Metabolic syndrome (MetS) and metabolic dysfunction-associated steatotic liver disease (MASLD) are closely related, with rapidly increasing prevalence globally, driving significant public health concerns. Both conditions share common pathophysiological mechanisms such as insulin resistance (IR), adipose tissue dysfunction, oxidative stress, and gut microbiota dysbiosis, which contribute to their co-occurrence and progression. While the clinical implications of this overlap, including increased cardiovascular, renal, and hepatic risk, are well recognized, current diagnostic and therapeutic approaches remain insufficient due to the clinical and individuals' heterogeneity and complexity of these diseases. This review aims to provide an in-depth exploration of the molecular mechanisms linking MetS and MASLD, identify critical gaps in our understanding, and highlight existing challenges in early detection and treatment. Despite advancements in biomarkers and therapeutic interventions, the need for a comprehensive, integrated approach remains. The review also discusses emerging therapies targeting specific pathways, the potential of precision medicine, and the growing role of artificial intelligence in enhancing research and clinical management. Future research is urgently needed to combine multi-omics data, precision medicine, and novel biomarkers to better understand the complex interactions between MetS and MASLD. Collaborative, multidisciplinary efforts are essential to develop more effective diagnostic tools and therapies to address these diseases on a global scale.

Skeletal muscle wasting is a critical clinical problem associated with several diseases that significantly impair patient outcomes due to the progressive loss of muscle mass and function. This study explores the potential of 3-hydroxybutyrate (3-HB) as a therapeutic agent to counteract muscle atrophy by promoting the proliferation and differentiation of C2C12 myoblasts. Using nuclear magnetic resonance (NMR)-based metabolomics analysis, we uncover the underlying mechanisms by which 3-HB exerts its effects. Our findings demonstrate that 3-HB exerts its effects through two distinct mechanisms: as a metabolic substrate and as a signaling molecule. As a metabolic substrate, 3-HB enhances myoblast energy efficiency by stimulating the expression of G protein-coupled receptor 109a (GPR109a), which subsequently upregulates the 3-HB transporters MCT1 and CD147, the utilization enzyme OXCT1, and phosphorylated AMPK, thereby increasing ATP production. As a signaling molecule, 3-HB activates GPR109a, promoting calcium influx, improving calcium homeostasis, and increasing the expression of Ca2+-related proteins such as CAMKK2. This signaling cascade activates calcineurin (CaN), facilitating NFAT translocation to the nucleus and gene expression that drives myoblast proliferation and differentiation. By elucidating the dual regulatory roles of 3-HB in energy metabolism and cellular signaling, this study not only advances our understanding of muscle physiology but also highlights the potential of 3-HB as a novel therapeutic approach for the prevention or treatment of skeletal muscle atrophy.

Insulin resistance (IR) is a metabolic disorder characterized by an impaired response to insulin. This condition is associated with excess adiposity and metabolic inflammation, contributing to an increased risk for related chronic diseases. Single-nucleotide polymorphisms (SNPs) can affect genes related to metabolic pathways which are related to IR and the individual response to nutrients and dietary patterns, affecting metabolic inflammation and insulin sensitivity. This narrative review explores the current evidence on interactions between genetic variants and dietary factors, specifically their effects in modulating IR and metabolic inflammation. A comprehensive search of the literature was conducted in PubMed, Google Scholar, and Web of Science, and a total of 95 articles were reviewed. The key findings reveal that SNPs in the TCF7L2, ADIPOQ, and TNF genes significantly influence metabolic responses and modulate the effects of the Mediterranean diet on biomarkers of inflammation and IR. Genotype-dependent variations in IR and inflammation biomarkers were observed in the response to different diets for SNPs in the TCF7L2, ADIPOQ, and TNF genes. Additionally, polygenic risk scores (PRSs) can also predict the response to the intake of nutrients and specific diets, and offer a promising tool for assessing genetic predisposition to IR. This review underscores the pivotal role of an individual's genetic background in the effects of their nutrient intake and in the responses to dietetic interventions, thereby laying the foundation for personalized and effective nutritional strategies tailored to each individual's necessity in mitigating IR and its associated risk factors for chronic diseases.

Background/Objectives: Few studies have compared the associations of different adiposity markers with cardiometabolic risk factors in individuals without diabetes or cardiovascular disease (CVD), particularly in South America. Moreover, the associations with more severe cardiometabolic risk, defined by the simultaneous presence of altered glycemia, blood pressure, and dyslipidemia, remain unknown. We examined whether the waist-to-height ratio (W-HtR), waist circumference (WC), and BMI were independently associated with cardiometabolic risk in a chronic disease prevention program in Medellín, Colombia. Methods: A cross-sectional study was conducted in 29,236 adults (age: 19-121 years) without diabetes or CVD. Exposures included increased W-HtR (>0.5), increased WC (≥80 cm for women, ≥90 cm for men), and overweight/obesity. The outcomes were dyslipidemia, elevated glycemia, high blood pressure, and full cardiometabolic risk (FCMR), defined as the presence of all three factors. Logistic regressions adjusted for sociodemographic and lifestyle covariates and additional adiposity markers were used. Cubic spline analyses examined the shape of associations. Results: Most individuals were over 40 years old (97.6%), only 40 were ≥100 years, and 16.5% (n = 4821) had FCMR. Increased W-HtR tripled the odds of FCMR compared with normal W-HtR (OR: 3.04, 95%CI: 2.45-3.77, p < 0.001). Increased WC doubled the odds of FCMR (p < 0.001). W-HtR remained the strongest predictor after adjusting for WC (OR: 1.99, 95%CI: 1.59-2.50) and BMI (OR: 2.48, 95%CI: 1.99-3.08). Cubic spline analyses showed a linear association between W-HtR and FCMR, whereas the BMI-FCMR association plateaued at approximately 30 kg/m2. Conclusions: In this cross-sectional study of a large middle-to-older-aged cohort, W-HtR was the strongest adiposity marker correlated with cardiometabolic risk.

Metabolic syndrome-related diseases frequently involve disturbances in skeletal muscle lipid metabolism. The accumulation of lipid metabolites, lipid-induced mitochondrial stress in skeletal muscle cells, as well as the inflammation of adjacent adipose tissue, are associated with the development of insulin resistance and metabolic dysfunction. Consequently, when antidiabetic medications are used to treat various chronic conditions related to hyperglycaemia, the impact on skeletal muscle lipid metabolism should not be overlooked. However, current research has predominantly focused on muscle mass rather than skeletal muscle lipid metabolism and its interplay with glucose metabolism. In this review, we summarised the latest research on the effects of antidiabetic drugs and certain natural compounds with antidiabetic activity on skeletal muscle lipid metabolism, focusing on data from preclinical to clinical studies. Given the widespread use of antidiabetic drugs, a better understanding of their effects on skeletal muscle lipid metabolism merits further attention in future research.

The association between triglyceride(TG) levels and the risk of diabetes mellitus (DM) continues to be a subject of considerable interest and debate within the scientific community. To date, there has been a lack of studies specifically examining this relationship within the Chinese population. This study seeks to elucidate the correlation between TG levels and the incidence of DM among the Chinese demographic.

This study constitutes a secondary analysis of a retrospective cohort investigation comprising 202,888 Chinese participants who were free of DM at baseline and were subsequently followed from 2010 to 2016. Cox regression method and sensitivity analyses were used to examine the relationship between TG levels and DM. To examine the potential non-linear relationship between TG levels and the incidence of DM, Cox proportional hazards regression incorporating cubic spline functions and smooth curve fitting was employed. Additionally, a two-piece Cox proportional hazards regression model was utilized to identify the inflection point at which TG levels influence the risk of developing DM.

In participants with DM, baseline TG levels were elevated. After adjusting for confounding variables, baseline TG levels were positively associated with incident DM. (HR:1.25,95% CI:1.21-1.30,P<0.001). In addition, we conducted sensitivity analyses to ensure the results were robust. There was a 88% increase in DM risk from the top TG tertile to the bottom TG tertile.Our research discovered a significant link between TG and DM when TG levels were below 1.27 mmol/L (HR:2.35, 95% CI: 1.95-2.83,P < 0.001).

This study shows that TG was positively and non-linearly associated with the risk of DM after adjusting for other confounding factors.Below 1.27 mmol/L, increasing TG levels greatly heighten the risk of DM, whereas above this level, the risk is lower.

Insulin resistance (IR) disrupts hepatic glucose metabolism and mitochondrial function, which contributes to metabolic disorders. The present study examined the effects of tomatine on glucose metabolism in high-glucose-induced IR hepatocytes and explored its underlying mechanisms using AML12 and HepG2 cell models. The results showed that tomatine did not exhibit cytotoxic effects. Under IR conditions, tomatine dose-dependently improved glucose metabolism by enhancing glucose consumption and restoring the mRNA expression of the glucose transporter Glut2 and gluconeogenesis-related genes (Pepck and G6pase). Mechanistically, tomatine activated the phosphorylation of AMP-activated protein kinase (AMPK) and upregulated the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), reversing the IR-induced suppression of the AMPK/PGC1α pathway. In addition, tomatine enhanced mitochondrial oxidative function by restoring the oxygen consumption rate, increasing ATP production, and upregulating mitochondrial oxidative phosphorylation complex proteins. Both genetic and pharmacological inhibition of AMPK abolished these beneficial effects, confirming its central role in mediating tomatine's actions. Overall, our findings suggest that tomatine is a promising therapeutic candidate for enhancing hepatic glucose metabolism and mitochondrial function in IR-associated metabolic disorders through AMPK activation.

Genetic variations in the lipoprotein lipase (LPL) gene including the HindIII polymorphism (rs320) have been reported to modify fat metabolism, adiposity, and body weight. However, little attention has been given to the African population. The present study aimed to investigate the relationship between the rs320 gene polymorphism and a number of metabolic and anthropometric parameters in a sample of the Nigerian population. We recruited 236 participants for the study. The participants were required to sign informed consent forms after which information related to their calorie intake and utilization as well as anthropometric measurements were recorded. Plasma metabolic parameters were subsequently determined using an autoanalyzer. Genotyping for HindIII polymorphism was performed using the PCR-RFLP method. The frequencies (n) of T and G alleles were 0.841 (397) and 0.158 (75), while the frequencies (n) of TT, TG, and GG were 0.691(163), 0.301(71), and 0.01(2), respectively. The population was not in Hardy-Weinberg equilibrium (χ2 = 3.717, df = 1, p = 0.841). The anthropometric parameters, the fasting blood glucose, and low-density lipoprotein cholesterol showed no association with the alleles, while plasma high-density lipoprotein cholesterol and total cholesterol were significantly higher among the G allele carriers. However, triglyceride and total protein were significantly higher among the non-G allele carriers. The LPL HindIII gene polymorphism is associated with changes in plasma lipid profile in a sample of the Nigerian population.

Cardiometabolic index (CMI), visceral adiposity index (VAI), and lipid accumulation product (LAP) are lipid-related parameters that reflect central obesity, which is closely associated with the development of non-alcoholic fatty liver disease (NAFLD). The aim of this study is to investigate the effectiveness of these lipid-related parameters in diagnosing NAFLD and to compare their predictive abilities.

This population-based study extracted datasets from the National Health and Nutrition Examination Survey (NHANES) 2017-2020. CMI, VAI, and LAP were included in the multivariate logistic model as both continuous and categorical variables to assess the relationship between different lipid-related parameters and NAFLD. To further elucidate this connection, we utilized restricted cubic splines and conducted subgroup analysis. Additionally, the receiver operating characteristics (ROC) curve was employed to evaluate the predictive effectiveness of CMI, VAI, and LAP for NAFLD.

The study included 2,878 adults as the study population, of whom 1,263 participants were diagnosed with NAFLD. When lipid-related parameters were analyzed as continuous variables, they showed a positive correlation with NAFLD. The OR(95%CI) were 2.29(1.81,2.89) for CMI (per 1-unit), 1.40(1.28,1.52) for VAI (per 1-unit) and 1.15(1.11,1.20) for LAP (per 10-units). This correlation remains statistically significant when the lipid-related parameters are analyzed as categorical variables. In descending order of diagnostic capability for NAFLD, the AUC values are as follows: LAP (0.794), CMI (0.752), and VAI (0.719).

CMI, VAI, and LAP may be important clinical indicators for identifying NAFLD, with LAP demonstrating the best predictive ability among them.

Prediabetes is a condition that often precedes the onset of type 2 diabetes mellitus (T2DM). Literature evidence indicates that prediabetes is reversible, making it an important therapeutic target for preventing the progression to T2DM. Several studies have investigated intermittent fasting as a possible method to manage or treat prediabetes.

This study evaluated the impact of a 14:10-hour time-restricted feeding (TRF) regimen on leptin concentration, insulin sensitivity and selected markers associated with the insulin signalling pathway and glucose homeostasis in diet-induced prediabetic rats.

Twenty-four male Sprague Dawley rats were obtained and randomly divided into two dietary groups: group 1 (n = 6) received a standard diet and water, while group 2 (n = 18) was provided a high-fat, high-carbohydrate (HFHC) diet supplemented with 15% fructose for a period of 20 weeks to induce prediabetes. After confirming prediabetes, an intermittent fasting (IF) regimen was assigned to the rats while also having untreated and metformin-treated prediabetic rats serving as controls.

Both IF and HFHC-Met groups yield significantly lower blood glucose, leptin and BMI results compared to the prediabetic group. The IF group yielded significantly lower insulin, HOMA-IR and HbA1C than both controls.

The study showed the potential of IF in alleviating prediabetes-induced dysregulation of glucose homeostasis and therefore warrants further investigations into its use in the management of prediabetes.

Diabetes mellitus (DM) is a fatal metabolic disease characterized by persistent hyperglycemia. In recent studies, mesenchymal stem cell (MSC)-derived exosomes, which are being investigated clinically as a cell-free therapy for various diseases, have gained attention due to their biomimetic properties that closely resemble natural cellular communication systems. These MSC-derived exosomes inherit the regenerative and protective effects from MSCs, inducing pancreatic β-cell proliferation and inhibiting apoptosis, as well as ameliorating insulin resistance by suppressing the release of various inflammatory cytokines. Consequently, MSC-derived exosomes have attracted attention as a novel treatment for DM as an alternative to stem cell therapy. In this review, we will introduce the potential of MSC-derived exosomes for the treatment of DM by discussing the studies that have used MSC-derived exosomes to treat DM, which have shown therapeutic effects in both type 1 and type 2 DM.

Lipid droplets (LDs) are highly specialized energy storage organelles involved in the maintenance of lipid homoeostasis by regulating lipid flux within white adipose tissue (WAT). The physiological function of adipocytes and LDs can be compromised by mutations in several genes, leading to NEFA-induced lipotoxicity, which ultimately manifests as metabolic complications, predominantly in the form of dyslipidemia, ectopic fat accumulation, and insulin resistance. In this review, we delineate the effects of mutations and deficiencies in genes - CIDEC, PPARG, BSCL2, AGPAT2, PLIN1, LIPE, LMNA, CAV1, CEACAM1, and INSR - involved in lipid droplet metabolism and their associated pathophysiological impairments, highlighting their roles in the development of lipodystrophies and metabolic dysfunction.

To examine the changes in obesity-related hormones and metabolic syndrome markers in male high school students with obesity following a weekend-focused moderate- or high-intensity exercise program at the recommended weekly physical activity level, or a program of regular exercise 3 times a week at moderate intensity, over a 10-week period. Forty-eight male high school students who were obese with a body fat percentage of ≥25% were randomly assigned to one of three groups: a regular moderate-intensity exercise group (n=17) that freely selected and performed moderate-intensity aerobic and resistance training exercises, every Monday, Wednesday, and Friday, for a total of 150-300 min/wk; a weekend-focused moderate-intensity exercise group (n=15) that freely selected and performed aerobic and resistance training exercises every Saturday for 150-300 min; and a week-end-focused high-intensity exercise group (n=16) that freely selected and performed aerobic and resistance training exercises every Sunday for 75-150 min. Insulin and leptin levels significantly decreased in all the groups, with the greatest reduction in the regular exercise group. Abdominal circumference and triglyceride levels significantly decreased in all the groups. Fasting glucose decreased only in the regular exercise group. High-density lipoprotein cholesterol significantly increased in both the regular and weekend-focused moderate-intensity exercise groups. No significant differences in adiponectin levels, and systolic and diastolic blood pressure were observed between the groups. A weekend-focused exercise program has health effects similar to those of regular exercise, highlighting the importance of meeting the recommended weekly physical activity levels.

Pompe disease is a rare glycogen storage disease caused by mutations in the enzyme acid α-glucosidase (GAA) resulting in pathological accumulation of glycogen in muscle tissues leading to progressive weakness and respiratory dysfunction. Enzyme replacement therapy (ERT) with GAA is currently the sole treatment option for patients with Pompe disease. ERT burdens patients with frequent intravenous infusions while insufficiently halting disease progression due to incomplete ERT skeletal muscle distribution. Glycogen synthase 1 (GYS1) has been proposed as a substrate reduction therapy (SRT) target for Pompe disease. Here, we report results from the first-in-human study of the orally available GYS1 inhibitor MZE001 in healthy subjects. In 88 participants, MZE001 was well-tolerated up to a single dose of 480 mg BID and multiple doses of 720 mg BID for 10 days. Noncompartmental analysis determined that the half-life and Ctrough concentrations of MZE001 could provide efficacious exposures with once or twice daily oral dosing. Change from baseline of peripheral blood mononuclear cell (PBMC) glycogen, which correlated with muscle glycogen levels in preclinical models, was significantly reduced dose-dependently following 10 days of MZE001 treatment in healthy subjects. A muscle biopsy sub-study demonstrated that 10 days of MZE001 (480 mg BID) dosing safely and substantially lowered muscle glycogen stores in healthy adults. This correlated with the PBMC exposure response and supports the use of PBMC glycogen reduction as a surrogate for muscle response, and MZE001 potential for development as the first oral substrate reduction therapy for patients with Pompe disease.

The infiltration of macrophages into adipose tissue mediates chronic inflammation that is associated with insulin resistance in obesity. Although vitamin E is beneficial against insulin resistance, its impact on adipose tissue inflammation has not been elucidated. This study aims to investigate the effects of α-tocopherol and γ-tocopherol, major vitamin E isoforms, on the interaction between macrophages and adipocytes with regard to obesity-induced inflammation and insulin resistance.

Hypertrophied 3T3-L1 adipocytes were cocultured with RAW 264.7 macrophages and treated with α-tocopherol or γ-tocopherol at 12.5, 25, and 50 µM. The inflammatory cytokines (monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-6) and free fatty acid (FFA) release were measured by assay kits, and nuclear factor-kappaB (NF-κB) and c-Jun NH2 terminal kinase (JNK) signals were evaluated by immunoblotting. Glucose uptake was measured with a fluorescent glucose derivative.

Treatment with α-tocopherol and γ-tocopherol restrained the coculture-induced increase in cytokines and FFA release. γ-Tocopherol exhibited greater suppression of inflammatory cytokines at 12.5 and 25 µM (P < 0.001). Both tocopherols inhibited NF-κB activation by limiting translocation of NF-κB (p65) to the nucleus, with γ-tocopherol showing a stronger effect compared to α-tocopherol. α-Tocopherol inhibited JNK phosphorylation at 50 μM, whereas γ-tocopherol did not. Furthermore, coculture with macrophages impaired glucose uptake in response to insulin, but both tocopherols restored insulin responsiveness (P < 0.01).

α-Tocopherol and γ-tocopherol effectively mitigate inflammation induced by adipocyte-macrophage interaction, thereby ameliorating coculture-induced insulin resistance. These findings suggest the therapeutic potential of tocopherols in managing obesity-related metabolic dysfunction.

Metabolic dysfunction-associated steatosis liver disease (MASLD) is one of the most common metabolic liver diseases around the world, whose prevalence continues to increase. Currently, there are few medications to treat MASLD. Ergothioneine is a natural compound derived from mushrooms whose sulfhydryl groups confer unique antioxidant, anti-inflammatory and detoxifying effects. Currently, research on the therapeutic effects of ergothioneine in MASLD is unknown. Therefore, this study explored the effect and mechanism of EGT in MASLD.

The ameliorative effects and mechanisms of ergothioneine on MASLD were evaluated using HFD mice and PA-treated AML12 cells. Mouse body weight, body fat, IPGTT, IPITT, immunohistochemistry, serum biochemical indices, and staining of liver sections were assayed to verify the protective role of ergothioneine in MASLD. RNA-seq was applied to explore the mechanism of action of ergothioneine. The role of ergothioneine in AML12 was confirmed by western blotting, qPCR, ELISA, Oil Red O staining, flow cytometry, and ROS assays. Subsequently, the 3-methyladenine (3-MA, an autophagy inhibitor) was subsequently used to confirm that ergothioneine alleviated MASLD by promoting autophagy.

Ergothioneine reduced body weight, body fat and blood lipids, and improved insulin resistance and lipid and glycogen deposition in MASLD mice. Furthermore, ergothioneine was found to increase autophagy levels and attenuate oxidative damage, inflammation, and apoptosis. In contrast, intervention with 3-MA abrogated these effects, suggesting that ergothioneine ameliorated effects by promoting autophagy.

Ergothioneine may be a drug with great therapeutic potential for MASLD. Furthermore, this protective effect was mediated through the activation of autophagy.

The complement system, a coordinator and facilitator of the innate immune response, plays an essential role in maintaining host homeostasis. It promotes clearance of pathogen- and danger-associated molecular patterns, regulates adaptive immunity, and can modify various metabolic processes such as energy expenditure, lipid metabolism, and glucose homeostasis. In this review, we will focus on the intricate interplay between complement components and lipid metabolism. More precisely, we will display how alterations in the activation and regulation of the complement system affect pathological outcome in lipid-associated diseases, such as atherosclerosis, obesity, metabolic syndrome, age-related macular degeneration, and metabolic dysfunction-associated steatotic liver disease. In addition to that, we will present and evaluate underlying complement-mediated physiological mechanisms, observed both in vitro and in vivo. Our manuscript will demonstrate the clinical significance of the complement system as a bridging figure between innate immunity and lipid homeostasis.

Addressing abdominal obesity requires multifaceted strategies, with physical activity and diet playing a pivotal role. The objective of this study was to assess alterations in body composition, adipokine concentrations, insulin resistance parameters, and lipid metabolism in males with abdominal obesity following two distinct interventions: exercise alone and exercise combined with a specific diet. The study involved 44 males with abdominal obesity (average age 34.7 ± 5.5 years, waist circumference [WC] 110.3 ± 8.5), randomly assigned to three groups: an experimental group with aerobic-resistance exercise (EG, n = 16), an experimental group with aerobic-resistance exercise combined with a high-protein, low-glycemic index carbohydrate diet (EDG, n = 16), both interventions lasting 6 weeks, and a control group without interventions (CG, n = 12). Body composition (body mass [BM], body fat percentage [BF%], fat-free mass [FFM], android body fat percentage [ANDR]), as well as biochemical blood analyses (asprosin [ASP], leptin [LEP], quantitative insulin sensitivity check index [QUICKI], and total cholesterol [TC]), were conducted at baseline and after 6 weeks of intervention. The impact of interventions on the analyzed variables among groups was assessed using mixed ANOVA tests with post-hoc comparisons. Effect size (ES) was also evaluated using 𝜂p2. Significant reductions in ASP concentration after intervention were observed in both EG (p = 0.04) and EDG (p = 0.01). However, post-hoc tests revealed a decrease in LEP only in the EDG group (p < 0.01). In EDG substantial decreases after 6 weeks of intervention were noted in BM (p < 0.01), BF% (p < 0.01), ANDR (p < 0.01) and TC (p < 0.01). The most notable increase in FFM was observed in the EDG group (p < 0.01). More favourable metabolic outcomes were confirmed in the group combining diet with exercise, where there was a notable reduction in ASP levels by 16% and LEP by 48% after 6 weeks of intervention, compared to the group undergoing exercise alone.

Background: The study investigates the association between lipid accumulation product (LAP) and the risk of prediabetes and diabetes. LAP, a measure indicating lipid overaccumulation, is hypothesized to be a significant predictor for these conditions. This research utilizes data from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2018. Methods: The study followed a structured methodology, starting with data extraction from the NHANES database. Participants' eligibility was determined based on specific inclusion and exclusion criteria, resulting in a final sample size of 24,121 individuals. LAP was calculated using established formulas for men and women. The diagnosis of prediabetes and diabetes was based on standard medical criteria, including HbA1c levels, fasting plasma glucose, and oral glucose tolerance test (OGTT) results. Covariates like demographic variables, lifestyle factors, and other health indicators were also considered. Statistical analysis involved categorizing LAP into quartiles and employing logistic regression models to examine the relationship between LAP and the risk of prediabetes and diabetes. Results: Participants in the highest LAP quartile exhibited distinct characteristics: older age, lower education levels, more former smokers and drinkers, higher blood pressure and cholesterol levels, and greater use of medications. A positive association was observed between LAP and the incidence of prediabetes and diabetes across all models. Specifically, each 10-unit increase in LAP was linked to a 22% increase in risk. Nonlinear relationships were also explored, revealing an inflection point in the risk correlation at an LAP value of 68.1. Conclusion: The study concludes that LAP is a significant predictor of prediabetes and diabetes risk, with higher LAP levels correlating with increased risk. This finding underscores the potential of LAP as a useful marker in identifying individuals at higher risk for these conditions. It also highlights the importance of considering LAP in preventive health strategies.

Adipose tissue accumulation around non-adipose tissues is associated with obesity and metabolic disease. One relatively unstudied depot is peripancreatic adipose tissue (PAT) that accumulates in obesity and insulin resistance and may impact beta cell function. Pancreatic lipid accumulation and PAT content are negatively related to metabolic outcomes in humans, but these studies are limited by the inability to pursue mechanisms.

We obtained PAT from human donors through the Human Pancreas Analysis Program to evaluate differences in paracrine signaling compared to subcutaneous adipose tissue (SAT), as well as effects of the PAT secretome on aortic vasodilation, human islet insulin secretion, and gene transcription using RNAseq.

PAT had greater secretion of IFN-γ and most inflammatory eicosanoids compared to SAT. Secretion of adipokines negatively related to metabolic health were also increased in PAT compared to SAT. We found no overall effects of PAT compared to SAT on human islet insulin secretion, however, insulin secretion was suppressed after PAT exposure from men compared to women. Vasodilation was significantly dampened by PAT conditioned media, an effect explained almost completely by PAT from men and not women. Islets treated with PAT showed selective changes in lipid metabolism pathways while SAT altered cellular signaling and growth. RNAseq analysis showed changes in islet gene transcription impacted by PAT compared to SAT, with the biggest changes found between PAT based on sex.

The PAT secretome is metabolically negative compared to SAT, and impacts islet insulin secretion, blood flow, and gene transcription in a sex dependent manner.

Inhibition of the ceramide synthetic pathway with myriocin or an antisense oligonucleotide (ASO) targeting dihydroceramide desaturase (DES1) both improved hepatic insulin sensitivity in rats fed either a saturated or unsaturated fat diet and was associated with reductions in both hepatic ceramide and plasma membrane (PM)-sn-1,2-diacylglycerol (DAG) content. The insulin sensitizing effects of myriocin and Des1 ASO were abrogated by acute treatment with an ASO against DGAT2, which increased hepatic PM-sn-1,2-DAG but not hepatic C16 ceramide content. Increased PM-sn-1,2-DAG content was associated with protein kinase C (PKC)ε activation, increased insulin receptor (INSR)T1150 phosphorylation leading to reduced insulin-stimulated INSRY1152/AktS473 phosphorylation, and impaired insulin-mediated suppression of endogenous glucose production. These results demonstrate that inhibition of de novo ceramide synthesis by either myriocin treatment or DES1 knockdown protects against lipid-induced hepatic insulin resistance through a C16 ceramide-independent mechanism and that they mediate their effects to protect from lipid-induced hepatic insulin resistance via the PM-sn-1,2-DAG-PKCε-INSRT1150 phosphorylation pathway.

Studying the molecular mechanisms of lipodystrophy can provide valuable insights into the pathophysiology of insulin resistance (IR), type 2 diabetes (T2D), and other clustering diseases [metabolic syndrome (MetS)] and its underlying adipocentric disease (MetS disease).

A high-confidence lipodystrophy gene panel comprising 50 genes was created, and their expressions were measured in the visceral and subcutaneous (both peripheral and abdominal) adipose depots of MetS and non-MetS individuals at a tertiary care medical facility.

Most lipodystrophy genes showed significant downregulation in MetS individuals compared to non-MetS individuals in both subcutaneous and visceral depots. In the abdominal compartment, all the genes showed relatively higher expression in visceral depot as compared to their subcutaneous counterpart, and this difference narrowed with increasing severity of MetS. Their expression level shows an inverse correlation with T2D, MetS, and HOMA-IR and with other T2D-related intermediate traits. Results also demonstrated that individualization of MetS patients could be done based on adipose tissue expression of just 12 genes.

Adipose tissue expression of lipodystrophy genes shows an association with MetS and its intermediate phenotypic traits. Mutations of these genes are known to cause congenital lipodystrophy syndromes, whereas their altered expression in adipose tissue contributes to the pathogenesis of IR, T2D, and MetS.

Malate dehydrogenase (MDH) enzymes play critical roles in cellular metabolism, facilitating the reversible conversion of malate to oxaloacetate using NAD+/NADH as a cofactor. The two human isoforms of MDH have roles in the citric acid cycle and the malate-aspartate shuttle, and thus both are key enzymes in aerobic respiration as well as regenerating the pool of NAD+ used in glycolysis. This review highlights the potential of MDH as a therapeutic drug target in various diseases, including metabolic and neurological disorders, cancer, and infectious diseases. The most promising molecules for targeting MDH have been examined in the context of human malignancies, where MDH is frequently overexpressed. Recent studies have led to the identification of several antagonists, some of which are broad MDH inhibitors while others have selectivity for either of the two human MDH isoforms. Other promising compounds have been studied in the context of parasitic MDH, as inhibiting the function of the enzyme could selectively kill the parasite. Research is ongoing with these chemical scaffolds to develop more effective small-molecule drug leads that would have great potential for clinical applications.

Pompe disease is a rare genetic disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA). This enzyme is responsible for breaking down glycogen, leading to the abnormal accumulation of glycogen, which results in progressive muscle weakness and metabolic dysregulation. In this study, we investigated the hypothesis that the small molecule inhibition of glycogen synthase I (GYS1) may reduce muscle glycogen content and improve metabolic dysregulation in a mouse model of Pompe disease. To address this hypothesis, we studied four groups of male mice: a control group of wild-type (WT) B6129SF1/J mice fed either regular chow or a GYS1 inhibitor (MZ-101) diet (WT-GYS1), and Pompe model mice B6;129-Gaatm1Rabn/J fed either regular chow (GAA-KO) or MZ-101 diet (GAA-GYS1) for 7 days. Our findings revealed that GAA-KO mice exhibited abnormal glycogen accumulation in the gastrocnemius, heart, and diaphragm. In contrast, inhibiting GYS1 reduced glycogen levels in all tissues compared with GAA-KO mice. Furthermore, GAA-KO mice displayed reduced spontaneous activity during the dark cycle compared with WT mice, whereas GYS1 inhibition counteracted this effect. Compared with GAA-KO mice, GAA-GYS1 mice exhibited improved glucose tolerance and whole body insulin sensitivity. These improvements in insulin sensitivity could be attributed to increased AMP-activated protein kinase phosphorylation in the gastrocnemius of WT-GYS1 and GAA-GYS1 mice. Additionally, the GYS1 inhibitor led to a reduction in the phosphorylation of GSS641 and the LC3 autophagy marker. Together, our results suggest that targeting GYS1 could serve as a potential strategy for treating glycogen storage disorders and metabolic dysregulation.NEW & NOTEWORTHY We investigated the effects of small molecule inhibition of glycogen synthase I (GYS1) on glucose metabolism in a mouse model of Pompe disease. GYS1 inhibition reduces abnormal glycogen accumulation and molecular biomarkers associated with Pompe disease while also improving glucose intolerance. Our results collectively demonstrate that the GYS1 inhibitor represents a novel approach to substrate reduction therapy for Pompe disease.

The review focused mainly on the pathogenesis of hepatogenous diabetes (HD) in liver cirrhosis (LC). This review reveals parallels between the mechanisms of metabolic dysfunction observed in LC and type II diabetes (T2DM), suggesting a shared pathway leading to HD. It underscores the role of insulin in HD pathogenesis, highlighting key factors such as insulin signaling, glucose metabolism, insulin resistance (IR), and the influence of adipocytes. Furthermore, the impact of adipose tissue accumulation, fatty acid metabolism, and pro-inflammatory cytokines like Tumor necrosis factor-α (TNF-α) on IR are discussed in the context of HD. Altered signaling pathways, disruptions in the endocrine system, liver inflammation, changes in muscle mass and composition, and modifications to the gut microbiota collectively contribute to the complex interplay linking cirrhosis and HD. This study highlights how important it is to identify and treat this complex condition in cirrhotic patients by thoroughly analyzing the link between cirrhosis, IR, and HD. It also emphasizes the vitality of targeted interventions. Cellular and molecular investigations into IR have revealed potential therapeutic targets for managing and preventing HD.

Metabolic diseases such as obesity and type 2 diabetes are marked by insulin resistance1,2. Cells within the arcuate nucleus of the hypothalamus (ARC), which are crucial for regulating metabolism, become insulin resistant during the progression of metabolic disease3-8, but these mechanisms are not fully understood. Here we investigated the role of a specialized chondroitin sulfate proteoglycan extracellular matrix, termed a perineuronal net, which surrounds ARC neurons. In metabolic disease, the perineuronal net of the ARC becomes augmented and remodelled, driving insulin resistance and metabolic dysfunction. Disruption of the perineuronal net in obese mice, either enzymatically or with small molecules, improves insulin access to the brain, reversing neuronal insulin resistance and enhancing metabolic health. Our findings identify ARC extracellular matrix remodelling as a fundamental mechanism driving metabolic diseases.

Suboptimal nutrition is a leading cause of cardiometabolic disease and mortality. Biological sex is a variable that influences individual responses to dietary components and may modulate the impact of diet on metabolic health and disease risk. This review describes findings of studies reporting how biological sex may associate with or affect metabolic outcomes or disease risk in response to varying dietary macronutrient content, Mediterranean diet, Western diet, and medical very low-calorie diet. Although few dietary interventions have been specifically designed to identify sex-diet interactions, future studies improving understanding how sex influences dietary responses could inform precision nutrition interventions for disease prevention and management.

The global prevalence of Metabolic Syndrome (MetS) is continuously rising and exposure to environmental toxicants such as arsenic could be contributing to this rapid surge. In this study, we have assessed the effects of prenatal arsenic exposure on insulin resistance and MetS parameters in a mouse model, and an underlying mechanism was identified. We found that prenatal arsenic exposure promotes insulin resistance and adipocyte dysfunction which leads to the early onset of MetS in male offspring. Primary adipocytes isolated from 20-week-old arsenic-exposed offspring showed hypertrophy, elevated basal lipolysis, and impaired insulin response along with enhanced expression of Tumor necrosis factor-alpha (TNF-α). TNF-α levels were consistently high at gestational day 15.5 (GD15.5) as well as primary adipocytes of 6-week-old arsenic-exposed male offspring. Along with TNF-α, downstream p-JNK1/2 levels were also increased, which led to inhibitory phosphorylation of IRS1and reduced GLUT4 translocation upon insulin stimulation in adipocytes. Insulin response and downstream signaling were restored upon TNF-α inhibition, confirming its central role. The persistent overexpression of TNF-α in adipocytes of arsenic-exposed mice resulted from diminished EZH2 occupancy and reduced H3K27me3 (gene silencing histone marks) at the TNF-α promoter. This further led to chromatin relaxation, recruitment of c-Jun and CBP/p300, formation of an enhanceosome complex, and TNF-α expression. Our findings show how prenatal arsenic exposure can epigenetically modulate TNF-α expression to promote adipocyte dysfunction and insulin resistance which contributes to the early onset of MetS in offspring.

The available evidence on the connection between excessive alcohol consumption and diabetes is controversial. Therefore, the primary objective of this investigation was to examine the connection between excessive alcohol consumption and incident diabetes in a Japanese population through the utilization of propensity score matching (PSM) analysis. Our retrospective cohort study encompassed a sample of 15,464 Japanese individuals who were initially free of diabetes between the years 2004 and 2015. The study utilized comprehensive medical records of individuals who underwent a physical examination. Employing a one:one PSM analysis, the current research included 2298 individuals with and without excessive alcohol consumption. Furthermore, a doubly robust estimation method was employed to ascertain the connection between excessive alcohol consumption and diabetes. The findings revealed that individuals with excessive alcohol consumption exhibited a 73% higher likelihood of developing diabetes (HR = 1.73, 95% CI 1.08-2.77). Furthermore, upon adjusting for variables, the PSM cohort demonstrated that individuals with excessive alcohol consumption had a 78% increased risk of developing diabetes in comparison to those with non-excessive alcohol consumption (HR = 1.78, 95% CI 1.08-2.93). Individuals with excessive alcohol consumption were found to have a 73% higher risk of developing diabetes compared to those with non-excessive alcohol consumption, even after controlling for propensity score (HR = 1.73, 95% CI 1.08-2.78). Participants in the PSM cohort with excessive alcohol consumption had a 73% higher risk of developing diabetes than those with non-excessive alcohol consumption after controlling for confounding factors. These findings underscore the importance of alcohol consumption guidelines aimed at reducing excessive drinking. Clinicians should be vigilant in screening for alcohol use in patients, particularly those at risk for diabetes, and provide appropriate counseling and resources to support alcohol reduction.

In fat and skeletal muscle cells, insulin causes plasma membrane translocation of specialized insulin-responsive vesicles, or IRVs. These vesicles consist of multiple copies of Glut4, sortilin, IRAP, and LRP1 as well as several auxiliary components. Major IRV proteins have relatively long half-life inside the cell and survive multiple rounds of translocation to and from the cell surface. Here, we summarize evidence showing how the IRVs are self-assembled from pre-synthesized Glut4, sortilin, IRAP, and LRP1 after each translocation event. Furthermore, the cytoplasmic tail of sortilin binds Akt while cytoplasmic tails of IRAP and LRP1 interact with the Akt target, TBC1D4. Recruitment of signaling proteins to the IRVs may render insulin responsiveness to this compartment and thus distinguish it from other intracellular membrane vesicles.

Spinibarbus sinensis, also known as Qingbo, is an important economic fish in China. However, the detailed mechanisms underlying its growth are still unknown. To excavate the genes and signaling pathways related to its growth, we compared the transcriptome profiles of the hepatopancreas tissues of S. sinensis, with two groups of growth rate for evaluation. An average of 66,304,909 and 68,739,585 clean reads were obtained in the fast growth (FG) and slow growth (SG) group, respectively. The differential gene expression analysis results showed that 272 differentially expressed genes (DEGs) were screened between the FG and SG groups, including 101 up-regulated genes and 171 down-regulated genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis results showed that GO terms related to metabolic process, organic substance metabolic process, and catalytic activity were enriched, pathway signals related to steroid biosynthesis and protein digestion and absorption were also detected. Meanwhile, the potential key regulatory genes sst2, fndc4, and cckra related to the growth of S. sinensis were screened. Reverse transcript fluorescence quantitative PCR (RT-qPCR) validation of 18 DEGs associated with growth differences showed that the RT-qPCR results were consistent with RNA-seq analysis, and nine genes, stk31, gpr149, angptl1, fstl1, sik1, ror2, nlrc3, pdlim2, and nav2 were significantly expressed in the FG group. bmp1, stc1, gpatch8, sstrt2, s100a1, ktf6, cckar6, sync1, bhlha15, a total of nine genes were significantly expressed in the SG group. This study provides basic information for improving the growth characteristics of S. sinensis and the functional research of candidate genes.

Gestational diabetes mellitus (GDM) has been found to be a common complication in pregnant women, known to escalate the risk of negative obstetric outcomes. In our study, we genotyped 1,566 Chinese pregnant women for two single nucleotide polymorphisms (SNPs) in the LINGO2 gene and one SNP in the GLIS3 gene, utilizing targeted next-generation sequencing. The impact of two interacting genes, and the interaction of genes with the environment─including exposure to particulate matter (PM2.5), ozone (O3), and variations in prepregnancy body mass index (BMI)─on the incidence of GDM were analyzed using logistic regression. Our findings identify the variants LINGO2 rs10968576 (P = 0.022, OR = 1.224) and rs1412239 (P = 0.018, OR = 1.231), as well as GLIS3 rs10814916 (P = 0.028, OR = 1.172), as risk mutations significantly linked to increased susceptibility to GDM. Further analysis underscores the crucial role of gene-gene and gene-environment interactions in the development of GDM among Chinese women (P < 0.05). Particularly, the individuals carrying the rs10968576 G-rs1412239 G-rs10814916 C haplotype exhibit increased susceptibility to GDM during the prepregnancy period when interacting with PM2.5, O3, and BMI (P = 8.004 × 10-7, OR = 1.206; P = 6.3264 × 10-11, OR = 1.280; P = 9.928 × 10-7, OR = 1.334, respectively). In conclusion, our research emphasizes the importance of the interaction between specific gene variations─LINGO2 and GLIS3─and environmental factors in influencing GDM risk. Notably, we found significant associations between these gene variations and GDM risk across various environmental exposure periods.

Sarcopenia, a prevalent muscle disease characterized by muscle mass and strength reduction, is associated with impaired skeletal muscle regeneration. However, the influence of the biomechanical properties of sarcopenic skeletal muscle on the efficiency of the myogenic program remains unclear. Herein, we established a mouse model of sarcopenia and observed a reduction in stiffness within the sarcopenic skeletal muscle in vivo. To investigate whether the biomechanical properties of skeletal muscle directly impact the myogenic program, we established an in vitro system to explore the intrinsic mechanism involving matrix stiffness control of myogenic differentiation. Our findings identify the microtubule motor protein, kinesin-1, as a mechano-transduction hub that senses and responds to matrix stiffness, crucial for myogenic differentiation and muscle regeneration. Specifically, kinesin-1 activity is positively regulated by stiff matrices, facilitating its role in transporting mitochondria and enhancing translocation of the glucose transporter GLUT4 to the cell surface for glucose uptake. Conversely, the softer matrices significantly suppress kinesin-1 activity, leading to the accumulation of mitochondria around nuclei and hindering glucose uptake by inhibiting GLUT4 membrane translocation, consequently impairing myogenic differentiation. The insights gained from the in-vitro system highlight the mechano-transduction significance of kinesin-1 motor proteins in myogenic differentiation. Furthermore, our study confirms that enhancing kinesin-1 activity in the sarcopenic mouse model restores satellite cell expansion, myogenic differentiation, and muscle regeneration. Taken together, our findings provide a potential target for improving muscle regeneration in sarcopenia.

Diabetes mellitus (DM) has different prevalence by region. This study aimed to identify the differences in the effects of obesity and depression on DM in South Korean adults by region.

The participants were 14,343 adults (≥30 yr) from Ulsan (regions with the lowest prevalence of DM) and Jeonbuk (regions with the highest prevalence of DM), and data were extracted from the Community Health Survey 2019. We applied a complex sampling design analysis to reflect the stratified, clustering and weights. The data were analyzed using the unweighted frequencies, weighted percentage, mean, standard error, Chi-Square test and multiple logistic regression analysis (SPSS 25.0).

Regarding the main result for Ulsan, the odds ratio of DM increased by 1.94, 2.52,1.57, and 4.87 times for obesity(25-29.9kg/m2), high obesity(≥30kg/m2), depression, and receipt of psychological counseling for depression, respectively. In Jeonbuk, the odds ratio of DM increased by 1.79, 2.84, and 3.59 times for obesity, high obesity, and unmet medical experience, respectively. On the other hand, depression-related variables were found to not influence DM.

We provided the rationale for conducting a health project that interventions for obesity and depression should be included in DM management programs differently in Ulsan and Jeonbuk regions.

Overexpression of protein tyrosine phosphatase 1B (PTP1B) disrupts signaling pathways and results in numerous human diseases. In particular, its involvement has been well documented in the pathogenesis of metabolic disorders (diabetes mellitus type I and type II, fatty liver disease, and obesity); neurodegenerative diseases (Alzheimer's disease, Parkinson's disease); major depressive disorder; calcific aortic valve disease; as well as several cancer types. Given this multitude of therapeutic applications, shortly after identification of PTP1B and its role, the pursuit to introduce safe and selective enzyme inhibitors began. Regrettably, efforts undertaken so far have proved unsuccessful, since all proposed PTP1B inhibitors failed, or are yet to complete, clinical trials. Intending to aid introduction of the new generation of PTP1B inhibitors, this work collects and organizes the current state of the art. In particular, this review intends to elucidate intricate relations between numerous diseases associated with the overexpression of PTP1B, as we believe that it is of the utmost significance to establish and follow a brand-new holistic approach in the treatment of interconnected conditions. With this in mind, this comprehensive review aims to validate the PTP1B enzyme as a promising molecular target, and to reinforce future research in this direction.

Diabetes mellitus (DM) is a prevalent chronic disease in the 21st century due to increased lifespan and unhealthy lifestyle choices. Extensive research indicates that exercise can play a significant role in regulating systemic metabolism by improving energy metabolism and mitigating various metabolic disorders, including DM. Irisin, a well-known exerkine, was initially reported to enhance energy expenditure by indicating the browning of white adipose tissue (WAT) through peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) signaling. In this review, we summarize the potential mechanisms underlying the beneficial effects of Irisin on glucose dysmetabolism, including reducing gluconeogenesis, enhancing insulin energy expenditure, and promoting glycogenesis. Additionally, we highlight Irisin's potential to improve diabetic vascular diseases by stimulating nitric oxide (NO) production, reducing oxidative and nitrosative stress, curbing inflammation, and attenuating endothelial cell aging. Furthermore, we discuss the potential of Irisin to improve diabetic cardiomyopathy by preventing cardiomyocyte loss and reducing myocardial hypertrophy and fibrosis. Given Irisin's promising functions in managing diabetic cardiomyopathy and vascular diseases, targeting Irisin for therapeutic purposes could be a fruitful avenue for future research and clinical interventions.

Several models of mice-fed high-fat diets have been used to trigger non-alcoholic steatohepatitis and some chemical substances, such as carbon tetrachloride. The present study aimed to evaluate the joint action of a high-fat diet and CCl4 in developing a short-term non-alcoholic steatohepatitis model. C57BL6/J mice were divided into two groups: standard diet-fed (SD), the high-fat diet-fed (HFD) and HFD + fructose-fed and carbon tetrachloride (HFD+CCl4). The animals fed with HFD+CCl4 presented increased lipid deposition compared with both SD and HFD mice. Plasma cholesterol was increased in animals from the HFD+CCl4 group compared with the SD and HFD groups, without significant differences between the SD and HFD groups. Plasma triglycerides showed no significant difference between the groups. The HFD+CCl4 animals had increased collagen deposition in the liver compared with both SD and HFD groups. Hydroxyproline was also increased in the HFD+CCl4 group. Liver enzymes, alanine aminotransferase and aspartate aminotransferase, were increased in the HFD+CCl4 group, compared with SD and HFD groups. Also, CCl4 was able to trigger an inflammatory process in the liver of HFD-fed animals by promoting an increase of ∼2 times in macrophage activity, ∼6 times in F4/80 gene expression, and pro-inflammatory cytokines (IL-1b and TNFa), in addition to an increase in inflammatory pathway protein phosphorylation (IKKbp). HFD e HFD+CCl4 animals increased glucose intolerance compared with SD mice, associated with reduced insulin-stimulated AKT activity in the liver. Therefore, our study has shown that short-term HFD feeding associated with fructose and CCl4 can trigger non-alcoholic steatohepatitis and cause damage to glucose metabolism.

Sterol regulatory element binding protein (SREBP) 1 is considered to be a crucial regulator for lipid synthesis in vertebrates. However, whether SREBP1 could regulate hepatic gluconeogenesis under high-fat diet (HFD) condition is still unknown, and the underlying mechanism is also unclear.

This study aimed to determine gluconeogenesis-related gene and protein expressions in response to HFD in large yellow croaker and explore the role and mechanism of SREBP1 in regulating the related transcription and signaling.

Croakers (mean weight, 15.61 ± 0.10 g) were fed with diets containing 12% crude lipid [control diet (ND)] or 18% crude lipid (HFD) for 10 weeks. The glucose tolerance, insulin tolerance, hepatic gluconeogenesis-related genes, and proteins expressions were determined. To explore the role of SREBP1 in HFD-induced gluconeogenesis, SREBP1 was inhibited by pharmacologic inhibitor (fatostatin) or genetic knockdown in croaker hepatocytes under palmitic acid (PA) condition. To explore the underlying mechanism, luciferase reporter and chromatin immunoprecipitation assays were conducted in HEK293T cells. Data were analyzed using analysis of variance or Student t test.

Compared with ND, HFD increased the mRNA expressions of gluconeogenesis genes (2.40-fold to 2.60-fold) (P < 0.05) and reduced protein kinase B (AKT) phosphorylation levels (0.28-fold to 0.34-fold) (P < 0.05) in croakers. However, inhibition of SREBP1 by fatostatin addition or SREBP1 knockdown reduced the mRNA expressions of gluconeogenesis genes (P < 0.05) and increased AKT phosphorylation levels (P < 0.05) in hepatocytes, compared with that by PA treatment. Moreover, fatostatin addition or SREBP1 knockdown also increased the mRNA expressions of irs1 (P < 0.05) and reduced serine phosphorylation of IRS1 (P < 0.05). Furthermore, SREBP1 inhibited IRS1 transcriptions by binding to its promoter and induced IRS1 serine phosphorylation by activating diacylglycerol-protein kinase Cε signaling.

This study reveals the role of SREBP1 in hepatic gluconeogenesis under HFD condition in croakers, which may provide a potential strategy for improving HFD-induced glucose intolerance.

Obesity triggers inflammatory responses in the microenvironment of white adipose tissue, resulting in chronic systemic inflammation and the subsequent development of non-communicable diseases, including type 2 diabetes, coronary heart disease, and breast cancer. Current therapy approaches for obesity-induced non-communicable diseases persist in prioritizing symptom remission while frequently overlooking the criticality of targeting and alleviating inflammation at its source. Accordingly, this review highlights the importance of the microenvironment of obese white adipose tissue and the promising potential of employing immunotherapy to target it as an effective therapeutic approach for non-communicable diseases induced by obesity. Additionally, this review discusses the challenges and offers perspective about the immunotherapy targeting the microenvironment of obese white adipose tissue.