) and insulin AUC (45,121 ± 16,204 vs. 27,079 ± 11,527 pmol/L × 120 min, P = 0.01) were higher in PCOS than CTRL. Pre-OGTT, FBF was not different between PCOS and CTRL (211 ± 50 vs. 210 ± 44 mL/min, P = 0.95). FBF increased across all time points postbolus in CTRL but remained unchanged in PCOS (OGTT × group, P < 0.01). Indeed, FBF was lower in PCOS than CTRL at 30 (224 ± 33 vs. 277 ± 48 mL/min, P = 0.01), 60 (227 ± 37 vs. 305 ± 48 mL/min, P < 0.01), 90 (217 ± 45 vs. 308 ± 64 mL/min, P < 0.01), and 120 min (205 ± 47 vs. 258 ± 55 mL/min, P = 0.04) postbolus. In sum, nonobese females with PCOS demonstrated a complete absence of OGTT-stimulated increases in peripheral artery blood flow, suggesting that PCOS is associated with profound vascular dysfunction following acute hyperglycemia.NEW & NOTEWORTHY To the best of our knowledge, this is the first study to demonstrate that nonobese females with polycystic ovary syndrome (PCOS) do not exhibit oral glucose tolerance test-induced increases in peripheral blood flow, unlike healthy controls. These findings highlight the peripheral vasculature as a critical and overlooked component of cardiometabolic dysfunction in PCOS, even in the absence of obesity and other cardiometabolic risk factors (e.g., hypertension and diabetes).

Long-chain triglycerides (LCTs) exert obesogenic effects, whereas medium-chain triglycerides (MCTs) exert antiobesity effects. To date, most studies examining the distinct effects of MCTs and LCTs have been conducted under extreme conditions using high-fat diets (45-60 kcal% fat). In this study, we aimed to investigate the health effects of varying MCT/LCT intake ratios in 30 kcal% high-fat diets, using liver-specific medium-chain acyl-CoA dehydrogenase (MCAD)-deficient (MCAD^L-/-) mice. Since this fat level more closely resembles the human diet without causing overeating, it allows for a purer assessment of the metabolic effects of the MCT/LCT intake ratios compared with the results of studies using extreme high-fat conditions. We fed MCAD^L-/- mice 30 kcal% fat MCT and LCT diets for 12 wk. Notably, MCAD^L-/- mice consumed the LCT diet more than the MCT diet, without any difference in the total caloric intake. Despite no difference in body weight, MCAD^L-/- mice exhibited impaired glucose tolerance and elevated hepatic triacylglycerol and cholesterol levels. Moreover, lipid droplet size and gene expression levels of some inflammatory markers increased in the adipose tissues of MCAD^L-/- mice. Overall, these results suggest that the intact metabolism of medium-chain fatty acids in the liver is crucial for dietary fat preference regulation. Furthermore, antiobesity effects of MCTs are observed even when the percentage of MCT intake is increased without altering the total fat intake.NEW & NOTEWORTHY Medium-chain triglycerides (MCTs) exert antiobesity effects; however, whether these antiobesity effects are observed when the MCT/long-chain triglyceride intake is altered using a high-fat diet (30 kcal% fat) remains unclear. This study found that impaired medium-chain fatty acid metabolism in the liver reduced MCT preference, without altering the total fat intake, resulting in metabolic dysfunction. Therefore, increasing the MCT ratio in dietary fats possibly reduces the risk of obesity.

Sexual dimorphism in glucose metabolism is increasingly recognized as a critical factor in metabolic homeostasis. Our prior study has highlighted the role of intestinal monocarboxylate transporter 1 (MCT1) in mediating lactate transport and its sex-specific effect on glucose metabolism in mice. Here, we investigated the sex-specific metabolic flux in the intestine and its impact on postprandial lactate shuttle and glucose homeostasis. Using a combination of isotopic tracing techniques and in vivo experiments, we discovered that intestinal epithelium exhibits sex-specific metabolic profiles, leading to differential glucose metabolism. Female mice displayed higher oxidative phosphorylation activity and greater utilization of lactate/pyruvate in the tricarboxylic acid (TCA) cycle than male mice, resulting in improved glucose tolerance. In contrast, male mice exhibited higher glycolytic activity with an increased postprandial lactate level, correlating with poorer glucose tolerance than female mice. Estrogen treatment in male mice reduced intestinal interstitial lactate level and improved glucose tolerance. Castration of male mice also improved glucose tolerance, whereas androgen replacement reversed this effect. Conversely, ovariectomy in female mice impaired glucose tolerance, which was restored by estrogen replacement. Our findings thus underscore the importance of sex-specific glucose metabolism in the intestine and its implications for metabolic health, laying a foundation for developing sex-specific therapeutic strategies for metabolic disorders.NEW & NOTEWORTHY Sex dimorphic difference in glucose homeostasis has been well recognized; however, how glucose metabolism in the intestine contributes to this phenomenon is poorly known. We discovered that the male mice have an elevated rate of glycolysis in the intestine, whereas the female mice have an increased rate of oxidative phosphorylation, contributing to the sex difference in glucose tolerance. In addition, sex hormones are crucial in mediating such a difference between the two sexes.

Impaired cholesterol homeostasis is a major factor contributing to the development and progression of atherosclerosis. Previous studies have shown that metformin, the first-line antidiabetic therapy, has cardioprotective effects in patients with diabetes. However, the antiatherogenic effect of metformin in nondiabetic individuals remains unclear. The aim of this study was to determine the antiatherosclerotic effects of metformin under normoglycemic conditions and, mechanistically, to assess its impact on hematopoietic stem and progenitor cell (HSPC) biology and extramedullary myelopoiesis. Here, we demonstrated that metformin decreased atherosclerotic lesion size, reduced plaque macrophages, and lowered circulating atherogenic Ly6-C^hi monocytes and neutrophil levels in Apoe^-/- mice, independent of blood glucose regulation. Mechanistically, metformin-treated Apoe^-/- mice exhibited increased HSPC retention in the bone marrow and decreased numbers of circulating hematopoietic stem and progenitor cells (HSPCs), along with reduced levels of Ly6-C^hi monocytes and neutrophils in the spleen. Our results indicate that decreased circulating cholesterol and increased expression of the ATP-binding cassette transporter gene Abca1 in HSPCs, thereby promoting cholesterol efflux in these cells, are critical factors leading to the suppressed mobilization of HSPCs and myelopoiesis in metformin-treated mice. Collectively, our findings support the use of metformin as an antiatherosclerotic agent under euglycemic conditions. We reveal that this effect is achieved by dampening HSPC mobilization and extramedullary myelopoiesis, providing molecular evidence for metformin's role in reducing macrophage-driven inflammation and, consequently, attenuating atherosclerotic progression.NEW & NOTEWORTHY This study uncovers a novel role for metformin in reducing inflammatory and atherogenic monocytes by dampening extramedullary myelopoiesis, thereby delaying atherosclerosis development under normoglycemic conditions. We demonstrate that metformin suppresses hematopoietic stem and progenitor cell mobilization and reduces macrophage-driven inflammation, providing mechanistic evidence for its antiatherosclerotic potential beyond diabetes management. These findings highlight new therapeutic opportunities for metformin in cardiovascular disease, extending its clinical utility to the prevention of atherosclerosis in nondiabetic individuals.

Physical activity and exercise are widely recognized as effective ways to promote physical fitness and prevent disease; however, their underlying molecular mechanisms remain to be fully elucidated. Within the last few years, the discovery of lactylation has propelled the well-known exercise metabolite lactate into the scientific spotlight. As the end product of glycolysis, lactate was initially considered to be a "metabolic waste" leading to muscle fatigue; however, subsequent studies have demonstrated the importance of lactate as an energy substrate and a signal transduction molecule to coordinate various physiological processes. Importantly, the novel posttranslational modification, lactylation, establishes a bridge between lactate and epigenetics, and provides new perspectives for understanding the role of lactate in exercise-mediated health promotion. Although some recent evidence in rodents suggests that exercise increases protein lactylation, there are mixed findings in this area, with limited human studies showing no effects. This review summarizes current knowledge of exercise-mediated lactylation, why mixed findings in the literature may exist, and suggests future research that can add further clarity to this area of molecular biology.