American journal of physiology. Endocrinology and metabolism最新文献

Postprandial hyperglycemia transiently impairs endothelial function. Polycystic ovary syndrome (PCOS) is associated with endothelial dysfunction and impaired glucose tolerance-both risk factors for cardiometabolic diseases-but the effects of hyperglycemia on endothelial function have yet to be assessed in PCOS. Exogenous ketone monoester (KME) supplementation lowers blood glucose and improves endothelial function in individuals predisposed to cardiometabolic diseases but has yet to be assessed in PCOS. Thus, we investigated whether oral glucose tolerance test (OGTT)-induced hyperglycemia impairs endothelial function in PCOS, and whether acute KME mitigates these impairments. Ten females with PCOS [age: 27 ± 5 yr, body mass index (BMI): 23.8 ± 2.7 kg/m²] and 10 age- and BMI-matched controls (CTRL; age: 27 ± 4 yr, BMI: 23.7 ± 2.0 kg/m²) completed a randomized, double-blind, placebo-controlled, crossover study. In the overnight postabsorptive state, participants consumed KME [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate; 482 mg/kg] or a taste-matched placebo 30 min before a 75-g OGTT. Endothelial function was assessed via flow-mediated dilation (%FMD) pre-OGTT and at 0-, 60-, and 120-min postbolus. Following placebo, %FMD was lower in PCOS than CTRL (effect of group, P < 0.01). %FMD declined from baseline to 60-min post-OGTT bolus in both groups (PCOS: 6.3 ± 0.4 vs. 4.2 ± 0.4%, P < 0.01; CTRL: 9.7 ± 0.9 vs. 6.6 ± 0.9%, P < 0.01), with sustained impairments at 120 min in PCOS only (6.3 ± 0.4 vs. 4.0 ± 0.5%, P < 0.01). In both groups, KME reduced plasma glucose area under the curve (P < 0.01) and improved %FMD across the OGTT (P < 0.01). These data indicate that OGTT-induced endothelial dysfunction is exacerbated in PCOS, and that acute KME improved endothelial function during the OGTT. Overall, these data KME supplementation as a potential means of reducing cardiometabolic risk in PCOS.NEW & NOTEWORTHY To the best of our knowledge, this is the first study to demonstrate that nonobese females with polycystic ovary syndrome (PCOS) exhibit prolonged impairments in endothelial function following glucose intake, indicating sustained hyperglycemia-driven vascular dysfunction. Notably, acute ketone monoester (KME) supplementation improved both glycemic control and endothelial function, highlighting KME as a promising nonpharmacological strategy to mitigate early cardiometabolic risk in this vulnerable population.

Dysregulation of glucose and lipid metabolism is closely linked to metabolic diseases such as obesity, diabetes, and diabetic nephropathy, posing serious threats to human health. Orosomucoid (ORM), an acute-phase protein, exhibits diverse biological functions such as immunomodulation, drug transport, and barrier maintenance. Accumulating evidence has recently revealed ORM's critical regulatory role in metabolic processes. Studies indicate that ORM modulates glucose and lipid metabolism through multiple mechanisms, including regulating food intake, attenuating adipose tissue inflammation and fibrosis, inhibiting adipocyte differentiation and hepatic steatosis, and promoting glycogen synthesis. This review systematically examines the regulatory mechanisms of ORM expression under inflammatory and metabolic stress conditions, the effects of ORM on glucose and lipid homeostasis, and its clinical associations with metabolic diseases. These insights could inform innovative strategies for preventing and treating metabolic diseases.

Resting metabolic rate (RMR) is modulated by a variety of factors. Accurate prediction of RMR is essential for planning energy requirements but remains challenging due to interindividual variability. This study aimed to develop and evaluate machine learning models for predicting RMR using comprehensive data from the cross-sectional enable study and to identify the most predictive and stable features across different study populations. RMR was predicted using data from 454 participants of the enable phenotyping platform (Freising and Nuremberg cohort). We systematically compared linear and nonlinear machine learning models trained on either the full set of 94 predictors or a reduced set of routinely accessible variables, including sex, age, body weight, fat mass, and fat-free mass. Model performance was assessed by cross-validation. The best-performing model (Lasso) was further evaluated on independent test datasets from other cohorts. Feature importance and stability were assessed using repeated cross-validation and marginal variance decomposition. Lasso regression consistently outperformed other models, particularly when trained on the enable cohort feature set. The final model explained 76.8% of RMR variance in the Freising cohort. Key predictive features included fat-free mass, body weight, and mean outdoor temperature. Blood-based features contributed marginally, whereas microbiota and fecal short-chain fatty acids variables did not contribute to explaining RMR. This novel prediction model for RMR shows improved accuracy in comparison with traditional models. Although microbiota composition did not contribute to explain the residual variation in RMR, the inclusion of clinical blood parameters and outdoor temperature improved predictive performance. Clinical Trial Registry Number: DRKS00009797.NEW & NOTEWORTHY We introduce a novel machine learning framework for predicting resting metabolic rate (RMR), emphasizing the superior performance of Lasso regression. Our analysis incorporates both standard clinical variables and previously underexplored factors such as gut microbiota, fecal short-chain fatty acids (SCFAs), and mean outdoor temperature.

Type 2 diabetes involves progressive loss of functional β-cell mass. In a zebrafish muscle-specific insulin-resistant model, overnutrition triggers islet inflammation and nocturnal β-cell death. The cell death is prevented by the cyclophilin D (Ppid) inhibitor, cyclosporin A (CsA). Reducing mitochondrial reactive oxygen species with mito-TEMPO or mitochondrial calcium with Ru360 protects β cells, further implicating the mitochondrial permeability transition pore in β-cell loss. The timing of β-cell death coincides with lower mitochondrial antioxidant gene expression, indicating nocturnal mitochondrial vulnerability. Global ppid^-/- preserves β-cell mass without altering islet inflammation or macrophage recruitment. Conversely, β-cell-specific PPID reexpression restores-and exacerbates-β-cell loss, which remains CsA-sensitive. These findings identify Ppid as a β-cell-intrinsic mediator of overnutrition-induced β-cell loss.NEW & NOTEWORTHY This study provides the first evidence that Ppid-mediated opening of the mitochondrial permeability transition pore (mPTP) is necessary for overnutrition-induced β-cell death in zebrafish. Pharmacological inhibition of mPTP opening protected β cells. Global knockout of ppid prevented β-cell loss, which was reversed by transgenic PPID reexpression in the β cells. The time of β-cell death coincides with lower antioxidant gene expression at night. Thus, relieving mitochondrial stress at night may preserve β cells.

Resting energy expenditure (REE) declines during weight loss because of both organ-tissue mass loss and adaptive thermogenesis, but their relative contributions after bariatric surgery remain unclear. Our primary aim was to quantify these components during the first postoperative year, and secondarily to compare Roux-en-Y gastric bypass (RYGB) with one-anastomosis gastric bypass (OAGB). Forty-two adults with obesity (RYGB n=21; OAGB n=21) underwent dual-energy X-ray absorptiometry (DXA) before surgery and at 6 and 12 months, and organ-tissue masses were estimated using MRI-derived prediction equations. A smaller subset of 29 participants (RYGB n=16; OAGB n=13) had valid indirect calorimetry measurements for REE analysis. Participants lost 27.3 kg (21%) of baseline body weight at 6 months and 32.3 kg (25%) at 12 months, with no significant differences between procedures in the DXA-measured body composition outcomes or calculated organ-tissue masses. Measured REE decreased by 383 kcal/d at 6 months (P<0.001), of which 168 kcal/d (95% CI 59 to 276, P=0.004) was attributed to adaptive thermogenesis. At 12 months, REE remained 315 kcal/d below baseline (P<0.001), but adaptive thermogenesis was not statistically detectable (89 kcal/d; 95% CI -19 to 198, P=0.11). Adaptive thermogenesis did not significantly differ between procedures. In conclusion, ~44% of the early 6-month postoperative decline in REE was associated with adaptive thermogenesis, with the remaining ~56% associated with organ-tissue mass loss. Adaptive thermogenesis was no longer clearly evident at 12 months. RYGB and OAGB resulted in similar changes in body composition and REE.

Obesity promotes metabolic dysfunction-associated steatotic liver disease (MASLD). Gut microbiota can influence MASLD through local communication between the gut and liver. Bacterial components are often conceptualized only as contributors to chronic inflammation. However, certain postbiotics can protect against chronic inflammation and dysmetabolism by activating specific immune responses during obesity. Site-specific innate immune training can direct compartmentalized immune responses. We hypothesized that site-specific immunomodulation by gut-derived inactivated bacterial-based stimuli (i.e., postbiotics) would improve features of MASLD. We found that biweekly subcutaneous injections of obese mice with an inactivated bacterial preparation of a gut bacterium (QBECO from Escherichia coli) improved markers of steatosis, inflammation, and fibrosis of MASLD in obese mice. QBECO lowered liver mass, triglycerides, F4/80 macrophages, eosinophil peroxidase activity, and collagen content in the liver without altering food intake or body mass in obese mice. QBECO increased whole-body lipid oxidation without altering total energy expenditure in obese mice. QBECO had an immunomodulatory effect that lowered liver eosinophil peroxidase activity, lowered liver nitrite/arginase ratio, and increased CD163 positive cells, a marker of M2 macrophages in the liver of obese mice. We confirmed that multiple gut bacteria-derived postbiotics improved MASLD since injections of an inactivated bacterial preparation of Proteus mirabilis (QBPMI) also lowered markers of steatosis, inflammation, and fibrosis in obese mice. A postbiotic from Klebsiella variicola (QBKPN), a bacterium typically pathogenic outside the gut, did not alter MASLD in obese mice. Therefore, site-specific immunomodulators derived from gut bacteria can improve the hallmarks of MASLD without causing weight loss.

This review explores the various biological changes that occur during the aging process, elucidating the fundamental pathological mechanisms leading to a decline in muscle integrity and functionality. A primary focus of the review is the occurrence of fat infiltration within skeletal muscle, a phenomenon that becomes increasingly prevalent with advancing age. The study assesses the implications of fat infiltration on skeletal muscle performance, along with the regulatory signaling mechanisms potentially influenced by fat accumulation. Furthermore, it addresses a variety of intervention strategies aimed at alleviating these age-related changes, including nutritional supplements, exercise regimens, and pharmacological treatments. By integrating current findings in the field and addressing existing challenges, this review aims to conduct an in-depth exploration of the intricate connection between aging and skeletal muscle health, with the goal of guiding future research and clinical practices to improve the quality of life for older adults.

Background: Adipose tissue androgen turnover, dictated at least in part by the enzymes AKR1C2 and AKR1C3, has been linked to abdominal obesity. Recently, we investigated a single-nucleotide polymorphism (SNP) named rs28571858, that might increase AKR1C2 and AKR1C3 expression in human adipose tissue. Here, we studied the impact of rs28571848 on adipose tissue function and cardiometabolic health in bariatric surgery candidates. Methods: We genotyped a sample of 2776 bariatric surgery candidates and retrospectively obtained anthropometry, blood lipid and glucose profiles, menopausal status and medication use. In a subsample of 135 individuals (62% women, age 42 years, BMI of 51 kg/m2), we additionally assessed AKR1C2 and AKR1C3 expression in whole tissue by RT-qPCR. Features of adipose tissue dysfunction, such as mean adipocyte diameter and pericellular fibrosis were assessed by histological staining and semi-automated image analysis. Finally, adipose tissue AKR1C family enzyme activity was measured by fluorimetry. Results: The rs28571848 SNP affected AKR1C3 expression in both subcutaneous (SAT) and visceral adipose tissue (VAT) in women only, while not altering AKR1C2 expression in either men or women. Individuals carrying the minor allele exhibited increased VAT AKR1C activity compared to those with the wildtype genotype. Analysis of blood lipid profile in the whole cohort revealed that "TT" carriers had elevated total cholesterol, LDL-cholesterol, and indices of insulin resistance. Conclusion: The rs28571858 SNP increased adipose tissue AKR1C3 expression and activity in women. Increased AKR1C3 may contribute to an adipose tissue milieu that prompts lipogenesis, adversely affecting cardiometabolic health by disrupting lipid homeostasis and insulin sensitivity.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-enriched receptor that regulates phagocytosis, lipid metabolism, and inflammation resolution in the brain. Loss or mutation of TREM2, including the R47H variant, impairs amyloid-β clearance and lipid handling, thereby increasing the risk and accelerating the progression of Alzheimer's Disease (AD). TREM2 signaling couples debris recognition with mitochondrial activation and fatty acid oxidation, maintaining microglial energy balance and promoting a reparative phenotype. Pharmacologic TREM2 agonists, such as AL002, DNL919, and VG-3927, enhance microglial survival, plaque compaction, and mitochondrial respiration in AD models, although clinical efficacy may depend on disease stage and metabolic fitness. Exercise training represents a complementary strategy that similarly enhances TREM2 expression, restores microglial homeostasis, and improves mitochondrial metabolism. Both aerobic and resistance exercise activate TREM2-dependent signaling pathways to reduce neuroinflammation and support synaptic integrity. Collectively, these findings highlight TREM2 as a central immunometabolic regulator and suggest that combining TREM2-targeted therapeutics with exercise may offer a synergistic strategy to slow neurodegeneration in AD.