Retinoid X receptors (RXRs) are nuclear hormone receptors (NRs) functioning as transcription factors. There are three RXR isoforms: RXRA (NR2B1), RXRB (NR2B2), and RXRG (NR2B3). RXRs serve as master regulators of gene networks governing cell growth, differentiation, survival, and death. RXRs might affect insulin action, but very little data currently supports this relationship. The aim of the study was to analyze the relationship between the expression of RXRs in skeletal muscles and insulin sensitivity in young, normal-weight, overweight and obese people.

The research group consisted of 45 volunteers, 20 had normal body weight, 13 were overweight, and 12 were obese. Insulin sensitivity was measured with hyperinsulinemic-euglycemic clamp. Vastus lateralis muscle biopsies were taken before each clamp, and RXRs mRNA expression was analyzed.

RXRA expression was lower in overweight, obese subjects in comparison with normal-weight volunteers (P = 0.003, P = 0.002, respectively). RXRB and RXRG expression did not differ between the groups. RXRA expression in muscle was positively correlated with insulin sensitivity (r = 0.49, P = 0.001). The relationship between muscle tissue RXRA and insulin sensitivity was independent of BMI (β = 0.35, P = 0.02).

Our results indicate that RXRA expression in skeletal muscle is linked to insulin sensitivity. The data suggest that muscle-associated RXRs may play a role in modulating insulin action.

Pulsed ultrasound (US) is widely used both as a diagnostic imaging tool and a therapeutic approach. However, many of the mechanisms underlying the therapeutic effects of non-thermal US remain unclear, especially in skeletal muscles, which play a crucial role in the body's metabolism. The aim of this study was to investigate the effects of US on myotubes.

In this study, C2C12 myoblasts were utilized. After differentiating into myotubes, the cells were exposed to US irradiation at an intensity of 3.0 W/cm2, with a 20 % duty cycle, an acoustic frequency of 1 MHz, and a pulse repetition frequency of 100 Hz for 5 min. The cells were then collected and analyzed for genomic and metabolomic alterations, as well as mitochondrial function.

Cell viability remained unaffected after US irradiation. The mitogen-activated protein kinase (MAPK) signaling pathway was the most activated, while the expression of various RNAs was significantly altered. Purine metabolism was highly activated, with an increase in the abundance of metabolites associated with this pathway. Furthermore, mitochondrial respiration in the myotubes increased following US irradiation.

This study investigated the impact of US irradiation on myotubes using genomic analysis, metabolomic analysis, and mitochondrial function. US irradiation activated the MAPK signaling pathway, which in turn enhanced purine metabolism and improved mitochondrial respiration.

Achieving high maturity and functionality in in vitro skeletal muscle models is essential for advancing our understanding of muscle biology, disease mechanisms, and drug discovery. However, current models struggle to fully recapitulate key features such as sarcomere structure, muscle fiber composition, and contractile function while also ensuring consistency and rapid production. Adult stem cells residing in muscle tissue are known for their powerful regenerative potential, yet tissue-derived skeletal muscle organoids have not been established. In this study, we introduce droplet-engineered skeletal muscle organoids derived from primary tissue using cascade-tubing microfluidics. These droplet-engineered organoids (DEOs) exhibit high maturity, including well-developed striated sarcomeres, spontaneous and stimulated contractions, and recapitulation of parental muscle fiber types. Notably, DEOs are produced in just 8 d without the need for primary cell culture-substantially accelerating the 50- to 60-d process required by classical organoid models. Additionally, the cascade-tubing microfluidics platform enables high-throughput production of hundreds of uniform DEO replicates from a small tissue sample, providing a scalable and reproducible solution for skeletal muscle research and drug screening.

This study explores the association between the Wnt signaling pathway and T2DM, emphasizing the role of Tankyrase1 (TNKS1) in metabolic regulation. Using network pharmacology and computational approaches, it aims to identify potential FDA-approved drugs for repurposing as Wnt inhibitors to improve insulin sensitivity and reduce fat accumulation.

Network pharmacology analysis was performed to explore the association between the Wnt pathway and T2DM, identifying Catenin Beta 1 (CTNBB1) as a key hub gene involved in disease progression. A 2D structural similarity search was conducted using reference tankyrase inhibitors (E7449 and XAV939). Potential drug candidates were subjected to molecular docking and 100 ns molecular dynamics (MD) simulations with the Tankyrase I (PDB ID: 4W6E) protein. The shortlisted compounds were further evaluated for Wnt inhibitory activity using the TCF/LEF reporter assay, while their anti-diabetic potential was assessed through a glucose uptake assay in L6 myoblast cells.

Niclosamide, Capmatinib, Esomeprazole, and Fenofibrate were identified as promising candidates with strong binding affinities and stable interactions with key amino acids (Gly1185, Ser1221, Tyr1224, Asp1198, Tyr1213, and His1201). Experimental validation through in-vitro Wnt inhibition and glucose uptake assays confirmed that drugs Fenofibrate and Conivaptan exhibited significant Wnt inhibitory activity, suggesting their potential role in modulating T2DM-related pathways.

This study highlights the role of the Wnt signaling pathway in T2DM pathogenesis and identifies potential drug candidates for repurposing as Tankyrase1/Wnt inhibitors. The findings provide a foundation for further in-vivo investigations into the anti-diabetic potential of the identified drugs, paving the way for novel therapeutic strategies in T2DM management.

The increasing global aging population has brought greater focus to age-related diseases, particularly muscle-brain comorbidities such as sarcopenia and late-life depression. Sarcopenia, defined by the gradual loss of muscle mass and function, is notably prevalent among older individuals, while late-life depression profoundly affects their mental health and overall well-being. Epidemiological evidence suggests a high co-occurrence of these two conditions, although the precise biological mechanisms linking them remain inadequately understood. This review synthesizes the existing body of literature on sarcopenia and late-life depression, examining their definitions, prevalence, clinical presentations, and available treatments. The goal is to clarify the potential connections between these comorbidities and offer a theoretical framework for the development of future preventive and therapeutic strategies.

Insulin regulates glucose uptake and metabolism in muscle via the insulin receptor. Here, we show that Lrtm1 (leucine-rich repeat and transmembrane domain 1), a protein of unknown function enriched in insulin-responsive metabolic tissues, senses changes in insulin signaling in muscle and serves as a regulator of metabolic response. Thus, whole-body Lrtm1-deficient mice exhibit a reduced percentage of fat mass, an increased percentage of lean mass, and an enhanced glucose tolerance and insulin sensitivity compared with control mice under both chow and high-fat diet conditions. Lrtm1 whole-body deficiency also affects dopamine signaling in the brain, leading to hyperactivity. The improvements in glucose and insulin tolerance, but not behavioral or body composition changes, are also observed in skeletal muscle-specific Lrtm1 knockout mice. These effects occur with no change in classical insulin receptor-Akt signaling. Thus, Lrtm1 senses changes in insulin receptor signaling and serves as a novel postreceptor regulator of metabolic and behavioral activity.

Using HPLC-PDA and HRMS analysis, five compounds p-coumaric acid, sinapic acid, quercetin, trans-ferulic and gallic acid were identified in seeds of Amomum dealbatum Roxb. The GC-MS analysis identified 1-dodecanol, phenol, 3,5-bis(1,1-dimethylethyl), Oleic Acid and 1-Heptacosanol which possess anti-diabetic properpties. A bioassay-guided technique was used to determine the degree of inhibition that A. dealbatum seeds crude methanol extract and its most active sub-fraction had against the α-glucosidase and Helicobacter pylori urease enzymes. In the Rat L6 myoblast cell line, glucose absorption through the GLUT4 transporter of most active subfraction (EASF80) was examined. According to a molecular docking investigation, these compounds strongly interacted with the GLUT4 transporter, H pylori and α-glucosidase enzyme. Sinapic acid interacted most strongly with the H. pylori urease enzyme while gallic acid interacted with both the α-glucosidase enzyme and the GLUT4 transporter. Additionally, a molecular docking simulation study was carried out to recognise the stability of the complexes.

Polycystic ovary syndrome (PCOS) is strongly associated with metabolic abnormalities, with 50-70% of patients exhibiting insulin resistance (IR), which significantly impacts the reproductive health of women in their reproductive years. Growth differentiation factor 15 (GDF15), a hormone responsive to nutritional stress, has been implicated in several diseases. This study sought to clarify the relationship between GDF15 levels and IR condition in PCOS patients. Based on the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), patients were categorized into an IR-PCOS group (n = 124) and a non-insulin-resistant group (non-IR-PCOS group, n = 109). Fasting blood samples were collected to measure GDF15 concentrations. To assess metabolic complications in relation to GDF15 levels, patients were also classified into high and normal GDF15 groups. Serum GDF15 levels were significantly higher in IR-PCOS patients (median 772.94 pg/ml) compared to non-IR-PCOS patients (median 575.80 pg/ml, P < 0.05). The high GDF15 group showed more severe metabolic and lipid abnormalities than the normal GDF15 group. Spearman correlation analysis revealed a correlation between increased GDF15 levels and impaired glucose metabolism. Logistic regression analysis identified GDF15, HDL-C, and prolactin as risk factors for IR in PCOS, and the fully adjusted regression coefficient for GDF15 levels and IR prevalence was 4.490 (95% CI 1.541 to 13.088). Restricted cubic spline analysis confirmed a positive association between GDF15 levels and IR within a specific range. The combined predictive probability of GDF15, prolactin, and HDL-C for IR was 0.763 (95% CI 0.701 to 0.826) according to ROC analysis. Elevated GDF15 levels may be associated with IR in PCOS patients, suggesting a potential role for GDF15 in the pathophysiology of IR in this condition.

Relative muscle strength (RMS) serves as a valuable indicator of skeletal muscle function. As the body ages, skeletal muscle function declines gradually, leading to a range of adverse effects. Cardiometabolic multimorbidity (CMM) is a prevalent co-morbidity in middle-aged and elderly populations. However, there are few studies to investigate the association between RMS and CMM.

This study adopted a cross-sectional design, including participants from the China Health and Retirement Longitudinal Study (CHARLS) of 2011. Appendicular skeletal muscle mass (ASM) was estimated using previously validated anthropometric equations. RMS was defined as the ratio of maximum hand grip strength (HGS) to ASM. CMM was characterized by the presence of at least two cardiometabolic disorders (cardiopathy, stroke, and diabetes), as assessed through self-reported physician diagnoses. The relationship between RMS and CMM was evaluated through multifactor logistic regression analysis.

A total of 9,200 participants with a mean age of 59.49 years were included in this study. Among them, 6,844 (74.4%) had no cardiometabolic disease (CMD), 2,052 (22.3%) had a single CMD, and 304 (3.3%) had cardiometabolic multimorbidity (CMM). Multifactor logistic regression was used to evaluate the relationship between them. In the initial model, there was a negative correlation between RMS and CMM. After adjusting for confounders, this association remained statistically significant. Specifically, for each additional unit increase in RMS, the risk of CMM was reduced by 40% (OR: 0.60, 95%CI: (0.45, 0.78)). Additionally, the highest RMS value group had a lower risk of CMM compared to the lowest value group (OR: 0.46, 95%CI: (0.31, 0.67)). As indicated by the restricted cubic spline plots, there was an L-shape correlation between RMS and CMM (P for nonlinear = 0.003).

The RMS, calculated based on HGS and ASM, was a potential indicator of CMM in middle-aged and elderly adults in China.

Type 2 diabetes mellitus-related sarcopenia (T2DMRS) is a common complication in elderly and advanced diabetes patients that affects long-term prognosis and quality of life. Skeletal muscle is the main unit of glucose metabolism, and it is surrounded by extracellular matrix (ECM), which is a microenvironment that acts as an efficient highway system. The ECM is essential for cellular communication and nutrient transport and supports muscle cell growth and repair. When this "ECM highway" fails to function effectively because of damage or blockage, the development of T2DMRS can be triggered or exacerbated. In recent years, the ECM has been widely demonstrated to play a critical role in insulin resistance and skeletal muscle regeneration. However, how the remodeling of skeletal muscle ECM components specifically affects the T2DMRS mechanism of action has not been scientifically described in detail. In this review, we comprehensively summarize the T2DMRS-related mechanisms of ECM remodeling, suggesting that collagen and integrins may be potential therapeutic targets.

Skeletal muscle's elegant protein-based architecture powers motion throughout the animal kingdom, with its constituent actomyosin complexes driving intra- and extra-cellular motion. Classical motors and recently developed soft actuators cannot match the packing density and contractility of individual muscle fibers that scale to power the motion of ants and elephants alike. Accordingly, the interdisciplinary fields of robotics and tissue engineering have combined efforts to build living muscle actuators that can power a new class of robots to be more energy-efficient, dexterous, and safe than existing motor-powered and hydraulic paradigms. Doing so ethically and at scale─creating meter-scale tissue constructs from sustainable muscle progenitor cell lines─has inspired innovations in biomaterials and tissue culture methodology. We weave discussions of muscle cell biology, materials chemistry, tissue engineering, and biohybrid design to review the state of the art in soft actuator biofabrication. Looking forward, we outline a vision for meter-scale biohybrid robotic systems and tie discussions of recent progress to long-term research goals.

To assess the association between physical activity (PA), sedentary time (ST), and sleep with body composition, and to explore the effects of reallocating ST to PA or sleep on body composition in individuals with prediabetes and overweight/obesity.

Baseline data from the PREDIPHONE trial, including 159 participants (mean age 59.6 years) with prediabetes (Fasting Plasma Glucose 100-125 mg/dl) and overweight/obesity (Body Mass Index 27-40 kg/m²), were analyzed. Body composition was assessed via bioelectrical impedance, while PA, ST, and sleep were measured with accelerometry. Linear regression and isotemporal substitution models evaluated associations. Increased ST was positively associated with body fat mass (kg) (β = 0.016; CI 95%: 0.003-0.030), body fat mass (%) (β = 0.009; 0.001-0.018), and visceral adipose tissue (β = 0.005; 0.001-0.010). Moderate-to-vigorous PA (MVPA) was negatively associated with body fat mass (kg) [β = -0.031; 0.055- (-0.008)], body fat mass (%) [β = -0.017; -0.032-(-0.003)], and Visceral adipose tissue [β = -0.009; -0.02-(-0.002)]. Replacing ST with MVPA was linked to lower Visceral adipose tissue [β = -0.012; -0.024-(-0.001)] and body fat mass (kg) [β = -0.039; -0.074-(-0.006)], but not with lean mass. No significant associations were found when substituting ST with light PA or sleep.

In individuals with prediabetes and overweight/obesity, replacing ST with MVPA could reduce body fat and VAT but not increases lean mass.

Obesity and related metabolic disorders are closely linked to increased apoptosis in skeletal muscle, leading to muscle degeneration, insulin resistance, and the progression of diseases such as type 2 diabetes and sarcopenia. This review explores the combined effects of natural products, including resveratrol, curcumin, and quercetin, and physical exercise on modulating apoptosis pathways in skeletal muscle. Both natural products and regular physical activity independently reduce oxidative stress and improve mitochondrial function, thereby regulating the balance between pro-apoptotic and anti-apoptotic signals. When combined, these interventions amplify their protective effects on muscle health, promoting mitochondrial biogenesis, reducing apoptosis, and enhancing muscle regeneration. This review also discusses the molecular mechanisms by which these strategies influence apoptosis, with a focus on the Bcl-2 pathway, and explores the clinical implications for the prevention and treatment of obesity-related diseases. The synergistic benefits of combining exercise with natural product supplementation offer a promising therapeutic approach for managing metabolic disorders, preserving muscle function, and improving overall metabolic health.

The mechanistic complexity in type 2 diabetes (T2DM) is primarily responsible for the degrees of heterogeneity and development of complications. A complex mode of interactions between different pathophysiological events and diabetogenic environmental factors support for the genesis of diabetes heterogeneity both in phenotypic and clinical contexts. The currently used diabetes classification strategies suffer from several inconsistencies that cannot fully capture the inherent heterogeneity among the diabetes patients. To effectively address this pathobiological and heterogeneity-related issue in diabetes research, the current review proposes nine pathophysiological hallmarks of T2DM that aims to mechanistically explain complexities of diabetes associated pathophysiological events and their underlying features. These pathophysiological hallmarks are pancreatic beta cell dysfunction, insulin sensitivity, insulin resistance, obesity, aging, subclinical inflammation, metabolic dysregulation, prothrombotic state induction and hypertension. Detail knowledge of these pathophysiological hallmarks with their key molecular mediators, influencing factors, clinical biomarkers and clinical assessment methodologies will greatly support precision medicine approaches in diabetes including patient stratification, subtype diagnosis and treatment.

The online version contains supplementary material available at 10.1007/s13340-024-00783-w.

Disruptions of circadian rhythms are widespread in modern society and lead to accelerated and worsened symptoms of metabolic syndrome. In healthy mice, the circadian clock factor BMAL1 is required for skeletal muscle function and metabolism. However, the importance of muscle BMAL1 in the development of metabolic diseases, such as diet-induced obesity (DIO), remains unclear. Here, we demonstrate that skeletal muscle-specific BMAL1-deficient mice exhibit worsened glucose tolerance upon high-fat diet feeding, despite no evidence of increased weight gain. Metabolite profiling from Bmal1-deficient muscles revealed impaired glucose utilization specifically at early steps in glycolysis that dictate the switch between anabolic and catabolic glucose fate. We provide evidence that this is due to abnormal control of the nutrient stress-responsive hypoxia-inducible factor (HIF) pathway. Genetic HIF1α stabilization in muscle Bmal1-deficient mice restores glucose tolerance and expression of 217/736 dysregulated genes during DIO, including glycolytic enzymes. Together, these data indicate that during DIO, skeletal muscle BMAL1 is an important regulator of HIF-driven glycolysis and metabolic flexibility, which influences the development of high-fat-diet-induced glucose intolerance.

Thiazides, thiazide-like and loop diuretics are commonly prescribed to manage hypertension and heart failure. The main mechanism of action of these diuretics involve inhibition of Na+ reabsorption in the kidneys, leading to increased urine production. While effective, diuretics, particularly hydrochlorothiazide, have been linked to altered glucose metabolism and other metabolic issues. These disruptions in fuel homeostasis are not clearly related to their primary action of fluid management, raising concerns for patients with metabolic syndrome, in which high blood pressure coexists with obesity, insulin resistance, glucose intolerance and dyslipidemia. In this review, we conducted an extensive examination of existing literature on these classes of diuretics, covering publications from the late 1950s to the present. Our objective was to investigate the origins, development and current understanding of the widely recognized association between the use of diuretics in general and their potential negative impact on glucose homeostasis. We focused on the clinical and experimental evidence of the most commonly prescribed diuretics: hydrochlorothiazide, chlorthalidone, bumetanide and furosemide. On one hand, the clinical evidence supports the hypothesis that the metabolic effects on glucose homeostasis are primarily linked to hydrochlorothiazide, with little, if any impact observed in other diuretics. In addition, these metabolic effects do not appear to be related to their diuretic action or intended pharmacological targets, raising concerns about the long-term metabolic impact of specific diuretics, particularly in vulnerable populations, including those with metabolic syndrome. On the other hand, the experimental evidence using animal models suggest variable effects of diuretics in insulin secretion and general glucose metabolism. Although the mechanisms involved are not clearly understood, further research is needed to uncover the molecular mechanisms by which certain diuretics disrupt fuel metabolism and contribute to metabolic disturbances.

Insulin resistance (IR) is a significant factor in the development and progression of metabolic-related diseases like dyslipidemia, T2DM, hypertension, nonalcoholic fatty liver disease, cardiovascular and cerebrovascular disorders, and cancer. The pathogenesis of IR depends on multiple factors, including age, genetic predisposition, obesity, oxidative stress, among others. Abnormalities in the insulin-signaling cascade lead to IR in the host, including insulin receptor abnormalities, internal environment disturbances, and metabolic alterations in the muscle, liver, and cellular organelles. The complex and multifaceted characteristics of insulin signaling and insulin resistance envisage their thorough and comprehensive understanding at the cellular and molecular level. Therapeutic strategies for IR include exercise, dietary interventions, and pharmacotherapy. However, there are still gaps to be addressed, and more precise biomarkers for associated chronic diseases and lifestyle interventions are needed. Understanding these pathways is essential for developing effective treatments for IR, reducing healthcare costs, and improving quality of patient life.

The association between insulin resistance (IR), type 2 diabetes mellitus (T2DM), and cancer is increasingly recognized and poses an escalating global health challenge, as the incidence of these conditions continues to rise. Studies indicate that individuals with T2DM have a 10-20% increased risk of developing various solid tumors, including colorectal, breast, pancreatic, and liver cancers. The relative risk (RR) varies depending on cancer type, with pancreatic and liver cancers showing a particularly strong association (RR 2.0-2.5), while colorectal and breast cancers demonstrate a moderate increase (RR 1.2-1.5). Understanding these epidemiological trends is crucial for developing integrated management strategies. Given the global rise in T2DM and cancer cases, exploring the complex relationship between these conditions is critical. IR contributes to hyperglycemia, chronic inflammation, and altered lipid metabolism. Together, these factors create a pro-tumorigenic environment conducive to cancer development and progression. In individuals with IR, hyperinsulinemia triggers the insulin-insulin-like growth factor (IGF1R) signaling pathway, activating cancer-associated pathways such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PIK3CA), which promote cell proliferation and survival, thereby supporting tumor growth. Both IR and T2DM are linked to increased morbidity and mortality in patients with cancer. By providing an in-depth analysis of the molecular links between insulin resistance and cancer, this review offers valuable insights into the role of metabolic dysfunction in tumor progression. Addressing insulin resistance as a co-morbidity may open new avenues for risk assessment, early intervention, and the development of integrated treatment strategies to improve patient outcomes.

This cross-sectional study analyzed National Health and Nutrition Examination Survey data from 2011 to 2018, focusing on individuals aged ≥20 years. The association between metabolic score for insulin resistance (METS-IR) and sarcopenia was examined using weighted multivariable logistic regression, with dose-response relationships characterized by restricted cubic spline analysis. Subgroup and sensitivity analyses were performed, and receiver operating characteristic curve analysis assessed METS-IR's ability to detect sarcopenia, with the area under the curve used for evaluation. The study included 4553 participants (mean age, 40 years; 49.4% male and 50.6% female). In the descriptive analysis, METS-IR levels in sarcopenia (mean, 52.39) were significantly higher than METS-IR levels in nonsarcopenia (mean, 41.94), indicating an association with sarcopenia. A univariate logistic regression analysis showed that sarcopenia and METS-IR were positively correlated. Even after accounting for all variables, METS-IR maintained a stable positive correlation with the prevalence of sarcopenia (odds ratio, 1.06 [95% CI, 1.06-1.08]). The results remained stable when METS-IR was categorized into quartiles. METS-IR was found to positively correlate with sarcopenia prevalence using restricted cubic spline analysis. According to subgroup analysis, there is a consistent and stable positive correlation between the prevalence of sarcopenia and METS-IR. Sensitivity analysis showed that METS-IR and sarcopenia continued to have a significant positive connection even after excluding extreme findings. The area under the curve value of METS-IR in the receiver operating characteristic curve analysis was 0.7217, suggesting that METS-IR could be a useful predictor of sarcopenia.

Endocrine-disrupting chemicals (EDCs) play an important role in the incidence of type-2 diabetes. Di-2-ethyl hexyl Phthalate (DEHP) is one of the endocrine-disrupting chemicals used as a plasticizer to impart flexibility and softness to plastic-containing materials. Mono-2-ethylhexyl Phthalate (MEHP), a DEHP's primary metabolite, is preferentially absorbed once metabolized. A previous study from our laboratory showed that DEHP and MEHP altered the key proteins such as insulin receptor (INSR) and glucose transporter-4 (GLUT4) in L6 myotubes. In a sequel to the previous study, the present study hypothesized that DEHP and its metabolite MEHP may alter the Insr and Glut4 gene expression in L6 myotubes. Therefore, to find out the molecular mechanism behind the decreased INSR and GLUT4 protein levels in the previous study, the direct effect of DEHP and its metabolite MEHP in regulating Insr and Glut4 gene transcription in L6 myotubes was studied. The L6 myotubes were exposed to 50 and 100 μM DEHP and MEHP for 24 h, followed by insulin stimulation for 20 min. We observed decreased Insr and Glut4 mRNA levels in DEHP and MEHP-treated groups. Western blot data showed decreased protein levels of MEF2A and MyoD in treated groups. ChIP assay detected a decreased association of MEF2A and MyoD to the Glut4 gene promoter and HMGA1 to the Insr gene promoter. The study revealed that DEHP and MEHP diminished the Insr and Glut4 gene expression through weakened interaction of their transcription factors on the respective promoter.

Physical activity (PA) and exercise elicit adaptations and physiological responses in skeletal muscle, which are advantageous for preserving health and minimizing chronic illnesses. The complicated atmosphere of the exercise response can be attributed to hereditary and environmental variables. The primary cause of these adaptations and physiological responses is the transcriptional reactions that follow exercise, whether endurance- (ET) or resistance- training (RT). As a result, the essential metabolic and regulatory pathways and myogenic genes associated with skeletal muscle alter in response to acute and chronic exercise. Epigenetics is the study of the relationship between genetics and the environment. Exercise evokes signaling pathways that strongly alter myofiber metabolism and skeletal muscle physiological and contractile properties. Epigenetic modifications have recently come to light as essential regulators of exercise adaptations. Research has shown various epigenetic markers linked to PA and exercise. The most critical epigenetic alterations in gene transcription identified are DNA methylation and histone modifications, which are associated with the transcriptional response of skeletal muscle to exercise and facilitate the modification to exercise. Other changes in the epigenetic markers are starting to emerge as essential processes for gene transcription, including acetylation as a new epigenetic modification, mediated changes by methylation, phosphorylation, and micro-RNA (miRNA). This review briefly introduces PA and exercise and associated benefits, provides a summary of epigenetic modifications, and a fundamental review of skeletal muscle physiology. The objectives of this review are 1) to discuss exercise-induced adaptations related to epigenetics and 2) to examine the interaction between exercise metabolism and epigenetics.

Myostatin, a potent negative regulator of skeletal muscle mass, has garnered significant attention as a therapeutic target for muscle dystrophies. Despite extensive research and promising preclinical results, clinical trials targeting myostatin inhibition in muscle dystrophies have failed to yield substantial improvements in muscle function or fitness in patients. This review details the mechanisms behind myostatin's function and the various inhibitors that have been tested preclinically and clinically. It also examines the challenges encountered in clinical translation, including issues with drug specificity, differences in serum myostatin concentrations between animal models and humans, and the necessity of neural input for functional improvements. Additionally, we explore promising avenues of research beyond muscle dystrophies, particularly in the treatment of metabolic syndromes and orthopedic disorders. Insights from these alternative applications suggest that myostatin inhibition may hold the potential for addressing a broader range of pathologies, providing new directions for therapeutic development.

People with type 2 diabetes (T2D) have a 2-3-time higher risk of developing sarcopenia, a musculoskeletal disease marked by a progressive loss of skeletal muscle mass and strength, compared to people without T2D. This narrative review examines the effectiveness of lifestyle interventions in enhancing muscle mass and strength in people with T2D, emphasizing their growing importance with advancements in obesity treatments. PubMed and Google Scholar were utilized to identify the most relevant published studies based on the authors' knowledge. The maintenance of skeletal muscle strength and mass in people with T2D is becoming more prominent due to the advent of weight loss therapies such as low-energy diets, bariatric surgery and pharmacotherapies. Although the weight loss is to be commended, a large proportion (20-50%) of the weight loss comes from lean mass, indicative of a loss in muscle mass. There are currently no pharmacotherapies to increase, or mitigate the loss of, lean mass, with lifestyle strategies prominent in this arena. Resistance exercise is the most effective method to increase muscle mass and strength in people with T2D, but there is some evidence of an anabolic resistance. Aerobic exercise and increased dietary protein intake may result in small increases in muscle mass and strength, with no evidence of an anabolic resistance to these stimuli. Exercise and protein supplementation can increase, or aid in the retention of, muscle strength and mass in individuals with T2D, but further research is needed to explore their benefits in patients undergoing concomitant pharmaceutical and surgical treatments.

Type 2 diabetes (T2D) and metabolic (dysfunction)-associated steatotic liver disease (MASLD) affect a growing number of individuals worldwide. T2D and MASLD often coexist and substantially elevate the risk of adverse hepatic and cardiovascular clinical outcomes. Several common pathogenetic mechanisms are responsible for T2D and MASLD onset and progression, including insulin resistance, oxidative stress, and low-grade inflammation, among others. The latter can also be induced by gut microbiota and its derived metabolites. Natural bioactive compounds (NBCs) have been reported for their therapeutic potential in both T2D and MASLD. A large amount of evidence obtained from clinical trials suggests that compounds like berberine, curcumin, soluble fibers, and omega-3 fatty acids exhibit significant hypoglycemic, hypolipidemic, and hepatoprotective activity in humans and may be employed as adjunct therapy in T2D and MASLD management. In this review, the role of the most studied NBCs in the management of T2D and MASLD is discussed, emphasizing recent clinical evidence supporting these compounds' efficacy and safety. Also, prebiotics that act against metabolic dysfunction by modulating gut microbiota are evaluated.

Background and Objectives: Type 2 diabetes (T2D), closely associated with obesity, contributes to increased morbidity and mortality due to complications such as cardiometabolic disease. This review aims to evaluate the effectiveness of metabolic and bariatric surgeries (MBS) and endoscopic bariatric therapies (EBTs) in achieving diabetes remission and to examine key predictors influencing remission outcomes. Materials and Methods: This review synthesizes data from studies on MBS and EBT outcomes, focusing on predictors for diabetes remission such as preoperative insulin use, diabetes duration, HbA1c, and C-peptide levels. Additionally, predictive scoring systems, including the Individualized Metabolic Surgery (IMS), DiaRem, Advanced-DiaRem, ABCD, and Robert et al. scores, were analyzed for their utility in forecasting remission likelihood. Results: Key predictors of T2D remission include shorter diabetes duration, lower HbA1c, and higher C-peptide levels, while prolonged insulin use, and higher insulin doses are associated with lower remission rates. Scoring models like IMS and DiaRem demonstrate that lower scores correlate with a higher likelihood of remission, especially for procedures such as Roux-En-Y gastric bypass (RYGB). RYGB generally shows higher remission rates compared to sleeve gastrectomy (SG), particularly among patients with mild disease severity, while EBTs like ESG and IGBs contribute 5-20% total weight loss (TWL) and moderate glycemic control improvements. Conclusions: Both MBS and EBTs are effective for T2D management, with predictive scoring models aiding in individualized patient selection to optimize remission outcomes. Further research to validate these predictive tools across diverse populations could enhance treatment planning for both surgical and endoscopic interventions.

Trace elements such as manganese (Mn) are essential for various biological processes, including enzyme activation, metabolic pathways, and antioxidant defences. Given its involvement in these critical processes, maintaining adequate Mn levels is crucial for overall health.

The experimental design involved 24 male Wistar rats divided into three groups (n=8 per group): a control group receiving standard Mn supplementation (65 mg/kg), an Mn-deficient group, and a group supplemented with Mn2O₃ nanoparticles (65 mg/kg). The 12-week feeding trial assessed selected physiological parameters, tissue composition, caecal health, and biochemical markers.

Body and major organ weights were not significantly affected across groups (p=0.083 to p=0.579). However, significant differences were observed in fat tissue percentage (p=0.016) and lean tissue percentage (p<0.001). Caecal parameters showed higher ammonia levels (p=0.030) and increased pH (p=0.031) in the nano-Mn group. In turn, total SCFA concentrations were highest in the control group, followed by the Mn-deficient and nano-Mn groups (p<0.001). Enzymatic activities of caecal bacteria differed significantly between the groups, with reduced activity in the nano-Mn group (p<0.001). Blood plasma analysis revealed significantly lower insulin (p<0.001) and neurotransmitter levels, including dopamine and serotonin, in the Mn-deficient and nano-Mn groups compared to controls.

Our findings suggest that both Mn supplementation and deficiency can lead to physiological and biochemical alterations, affecting fat metabolism, gut health and microbial enzymatic activity or neurotransmitter levels highlighting the critical role of Mn in maintaining metabolic homeostasis or its potential implications for nutritional and pharmaceutical interventions.

Controlling energy and regulating metabolism have been key strategies in the treatment of metabolic disorders such as obesity. Yam glycoprotein (Y-Gly) is a polysaccharide-protein complex extracted from Chinese yam that has beneficial effects on glucose and lipid metabolism. This study aimed to investigate the role of Y-Gly in regulating energy metabolism in C2C12 and 3T3-L1 cells.

Y-Gly was subjected to extraction and chemo-profiling. Staining methods, assay kits, Western Blot and transcriptomics were mainly used to determine the role of Y-Gly. Additionally, the study sought to examine the impact of Y-Gly on white adipose browning in 3T3-L1 cells, employing a cell co-culture technique.

Y-Gly promoted myotube differentiation in C2C12 myoblasts, increased cellular glucose consumption, promoted ATP synthesis and mitochondrial biogenesis, and played an active role in energy expenditure and glycolipid metabolism related pathways such as AMPK and MAPK. The introduction of Y-Gly inhibited lipid accumulation after lipogenesis in 3T3-L1 cells, facilitated induction of white adipose browning related proteins such as PPARγ and UCP1 expression, and the effect was more significant after cell co-culture.

Y-Gly regulates glucose and lipid metabolism by activating the key proteins in the aforementioned pathways, and plays a role in energy metabolism regulation through crosstalk between muscle and adipose tissues. This suggests a possible role of Y-Gly in metabolism-related diseases.

The World Health Organization introduced intrinsic capacity (IC) as a metric for healthy aging. However, we found no report on the association between IC and type 2 diabetes mellitus (T2DM). We investigated the association between IC and incident T2DM in older Chinese from the Guangzhou Biobank Cohort Study.

IC was assessed across five domains equally: locomotion, vitality, cognition, psychological and sensory. Composite IC scores (0-10) were classified into three groups: poor (0-5.9), fair (6.0-8.9), and high (9.0-10), with higher scores representing greater IC. Multivariable linear regression and cox regression was used to analyze the association between IC with glycemia and T2DM, respectively.

Of 3582 participants with a mean age of 59.1 years (standard deviation (SD)=7.13) without baseline diabetes, during an average follow-up of 3.3 years (SD=0.86), 497 (13.87%) developed T2DM. After adjustments for potential confounders, those with baseline poor IC, versus high, had higher fasting glucose, 2-hour post-load glucose and glycosylated hemoglobin A1c at follow-up, and a higher risk of incident T2DM (HR (95%CI): 1.80 (1.20, 2.72)). Among IC domains, only vitality impairment was associated with an increased risk of T2DM (P for trend < 0.001).

We first reported the prospective associations of poor IC and vitality with higher glycemia and incident T2DM risk. Enhancing muscle strength to improve functional ability may be a possible intervention for reducing future risk of T2DM in older populations.

Although appendicular skeletal muscle mass (ASM) has been linked to the severity of hepatic steatosis, investigations of its correlation among younger age groups are lacking. We aimed to elucidate the role of ASM in determining the severity of metabolic dysfunction-associated steatotic liver disease (MASLD) in younger patients.

Retrospective data were collected from patients younger than 35 years who visited the Armed Forces Goyang Hospital between June 2022 and February 2024. Steatosis presence was determined by a controlled attenuation parameter score ≥ 250 dB/m, and significant fibrosis was identified with liver stiffness measurement > 8.0 kPa. ASM was measured using multifrequency bioelectrical impedance analysis (InBody 620).

Of 910 participants, 630 were diagnosed with MASLD. Patients with MASLD had lower ASM/fat mass (ASM/F) (1.02 vs. 1.91; p < 0.001), ASM/body mass index (BMI) (0.91 vs. 1.04/m2; p < 0.001), and ASM/body weight (ASM/W) (29.5% vs. 33.8%; p < 0.001) than non-MASLD patients. Additionally, ASM/F, ASM/BMI, and ASM/W significantly decreased with worsening steatosis severity and were notably lower in patients with significant fibrosis. Among 107 patients with MASLD who underwent two examinations with a median interval of 6.0 months, those with increased ASM/F showed a higher proportion of steatosis regression and a lower proportion of steatosis worsening than those with decreased ASM/F (steatosis regression, 43.1% vs. 22.9%; worsening, 11.1% vs. 28.6%; p = 0.031). All three ASM indices were significant factors in steatosis regression during the study period.

ASM is associated with the severity of steatosis and significant fibrosis in MASLD in young adults < 35 years.

Developing effective drug screening methods for type 2 diabetes requires physiologically relevant models. Traditional 2D cell cultures have limitations in replicating in vivo conditions, leading to challenges in assessing drug efficacy. To overcome these issues, we developed a 3D artificial muscle model that induces insulin resistance, a hallmark of type 2 diabetes. Using C2C12 myoblasts cultured in a scaffold of 1% alginate and 1 mg/mL collagen type 1, we optimized conditions for differentiation and structural stability. Insulin resistance was induced using palmitic acid (PA), and glucose uptake was assessed using the fluorescent glucose analog 2-NBDG. The 3D model demonstrated superior glucose uptake responses compared with 2D cultures, with a threefold increase in insulin-stimulated glucose uptake on days 4 and 8 of differentiation. Induced insulin resistance was observed with 0.1 mM PA, which maintained cell viability and differentiation capacity. The model was validated through comparative drug screening using rosiglitazone and metformin, as well as 165 candidate compounds provided by Korea Chemical Bank. Drug screening revealed that three out of five hit compounds identified in both 2D and 3D models exhibited greater efficacy in 3D cultures, with results consistent with ex vivo assays using mouse soleus muscle. This model closely mimics in vivo conditions, offering a robust platform for type 2 diabetes drug discovery while supporting ethical research practices.

Western dietary pattern is one of the main contributors to the increased risk of obesity and chronic diseases, through oxidative stress and inflammation, that are the two key mechanisms targeting metabolic organs, such as skeletal muscle and adipose tissue. The chronic exposure to high levels of dietary fatty acids can increase the amount of intramyocellular lipids in skeletal muscle, altering glucose homeostasis and contributing to a reduction in mitochondrial oxidative capacity. Probiotic administration is a promising approach as preventive strategy to attenuate metabolic damage induced by Western diet. Here, we investigated the beneficial effect of Limosillactobacillus reuteri DSM 17938 on the inflammatory state and oxidative balance in the skeletal muscle and adipose tissue of adult rats fed a western diet for 8 weeks, focusing on the role of skeletal muscle mitochondria. Limosillactobacillus reuteri DSM 17938 administration protected the skeletal muscle from mitochondrial dysfunction and oxidative stress, preventing the establishment of inflammation and insulin resistance. Interestingly, a further beneficial effect of the probiotic was exerted on body composition, favoring the deposition of protein mass and preventing adipose tissue hypertrophy and inflammation. These results open the possibility for the use of this probiotic in therapeutic approaches for nutrition-related diseases.

To investigate associations between glycaemic measures (HbA1c, random glucose), and grip strength (GS) in adults without prevalent diabetes.

We included 381,715 UK Biobank participants aged 38-73 years without diabetes (any type) with complete baseline measures for GS and HbA1c (main analyses), and glucose (supplementary analyses). Cross-sectional sex- and age-stratified associations between each glycaemic measure, GS, and probable sarcopenia (low GS) were examined with regression analyses. Changes in GS over 8.9 years were classified into four groups (decline, stable low, stable high, or reference (increase or maintained within the normal range)) in 36,228 participants and associations with baseline glycaemic measures explored using multinomial regression.

Higher HbA1c (mmol/mol) was associated with weaker mean GS (kg) (regression coefficient and 95% confidence intervals (CI): - 0.08 (- 0.09, - 0.07)), and increased odds of probable sarcopenia (odds ratio (OR) and 95% CIs: 1.02 (95% CI: 1.01, 1.02)) in males and across the age groups. In females, higher HbA1c was associated with weaker mean GS only in mid-life (e.g., 50-59 years: - 0.06 (- 0.07, - 0.05)). In males, but not in females with repeated GS, higher HbA1c was associated with decreased odds of stable high (0.97 (0.96, 0.99) and increased odds of stable low (1.03 (1.01, 1.04)) GS pattern (0.98 (0.97, 0.980)) over the follow-up. The results for glucose in supplementary analyses were mixed, especially in females.

The associations between HbA1c and GS in people without diabetes warrant replication and consideration of the effect on muscle strength when interventions to promote normoglycaemia are trialled.

The 'Body Mass Index' (BMI) is an anachronistic and outdated ratio that is used as an internationally accepted diagnostic criterion for obesity, and to prioritise, stratify, and outcome-assess its management options. On an individual level, the BMI has the potential to mislead, including inaccuracies in cardiovascular risk assessment. Furthermore, the BMI places excessive emphasis on a reduction in overall body weight (rather than optimised body composition) and contributes towards a misunderstanding of the quiddity of obesity and a dispassionate societal perspective and response to the global obesity problem. The overall objective of this review is to provide an overview of obesity that transitions away from the BMI and towards a novel vista: viewing obesity from the perspective of the skeletal muscle (SM). We resurrect the SM as a tissue hidden in plain sight and provide an overview of the key role that the SM plays in influencing metabolic health and efficiency. We discuss the complex interlinks between the SM and the adipose tissue (AT) through key myokines and adipokines, and argue that rather than two separate tissues, the SM and AT should be considered as a single entity: the 'Adipo-Muscle Axis'. We discuss the vicious circle of sarcopenic obesity, in which aging- and obesity-related decline in SM mass contributes to a worsened metabolic status and insulin resistance, which in turn further compounds SM mass and function. We provide an overview of the approaches that can mitigate against the decline in SM mass in the context of negative energy balance, including the optimisation of dietary protein intake and resistance physical exercises, and of novel molecules in development that target the SM, which will play an important role in the future management of obesity. Finally, we argue that the Adipo-Muscle Ratio (AMR) would provide a more clinically meaningful descriptor and definition of obesity than the BMI and would help to shift our focus regarding its effective management away from merely inducing weight loss and towards optimising the AMR with proper attention to the maintenance and augmentation of SM mass and function.

Sarcopenia may affect the onset of gestational diabetes mellitus (GDM). However, the causal relationship between sarcopenia and GDM remains unclear. In this study, we used a bi-directional Mendelian randomization (MR) approach to explore this intricate relationship.

This study utilized data from FinnGen datasets and genome-wide association studies. A bi-directional MR study was conducted. First, a forward MR analysis evaluated the causality of sarcopenia on GDM risk, with sarcopenia-related traits as exposures and GDM as the outcome. Second, in the reverse MR analysis, we assessed whether GDM influenced sarcopenia-related traits. Finally, sensitivity analysis was conducted to assess the robustness of the MR analysis.

Forward MR analysis revealed that appendicular lean mass (odds ratio [OR] = 1.2182, 95% confidence interval [CI]: 1.1397-1.3021, P < 0.0001), right-hand grip strength (OR= 1.4194, 95% CI: 1.0773-1.8701, P= 0.0128), left-hand grip strength (OR= 1.6064, 95% CI: 1.2829-2.0115, P < 0.0001), and usual walking pace (OR= 3.3676, 95% CI: 1.8769-6.0423, P < 0.0001) were associated with an increased risk of GDM. However, according to the reverse MR results, GDM had no causal effect on sarcopenia. No pleiotropy was observed.

In summary, sarcopenia had a significant causal influence on GDM, while GDM did not causally affect sarcopenia.

Obesity is a complex, multifactorial, chronic disease that acts as a gateway to a range of other diseases. Evidence from recent studies suggests that changes in oxygen availability in the microenvironment of metabolic organs may exert an important role in the development of obesity-related cardiometabolic complications. In this review, we will first discuss results from observational and controlled laboratory studies that examined the relationship between reduced oxygen availability and obesity-related metabolic derangements. Next, the effects of alterations in oxygen partial pressure (pO2) in the adipose tissue, skeletal muscle and the liver microenvironment on physiological processes in these key metabolic organs will be addressed, and how this might relate to cardiometabolic complications. Since many obesity-related chronic diseases, including type 2 diabetes mellitus, cardiovascular diseases, chronic kidney disease, chronic obstructive pulmonary disease and obstructive sleep apnea, are characterized by changes in pO2 in the tissue microenvironment, a better understanding of the metabolic impact of altered tissue oxygenation can provide valuable insights into the complex interplay between environmental and biological factors involved in the pathophysiology of metabolic impairments. This may ultimately contribute to the development of novel strategies to prevent and treat obesity-related cardiometabolic diseases.

New onset diabetes mellitus after organ transplantation (NODAT) is a frequent and serious complication of solid organ transplantation. It significantly impacts graft function, patient survival, and quality of life. NODAT is diagnosed based on the criteria for type 2 diabetes, with the oral glucose tolerance test (OGTT) serving as the gold standard for diagnosis. The development of NODAT is influenced by a range of risk factors, which are classified into modifiable and non-modifiable categories. Post-transplant, regular glycemic monitoring at specific intervals is essential for timely diagnosis and initiation of therapy. Early intervention can help prevent or delay the onset of diabetes-related complications. The treatment strategy for NODAT involves lifestyle modifications and pharmacological interventions. These include medications such as metformin, sulfonylureas, glinides, thiazolidinediones, DPP-4 inhibitors, GLP-1 agonists, SGLT-2 inhibitors, and insulin. Adjusting immunosuppressive therapy-either by reducing dosages or substituting drugs with lower diabetogenic potential-is a common preventative and therapeutic measure. However, this must be performed cautiously to avoid acute graft rejection, which poses a greater risk to the patient compared to NODAT itself. In addition to managing diabetes, addressing comorbidities such as hypertension and dyslipidemia is crucial, as they elevate the risk of cardiovascular events and mortality. Patients with NODAT are also prone to developing common diabetes-related complications, including diabetic nephropathy, neuropathy, retinopathy, and peripheral vascular disease. Therefore, regular follow-ups and appropriate treatment are vital to maintaining quality of life and improving long-term outcomes.

A key nutrient sensing process in all animal tissues is the dynamic attachment of O-linked N-acetylglucosamine (O-GlcNAc). Determining the targets and roles of O-GlcNAc glycoproteins has the potential to reveal insights into healthy and diseased metabolic states. In cell studies, thousands of proteins are known to be O-GlcNAcylated, but reference datasets for most tissue types in animals are lacking. Here, we apply a chemoenzymatic labeling study to compile a high coverage dataset of quadriceps skeletal muscle O-GlcNAc glycoproteins from mice. Our dataset contains over 550 proteins, and > 80% of the dataset matched known O-GlcNAc proteins. This dataset was further annotated via bioinformatics, revealing the distribution, protein interactions, and gene ontology (GO) functions of these skeletal muscle proteins. We compared these quadriceps glycoproteins with a high-coverage O-GlcNAc enrichment profile from mouse hearts and describe the key overlap and differences between these tissue types. Quadriceps muscles can be used for biopsies, so we envision this dataset to have potential biomedical relevance in detecting aberrant glycoproteins in metabolic diseases and physiological studies. This new knowledge adds to the growing collection of tissues with high-coverage O-GlcNAc profiles, which we anticipate will further the systems biology of O-GlcNAc mechanisms, functions, and roles in disease.

The genetic determinants of the glucocorticoid receptor (GR) metabolic action remain largely unelucidated. This is a compelling gap in knowledge for the GR single nucleotide polymorphism (SNP) rs6190 (p.R23K), which has been associated in humans with enhanced metabolic health but whose mechanism of action remains completely unknown. We generated transgenic knock-in mice genocopying this polymorphism to elucidate how the mutant GR impacts metabolism. Compared to non-mutant littermates, mutant mice showed increased insulin sensitivity on regular chow and high-fat diet, blunting the diet-induced adverse effects on adiposity and exercise intolerance. Overlay of RNA-seq and ChIP-seq profiling in skeletal muscle revealed increased transactivation of Foxc1 and Arid5A genes by the mutant GR. Using myotropic adeno-associated viruses for in vivo overexpression or knockdown in muscle, we found that Foxc1 was required and sufficient for normal expression levels of insulin response pathway genes Insr and Irs1, promoting muscle insulin sensitivity. In parallel, Arid5a was required and sufficient to transcriptionally repress the lipid uptake genes Cd36 and Fabp4, reducing muscle triacylglycerol accumulation. Moreover, the Foxc1 and Arid5a programs in muscle were divergently changed by glucocorticoid regimens with opposite metabolic outcomes in muscle. Finally, we found a direct human relevance for our mechanism of SNP action in the UK Biobank and All of Us datasets, where the rs6190 SNP correlated with pro-metabolic changes in BMI, lean mass, strength and glucose control according to zygosity. Collectively, our study leveraged a human nuclear receptor coding variant to unveil novel epigenetic regulators of muscle metabolism.

Obesity-induced muscle alterations, such as inflammation, metabolic dysregulation, and myosteatosis, lead to a decline in muscle mass and function, often resulting in sarcopenic obesity. Currently, there are no definitive treatments for sarcopenic obesity beyond lifestyle changes and dietary supplementation. Feruloylacetone (FER), a thermal degradation product of curcumin, and its analog demethoxyferuloylacetone (DFER), derived from the thermal degradation of bisdemethoxycurcumin, have shown potential antiobesity effects in previous studies. This study investigates the impact of FER and DFER on obesity-related glucose intolerance and muscle atrophy. High-fat diet (HFD) feeding resulted in muscle mass reduction and increased intramuscular triglyceride accumulation, both of which were mitigated by FER and DFER supplementation. The supplements activated the PI3K/Akt/mTOR signaling pathway, enhanced muscle protein synthesis, and decreased markers of muscle protein degradation. Additionally, FER and DFER supplementation improved glucose homeostasis in HFD-fed mice. The supplements also promoted the formation of a gut microbial consortium comprising Blautia intestinalis, Dubosiella newyorkensis, Faecalicatena fissicatena, Waltera intestinalis, Clostridium viride, and Caproiciproducens galactitolivorans, which contributed to the reduction of obesity-induced chronic inflammation. These findings suggest, for the first time, that FER and DFER may prevent obesity-related complications, including muscle atrophy and insulin resistance, thereby warranting further research into their long-term efficacy and safety.