American journal of physiology. Endocrinology and metabolism最新文献

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.

Kynurenic acid (KYNA) and quinolinic acid (QUIN) are metabolites of the kynurenine pathway of tryptophan degradation with opposing biological activities in the central nervous system. In the periphery, KYNA is known to positively affect metabolic health, whereas the effects of QUIN remain less explored. Interestingly, metabolic stressors, including exercise and obesity, differentially change the balance between circulating KYNA and QUIN. Here, we hypothesized that chronically elevated levels of circulating KYNA and reduced levels of QUIN would manifest as differences in whole body energy metabolism. To test this, we used a mouse model lacking the enzyme kynurenine 3-monooxygenase (KMO), thus shunting kynurenine away from QUIN synthesis and toward KYNA production. KMO-deficient and wild-type littermate male and female mice were evaluated under chow and high-fat diets. Comprehensive kynurenine pathway metabolite profiling in plasma showed that the loss of KMO elicits robust changes in circulating levels of kynurenine metabolites. This included a 45-fold increase in kynurenine, a 26-fold increase in KYNA, and a 99% decrease in QUIN levels, depending on the diet. However, despite these changes, loss of KMO did not significantly impact whole body energy metabolism or change the transcriptomic profile of subcutaneous adipose tissue on either diet. With KMO inhibitors being considered therapeutic candidates for various disorders, this work shows that chronic systemic KMO inhibition does not have widespread metabolic effects. Our data also indicate that the beneficial effects of KYNA on metabolism may depend on its acute, intermittent elevation in circulation, akin to transient exercise-induced signals that mediate improved metabolic health.NEW & NOTEWORTHY The kynurenine pathway of tryptophan degradation is influenced by metabolic stressors: exercise raises circulating KYNA levels, while obesity is linked to increased QUIN. We investigated whether a mouse model lacking KMO-leading to increased circulating KYNA and decreased QUIN-would exhibit changes in energy metabolism. We found that energy metabolism was largely unaffected despite robust changes in circulating kynurenine metabolites, suggesting that systemic KMO inhibition may not have widespread metabolic effects.

Exercise and nutritional modulation are potent stimuli for eliciting increases in mitochondrial mass and function. Collectively, these beneficial adaptations are increasingly recognized to coincide with improvements in skeletal muscle health. Mitochondrial dynamics of fission and fusion are increasingly implicated as having a central role in mediating aspects of key organelle adaptations that are seen with exercise. Exercise-induced mitochondrial adaptation dynamics that have been implicated are 1) increases to mitochondrial turnover, resulting from elevated rates of mitochondrial synthesis (biogenesis) and degradative (mitophagy) processes and 2) morphological changes to the three-dimensional (3-D) tubular network, known as the mitochondrial reticulum, that mitochondria form in skeletal muscle. Notably, mitochondrial fission has also been implicated in coordinating increases in mitophagy, following acute exercise. Furthermore, increased fusion following exercise training promotes increased connectivity of the mitochondrial reticulum and is associated with improved metabolism and mitochondrial function. However, the molecular basis and fashion in which exercise infers beneficial mitochondrial adaptations through mitochondrial dynamics remains to be fully elucidated. This review attempts to highlight recent developments investigating the effects of exercise on mitochondrial dynamics, while attempting to offer a perspective of the methodological refinements and potential variables, such as substrate/glycogen availability, which should be considered going forward.

The rising prevalence of metabolic diseases is a significant global health concern. Beyond lifestyle management, targeting key molecules involved in metabolic regulation is essential. C1q/TNF-related protein 6 (CTRP6) is notably associated with glucose and lipid metabolism, with numerous studies highlighting its regulatory functions in metabolic diseases. This review summarizes the current knowledge on CTRP6, focusing on its gene expression profiles, protein structure, gene regulation, and role in metabolic diseases. CTRP6 is widely expressed across various tissues and features four distinct domains, with the C1q domain predicted to bind to its receptor. Notably, serum levels of CTRP6 are significantly elevated in patients with obesity and type 2 diabetes. In these conditions, adipose tissue serves as a key source of CTRP6 and its involvement in adipose tissue expansion, inflammation, and nutrient sensing has been observed in several studies. CTRP6 is also implicated in type 1 diabetes, gestational diabetes mellitus, and diabetic complications, particularly diabetic nephropathy. Although some studies have suggested that CTRP6 has protective roles in atherosclerotic cell models, myocardial infarction rat models, and ischemia/reperfusion injury mouse models, methodological issues such as unreliable antibodies and unstrict controls make it difficult to draw accurate conclusions from these studies. Patients with polycystic ovary syndrome (PCOS) exhibit elevated serum levels of CTRP6, although its direct impact on PCOS phenotypes remains unclear. In conclusion, CTRP6 emerges as a promising therapeutic target for metabolic diseases. A deeper understanding of CTRP6 will empower the scientific community to develop effective interventions to address the increasing prevalence of these diseases.

The current study aimed to propose a method to directly measure right cervical vagal nerve activity (cVNA) alongside renal sympathetic nerve activity (RSNA) in conscious rats. The right cervical vagus nerve was surgically exposed and fitted with a bipolar electrode to record cVNA. A microcatheter was used to administer levobupivacaine to selectively block afferent cVNA. Upon levobupivacaine administration, cVNA was reduced by 84%, enabling the exclusive assessment of efferent cVNA. Intravenous and intraperitoneal administration of cholecystokinin-8 (CCK-8) demonstrated that peripherally acting CCK-8 influences the central nervous system through afferent cVNA without affecting the RSNA or efferent cVNA. This technique can be highly applicable for quantifying the dynamic changes in the interaction between vagal and sympathetic nerve activities, thereby shedding light on their roles in maintaining homeostasis and developing autonomic dysfunction, as in obesity and diabetes.NEW & NOTEWORTHY This study proposed a method for directly measuring cervical vagal nerve activity and reversibly blocking afferent cVNA in conscious rats. It demonstrated that CCK-8, when administered intraperitoneally, distinctly influences peripheral afferent vagal nerve activity without affecting renal sympathetic nerve activity, arterial pressure, or heart rate.

Protein kinetics can be quantified by coupling stable isotope tracer methods with mass spectrometry readouts; however, interconnected decision points in the experimental design affect the complexity of the workflow and impact data interpretations. For example, choosing between a single bolus (pulse-chase) or a continuous exposure protocol influences subsequent decisions regarding when to measure and how to model the temporal labeling of a target protein. Herein, we examine the merits of in vivo tracer protocols, and we direct attention toward stable isotope tracer experiments that rely on administering a single bolus since these are generally more practical to use as compared with continuous administration protocols. We demonstrate how the interplay between precursor and product kinetics impacts downstream analytics and calculations by contrasting fast versus slow turnover precursors (e.g., ¹³C-leucine vs. ²H-water, respectively). Although the data collected here underscore certain advantages of using longer-lived precursors (e.g., ²H- or ¹⁸O-water), the results also highlight the influence of tracer recycling on measures of protein turnover. We discuss the impact of tracer recycling and consider how the sampling interval is critical for interpreting studies. Finally, we demonstrate that tracer recycling does not limit the ability to perform back-to-back studies of protein kinetics. It is possible to run experiments in which subjects are used as their own controls even though the precursor and product remain labeled following an initial tracer dosing.NEW & NOTEWORTHY We demonstrate a simple and robust protocol for measuring protein synthesis, the work considers problems encountered in experimental design. The logic can enable biologists with limited resources and/or can facilitate scenarios where higher throughput experiments are needed.

Optimal adaptation to resistance exercise requires maximal rates of myofibrillar protein synthesis (MyoPS), which can be achieved by postexercise consumption of >20 g of protein or ~2 g of the essential amino acid (EAA) leucine. These nutritional recommendations are based on studies in males. The aim of the present study was to compare the postexercise MyoPS response to nutrition in young females. Twenty-eight healthy, females (age: 28±8 y; BMI: 24±3 kg⋅m²) received a primed-continuous infusion of L-[ring-²H₅]-phenylalanine and completed a bout of unilateral resistance exercise before ingesting a drink containing either 1.5 g EAA (n=10), 15 g (n=10) or 20 g (n=8) whey protein, containing 0.6, 1.5, and 2.0 g leucine, respectively. Blood and muscle samples were collected pre- and post-exercise and drink ingestion to assess MyoPS and gene expression. Drink ingestion increased plasma leucine concentrations following 15 and 20 g whey protein compared with 1.5 g EAA (P<0.0001). Exercise and drink ingestion increased basal (0.060±0.026, 0.063±0.034, 0.051±0.023%·h^-1) MyoPS rates between 0-2 h to 0.117±0.028, 0.098±0.051 and 0.116±0.034%·h^-1 (P<0.0001) and between 2-4 h to 0.110±0.028, 0.074±0.038, and 0.082±0.061%·h^-1 (P=0.009) for 1.5, 15, and 20 g drinks, respectively, with no differences observed between drinks (P=0.416). The postexercise changes in muscle mRNA expression of genes involved in protein turnover, substrate utilization, remodeling and inflammation, did not differ between drinks (P>0.050). Post-exercise MyoPS did not differ following ingestion of 1.5, 15 and 20 g drinks, hence 0.6 g leucine may be sufficient to stimulate post-exercise MyoPS in young females.

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 disease 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.