Diabetic cardiomyopathy (DCM) is a common complication of type 2 diabetes mellitus (T2DM). The effects of methylophiopogonanone A (MO-A), a natural homoisoflavonoid with anti-inflammatory effects, on DCM and its underlying mechanisms were investigated in this study.

The T2DM mouse model was induced by intraperitoneal injection of 30 mg/kg streptozotocin for 7 consecutive days and fed with a high-fat diet for 12 weeks. T2DM mice received MO-A (2.5, 5, or 10 mg/kg) treatment for two weeks. Cardiac function, hypertrophy, fibrosis, and inflammation were evaluated. The binding energy between MO-A and JNK1 was analyzed using molecular docking. The underlying mechanism was further investigated in high glucose (HG)-induced H9C2 cells. The cytotoxic effects, cardiomyocyte hypertrophy, fibrosis, inflammation, and relevant signaling proteins were assessed.

MO-A treatment alleviated cardiac function and histopathological changes in DCM mice. Moreover, MO-A treatment significantly decreased COLI, TGF-β1, MYH7, and ANP expression levels in DCM mice. Furthermore, TNF-α, IL-6, and IL-1β expression levels were notably downregulated after treatment with MO-A in DCM mice. Similar results were also observed in vitro. Mechanistically, MO-A targets JNK1 and downregulates its phosphorylation levels in DCM mice. The protective properties of MO-A were reversed by JNK1 overexpression in HG-induced H9C2 cells.

Our results revealed that MO-A could alleviate cardiac function, hypertrophy, fibrosis, and inflammation in DCM via inhibiting JNK1 signaling.

Chronic inflammation in type 2 diabetes (T2D), characterized by constitutively activated immune cells and elevated pro-inflammatory mediators along with hyperglycaemia and increased free fatty acids and branched chain amino acid levels, significantly alters the immuno-metabolic axis. Over the years, dietary intervention has been explored as an effective strategy for managing T2D. Evidence from experimental and clinical studies indicates that various diets, including Mediterranean, Nordic, Palaeolithic and ketogenic diets, increase insulin sensitivity, decrease gluconeogenesis, and adiposity, and exert anti-inflammatory effects, thus preserving immuno-metabolic homeostasis in individuals with T2D. Indian dietary sources are categorized as Sattvic, Rajasic, and Tamasic, depending on their impact on health and behaviour. The Yogic diet, commonly recommended during yoga practice, is predominantly Sattvic, emphasizing plant-based whole foods while limiting processed and high-glycaemic-index items. Yogic diet is also recommended for Mitahara, emphasizing mindful eating, which is attributed to calorie restriction. Adopting a Yogic diet, featuring low-fat vegetarian principles, strongly reduces inflammatory mediator levels. This diet not only ameliorates insulin resistance and maintains a healthy body weight but also regulates immunomodulation, enhances gut microbiome diversity and provides essential phytonutrients, collectively preventing inflammation. Although, preliminary studies show aforementioned beneficial role of Yogic diet in improving diabetes associated metabolic and inflammatory changes, precise cellular and molecular mechanisms are not yet understood. Hence, further studies are warranted to decipher the mechanisms. This review summarizes the multiple roles of Yogic diet and related dietary components in mitigating inflammation and enhancing glycaemic control in T2D.

Atherosclerosis is a closely related complication of diabetes mellitus (DM), driven by endothelial dysfunction, inflammation, and oxidative stress. The progression of atherosclerosis is accelerated by hyperglycemia, insulin resistance, and hyperlipidemia. Novel antidiabetic agents, SGLT2 inhibitors, and GLP-1 agonists improve glycemic control and offer cardiovascular protection, reducing the risk of major adverse cardiovascular events (MACEs) and heart failure hospitalization. These agents, along with nonsteroidal mineralocorticoid receptor antagonists (nsMRAs), promise to mitigate metabolic disorders and their impact on endothelial function, oxidative stress, and inflammation. This review explores the potential molecular mechanisms through which these drugs may prevent the development of atherosclerosis and cardiovascular disease (CVD), supported by a summary of preclinical and clinical evidence.

Obesity is a pervasive global health challenge that substantially reduces the quality of life of millions of individuals and impedes social and economic advancement. Obesity is an independent risk factor that contributes to a range of chronic non-communicable metabolic diseases, significantly affecting energy metabolism, mental health, cancer susceptibility, sleep quality, and other physiological processes. The PI3K/AKT signaling pathway, a significant glucose, lipid, and protein metabolism regulator, is integral to cellular growth, survival, and apoptosis. Apoptosis is a highly regulated form of programmed cell death that is critical for immune cell maturation and tissue repair. The present review examines the association between obesity, the PI3K/AKT pathway, and mitochondrial apoptosis to elucidate the potential mechanisms by which obesity may activate apoptotic pathways. These findings provide a theoretical foundation for mitigating obesity-related complications by targeting these critical pathways.

This study was carried out to systematically review and evaluate the influence of exercise with and without curcumin on body fat composition, glucose, and lipid metabolism in obese adults. Search for eligible studies through four databases, and then proceed with screening. The inclusion criteria are as follows: (1) obese adults; (2) randomized controlled trial (RCT); (3) classified the exercise intervention with curcumin supplementation as the exercise with curcumin (CU) group and without curcumin supplementation as the exercise without curcumin (EX) group; (4) Conducted pre- and post-training assessments, which include body fat composition, glucose and lipid metabolism parameters. Use the Cochrane bias risk assessment tool to evaluate the quality of the selected study. Select standardized mean difference (SMD) as the appropriate effect scale index, and use Revman 5.4 software to analyze the mean difference of the selected article data with a 95% confidence interval (CI). A total of seven studies fulfilled the inclusion criteria and were selected for the meta-analysis. The included studies involved 72 males and 111 females, where 94 belonged to the EX group and 89 from the CU group. The CU group benefited more from the reduced Fat% (SMD, 2.18 [0.12, 4.24], p < 0.05, I2 = 0%, p for heterogeneity = 0.98) than the EX group. The study demonstrated that the combined exercise intervention with curcumin supplementation significantly reduced Fat% in obese adults compared with exercise without supplementing curcumin.

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as nonalcoholic fatty liver disease) is a chronic liver disease affecting over a billion individuals worldwide. MASLD can gradually develop into more severe liver pathologies, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and liver malignancy. Notably, although being a global health problem, there are very limited therapeutic options against MASLD and its related diseases. While a thyroid hormone receptor agonist (resmetirom) is recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in MASLD and MASH incidence, it is urgent to develop novel and effective therapeutic strategies against these prevalent liver diseases. In this article, the pathogenic mechanisms of MASLD and MASH, including insulin resistance, dysregulated nuclear receptor signaling, and genetic risk factors (eg, patatin-like phospholipase domain-containing 3 and hydroxysteroid 17-β dehydrogenase-13), are introduced. Various therapeutic interventions against MASH are then explored, including approved medication (resmetirom), drugs that are currently in clinical trials (eg, glucagon-like peptide 1 receptor agonist, fibroblast growth factor 21 analog, and PPAR agonist), and those failed in previous trials (eg, obeticholic acid and stearoyl-CoA desaturase 1 antagonist). Moreover, given that the role of gut microbes in MASLD is increasingly acknowledged, alterations in the gut microbiota and microbial mechanisms in MASLD development are elucidated. Therapeutic approaches that target the gut microbiota (eg, dietary intervention and probiotics) against MASLD and related diseases are further explored. With better understanding of the multifaceted pathogenic mechanisms, the development of innovative therapeutics that target the root causes of MASLD and MASH is greatly facilitated. The possibility of alleviating MASH and achieving better patient outcomes is within reach. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, and it can progress to more severe pathologies, including steatohepatitis, cirrhosis, and liver cancer. Better understanding of the pathogenic mechanisms of these diseases has facilitated the development of innovative therapeutic strategies. Moreover, increasing evidence has illustrated the crucial role of gut microbiota in the pathogenesis of MASLD and related diseases. It may be clinically feasible to target gut microbes to alleviate MASLD in the future.

Chronic inflammatory diseases, e.g., obesity, cardiovascular disease and type-2 diabetes, progressively suppress the anti-inflammatory heat shock response (HSR) by impairing the synthesis of key components, perpetuating inflammation. Monitoring HSR progression offers predictive value for countering chronic inflammation. This study quantified HSR in high-fat diet (HFD) and normal chow (NC) mice by measuring 70 kDa heat shock protein (HSP70) expression after heat treatment of whole blood samples. To align with human translational relevance, animals were housed within their thermoneutral zone (TNZ). Whole blood was heat-challenged weekly at 42 °C for 1-2 hours over 22 weeks, and ΔHSP70 was calculated as the difference between HSP70 expressions at 42 °C and 37 °C. Results correlated with fasting glycaemia, oral glucose tolerance test, intraperitoneal insulin tolerance test and 2-hour post-glucose load glycaemia. ΔHSP70 levels >0.2250 indicated normal fasting glycaemia, while levels <0.2125 signalled insulin resistance and type-2 diabetes onset. A logistic model (five-parameter logistic) showed progressive HSR decline, with HFD mice exhibiting earlier ΔHSP70 reduction (t1/2 = 3.14 weeks) compared with NC mice (t1/2 = 8.24 weeks), highlighting compromised anti-inflammatory capacity in both groups of mice maintained at TNZ. Remarkably, even NC mice surpassed insulin resistance thresholds by week 22, relevant as control diets confronted interventions. Observed HSR decline mirrors tissue-level suppression in obese and type-2 diabetic individuals, underscoring HSR failure as a hallmark of obesity-driven inflammation. This study introduces a practical whole-blood assay to evaluate HSR suppression, allowing assessment of glycaemic status during obesity onset before any clinical manifestation.

Diabetes mellitus is associated with morphological and functional impairment of the heart primarily due to lipid toxicity caused by increased fatty acid metabolism. Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) have been implicated in the metabolism of fatty acids in the liver and skeletal muscles. However, their role in the heart in diabetes remains unclear. In this study, we tested our hypothesis that pharmacological inhibition of ERK1/2 alleviates cardiac remodeling in diabetic mice through a reduction in fatty acid metabolism.

ERK1/2 phosphorylation in diabetes was determined both in vitro and in vivo. H9C2 cells were subjected to high glucose, high palmitic acid, or both high glucose and palmitic acid. db/db and streptozotocin (STZ)-induced diabetic mice were analyzed for ERK1/2 phosphorylation levels as well as the effects of U0126 treatment on cardiac remodeling. Administration of STZ and U0126 in mice was performed via intraperitoneal injection. Blood glucose levels in mice were measured using a glucometer. Mouse heart total RNAs were purified for reverse transcription. Real-time polymerase chain reaction (PCR) analysis of the messenger ribonucleic acid (mRNA) expression was performed for hypertrophy (ANF, BNP, and βMHC), fibrosis (Col3α1), and fatty acid metabolism genes (PPARα, CPT1A, and FACS). Interstitial fibrosis of the myocardium was analyzed using Masson's trichrome staining of the paraffin-embedded tissues.

ERK1/2 phosphorylation was significantly increased in diabetic conditions. Inhibition of ERK1/2 by U0126 in both streptozotocin-induced diabetic mice and db/db mice resulted in a significant reduction in the expression of genes associated with hypertrophy and fibrosis. In contrast, elevated phosphorylation of ERK1/2 in Dusp6/8 knockout (DKO) mice resulted in fibrosis. Mechanistically, ERK1/2 activation enhanced the expression of fatty acid metabolism genes PPARα, CPT1A, and FACS in the heart, which was reversed by U0126 treatment.

ERK1/2 are potential therapeutic targets for diabetic cardiomyopathy by modulating fatty acid metabolism in the heart.

In addition to conventional treatments, there is growing interest in preventive and complementary therapies. Proper nutrition can prevent the manifestation of several chronic diseases such as obesity, diabetes, cardiovascular disease, and cancer, and can attenuate the severity of these diseases. Edible mushrooms have been used as nutrition and medicine for thousands of years. The spectrum and quantity of their medicinal compounds made them a widely investigated target both in basic research and clinical trials. The most abundant and medically important components are polysaccharides, terpenoids, phenols, and heterocyclic amines, but bioactive proteins, vitamins, including vitamin D, polyunsaturated fatty acids, and essential minerals are also important ingredients with noteworthy health benefits. Mushroom extracts have anti-diabetic, anti-hyperlipidemic, anti-inflammatory, antioxidant, cardioprotective, anti-osteoporotic, and anti-tumor effects and are well tolerated, even by cancer patients. In our previous review we detailed the molecular aspects of the development of type 2 diabetes, discussing the role of physical activity and diet, but we did not detail the role of medicinal mushrooms as part of nutrition. In this review, we aimed to summarize the most important medical mushrooms, along with their natural habitats, growing conditions, and components, that are presumably sufficient for the prevention and treatment of insulin resistance.

Background/Objectives: Influenza is a major global health challenge, causing thousands of deaths annually. Antiviral drugs, particularly oseltamivir, a neuraminidase inhibitor, have become essential therapeutic options due to their oral bioavailability and efficacy. Previous studies suggest a potential association between oseltamivir use and the onset of diabetes mellitus. However, further investigation is needed to establish a definitive link. Methods: This retrospective cohort study utilized data from the Taiwan National Health Insurance Research Database (NHIRD), including 1,631,968 patients (815,984 oseltamivir users) between 1 January 2009 and 28 December 2018. All statistical analyses were performed using SAS 9.4M8 software (SAS Institute Inc., Cary, NC, USA). Results: Cox proportional hazards regression and multivariate analyses revealed a statistically significant association between oseltamivir use and overall diabetes risk (HR = 1.027, p = 0.0186). While no significant association was observed for Type 1 diabetes (HR = 1.021; p = 0.06795), oseltamivir users showed a higher incidence of Type 2 diabetes (HR = 1.024; p < 0.05). Oseltamivir was also linked to increased risks of comorbidities, including dyslipidemia (HR = 1.295, p < 0.0001), chronic liver disease (HR = 1.446, p < 0.0001), hypertension (HR = 1.586, p < 0.0001), and obesity (HR = 2.949, p < 0.0001). Conclusions: Oseltamivir is associated with an increased risk of Type 2 diabetes but not Type 1, and related comorbidities.

Important health disparities are observed in the prevalence of obesity and associated non-communicable diseases (NCDs), including type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) among ethnic groups. Yet, the underlying factors accounting for these disparities remain poorly understood. Fructose has been widely proposed as a potential mediator of these NCDs, given that hepatic fructose catabolism can result in deleterious metabolic effects, including insulin resistance and hepatic steatosis. Moreover, the fermentation of fructose by the gut microbiota can produce metabolites such as ethanol and acetate, both which serve as potential substrates for de novo lipogenesis (DNL) and could therefore contribute to the development of these metabolic conditions. Significant inter-ethnic differences in gut microbiota composition have been observed. Moreover, fructose consumption varies across ethnic groups, and fructose intake has been demonstrated to significantly alter gut microbiota composition, which can influence its fermenting properties and metabolic effects. Therefore, ethnic differences in gut microbiota composition, which may be influenced by variations in fructose consumption, could contribute to the observed health disparities. This review provides an overview of the complex interactions between host and microbial fructose catabolism, the role of ethnicity in shaping these metabolic processes and their impact on host health. Understanding these interactions could provide insights into the mechanisms driving ethnic health disparities to improve personalized nutrition strategies. KEY POINTS: Dietary fructose consumption has increased substantially over recent decades, which has been associated with the rising prevalence of obesity and non-communicable diseases (NCDs) such as type 2 diabetes and metabolic dysfunction-associated steatotic liver disease. Pronounced disparities among different ethnic groups in NCD prevalence and dietary fructose consumption underscore the need to elucidate the underlying mechanisms of fructose catabolism and its health effects. Together with the well-known toxic effects of hepatic fructose catabolism, emerging evidence highlights a role for the small intestinal microbiota in fermenting sugars like fructose into various bacterial products with potential deleterious metabolic effects. There are significant ethnic differences in gut microbiota composition that, combined with varying fructose consumption, could mediate the observed health disparities. To comprehensively understand the role of the gut microbiota in mediating fructose-induced adverse metabolic effects, future research should focus on the small intestinal microbiota. Future research on fructose - microbiota - host interactions should account for ethnic differences in dietary habits and microbial composition to elucidate the potential role of the gut microbiota in driving the mentioned health disparities.

Insulin resistance (IR) and metabolic syndrome (MetS) are significant global health challenges that increase the risk of various chronic diseases. The lymphocyte-to-high-density lipoprotein cholesterol ratio (LHR) has emerged as a novel inflammatory metabolic marker. The present study focused on evaluating the association between the LHR and both IR and MetS.

We analyzed data from 14,779 adults aged ≥ 20 years from the National Health and Nutrition Examination Survey (2007-2018). To investigate the relationship between LHR and both IR and MetS, we conducted multivariable logistic regression analyses. The reliability of the results was validated through both stratified and sensitivity analyses. Furthermore, we thoroughly examined possible nonlinear associations by implementing a restricted cubic spline in conjunction with a threshold effect analysis.

Compared to the lowest LHR quartile, individuals in the highest quartile indicated significantly increased prevalence of IR (odds ratio = 3.72, 95% confidence intervals: 3.01-4.59) and MetS (odds ratio = 11.38, 95% confidence intervals: 8.85-14.63) in fully adjusted models. Subgroup analyses demonstrated that the association between the LHR and IR remained consistent across all subgroups, with no significant interaction effect observed. However, the association between LHR and MetS was more pronounced in female participants. Restricted cubic spline analyses revealed nonlinear associations between LHR and both IR and MetS. The threshold effect analyses identified inflection points at 0.055 for these non-linear relationships.

An elevated LHR was positively associated with the prevalence of IR and MetS, indicating its promising role in early screening and disease prevention through biological monitoring.

As the main type of pancreatic diabetes, patients with new diabetes after chronic pancreatitis are often difficult to manage and have poor prognosis. This study aimed to figure out the association between dietary mineral intake and glucose metabolism with chronic pancreatitis.

The study included 114 patients with chronic pancreatitis, who were grouped based on the sequence of onset for chronic pancreatitis and diabetes: normoglycaemia after chronic pancreatitis (NCP), type 2 diabetes (T2DM), and new-onset diabetes or pre-diabetes after chronic pancreatitis (NODCP). The habitual intake of 10 minerals (calcium, chlorine, iodine, iron, magnesium, phosphorus, potassium, selenium, sodium, and zinc) was assessed using a dietary health questionnaire. The differences in mineral intake between the groups were compared, and the relationship between mineral intake and key glucose metabolism markers, including fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), and fasting insulin, was analyzed using regression models.

Compared with normal glycaemic status after chronic pancreatitis, the intake of iron and phosphorus in patients with new diabetes/pre-diabetes after chronic pancreatitis (NODCP) has changed significantly. In the NODCP group, FPG levels were significantly negatively correlated with magnesium intake, while HbA1c levels were significantly negatively correlated with average phosphorus intake. In addition, there is a correlation between fasting insulin and average magnesium intake in the NODCP group. No correlation was found between the intake of other minerals and glucose metabolism in chronic pancreatitis.

The intake of minerals in the diet affects the glycaemic status after chronic pancreatitis. It is necessary to further explore the possible causal relationship and mechanism between mineral intake and diabetes after chronic pancreatitis, so as to provide evidence for nutritional intervention of high-risk patients.

Type 2 diabetes (T2D) is a disease that occurs when cells do not respond normally to insulin, a condition called insulin resistance, which leads to high blood glucose levels. Although it can be treated pharmacologically, dietary habits beyond carbohydrate restriction can be highly relevant in the management of T2D. Emerging evidence supports the possibility that natural products (NPs) could contribute to managing blood glucose or counteract the undesirable effects of hyperglycemia and insulin resistance. This chapter summarizes the relevant preclinical evidence involving the flavonoid (-)-epicatechin (EC) in the optimization of glucose homeostasis, reducing insulin resistance and/or diabetes-associated disorders. Major effects of EC are observed on (i) intestinal functions, including digestive enzymes, glucose transporters, microbiota, and intestinal permeability, and (ii) redox homeostasis, including oxidative stress and inflammation. There is still a need for further clinical studies to confirm the in vitro and rodent data, allowing recommendations for EC, particularly in prediabetic and T2D patients. The collection of similar data and the lack of clinical evidence for EC is also applicable to other NPs.

Heart failure with preserved ejection fraction (HFpEF) is a complex condition characterized by metabolic dysfunction and myocardial lipotoxicity. The roles of PTEN-induced kinase 1 (PINK1) and peroxiredoxin-2 (Prdx2) in HFpEF pathogenesis remain unclear.

This study aimed to investigate the interaction between PINK1 and Prdx2 to mitigate cardiac diastolic dysfunction in HFpEF.

In vivo, PINK1-knockout mice and cardiac-specific PINK1-overexpressing transgenic mice were used to establish an HFpEF mouse model via a high-fat diet and L-NAME. Myocardial lipotoxicity was induced by palmitic acid in vitro. Immunoprecipitation, western blotting and immunofluorescence analysis were performed to elucidate the molecular mechanisms involved.

We determined that PINK1 and Prdx2 were downregulated in the HFpEF mouse model. In vivo, PINK1 ablation exacerbated the reduction in Prdx2 expression, worsening cardiac dysfunction in HFpEF mice. Conversely, PINK1 overexpression restored Prdx2 levels and decreased reactive oxygen species and apoptosis, thereby reducing fibrosis and inflammation and ameliorating cardiac diastolic dysfunction in HFpEF mice. In vitro, an interaction between the N-terminal region (amino acids 1-133) of PINK1 and Prdx2 was identified. The overexpression of PINK1 induced Prdx2 expression and effectively attenuated palmitic acid-induced apoptosis through the c-Jun amino-terminal kinase (JNK) and mitogen-activated protein kinase (p38) pathways, whereas siRNA-mediated Prdx2 knockdown abolished the protective effect of PINK1.

PINK1 alleviates lipotoxicity-induced myocardial apoptosis and improves diastolic dysfunction in HFpEF through Prdx2, highlighting PINK1 overexpression as a potential therapeutic strategy for HFpEF.

Our investigation discloses a pivotal relationship between PINK1 and Prdx2 in the context of HFpEF. Notably, PINK1, in addition to its role in mitochondrial autophagy, can increase Prdx2 expression, effectively remove ROS and attenuate cardiomyocyte apoptosis by modulating the JNK and p38 pathways, thereby alleviating myocardial lipotoxicity and improving HFpEF cardiac function. Our studies offer valuable insights, opening avenues for the development of innovative therapeutic strategies in the prevention and treatment of HFpEF.

Obesity and type 2 diabetes mellitus (T2DM) are significant global health challenges, with adipose tissue inflammation being a pivotal contributor to metabolic dysfunction. The involvement of adipose tissue macrophages (ATMs) in obesity-associated inflammation is well recognized, yet the therapeutic strategies specifically targeting ATM-mediated inflammation remain limited.

This study aims to explore the effects of tirzepatide, a novel dual GLP-1 and GIP receptor agonist, on ATMs, adipose tissue inflammation, and insulin resistance in the context of obesity.

Obese mouse models were established through high-fat diet feeding and subsequently treated with tirzepatide at a dose of 1.2 mg/kg twice weekly for 12 weeks. The study assessed the impact on ATM phenotype, inflammatory markers, and key metabolic indicators.

Tirzepatide treatment significantly mitigated the infiltration of pro-inflammatory M1 ATMs within adipose tissue and concurrently reduced levels of inflammatory cytokines, thereby enhancing insulin sensitivity. Tirzepatide demonstrated therapeutic efficacy through its modulation of the ERK signaling pathway and promotion of M1-type macrophage apoptosis.

Tirzepatide's potential as a therapeutic strategy for addressing metabolic diseases associated with obesity and T2DM by targeting ATM activity and mitigating obesity-associated inflammation.

Background and aims: the usefulness of the weight-adjusted waist index (WWI) among persons with metabolic syndrome (MS) has not been previously evaluated. The objective of this study was to evaluate the ability of WWI to predict MS in a Caucasian population with obesity. Methods: we conducted a cross sectional study in 2162 Caucasian patients with obesity. Anthropometric data (weight, height, body mass index [BMI], waist circumference, [WWI]), bioimpedanciometer parameters (total fat mass [FM], skeletal muscle mass [SMM] and skeletal muscle mass index [SMMi]), blood pressure, presence of MS and biochemical parameters were recorded and compared by tertiles of WWI. Results: a total of 1,176 subjects had MS (54.4 %) and 986 did not show MS (45.6 %). Compared with the lowest WWI category Q1 (< 11.24 cm/√kg), the prevalence of MS increased in the logistic regression model adjusted by sex and age in the Q3 group (OR = 2.53, 95 % CI = 1.71-3.23; p = 0.001). In addition, the prevalence of MS was higher in the Q3 group than in Q2 (OR = 1.65, 95 % CI = 1.25-2.17; p = 0.005). Finally, the prevalence of MS in Q2 was higher than in the Q1 group (OR = 1.21, 95 % CI = 1.06-3.11; p = 0.01). The area under the curve (AUC) to assess the ability of WWI to identify MS showed values of 0.811 (0.687-0.871; p = 0.001). The cut-off point according to the Youden index was 11.59, with sensitivity and specificity of 70 % and 93.4 %, respectively. Conclusion: we described a good accuracy of WWI to identify MS an independent association between WWI in Caucasian patients with obesity.

Obesity has become a global epidemic and is associated with comorbidities, including diabetes, cardiovascular, and neurodegenerative diseases, among others. While appreciable insight has been gained into the mechanisms of obesity-associated comorbidities, effects of age, and duration of obesity on the female brain remain obscure. To address this gap, adolescent and mature adult female mice were subjected to a high-fat diet (HFD) for 13 or 26 weeks, whereas age-matched controls were fed a standard diet. Subsequently, the expression of inflammatory cytokines, neurotrophic/neuroprotective factors, and markers of microgliosis and astrogliosis were analyzed in the hypothalamus, hippocampus, and cerebral cortex, along with inflammation in visceral adipose tissue. HFD led to a typical obese phenotype in all groups independent of age and duration of HFD. However, the intermediate duration of obesity induced a limited inflammatory response in adolescent females' hypothalamus while the hippocampus, cerebral cortex, and visceral adipose tissue remained unaffected. In contrast, the prolonged duration of obesity resulted in inflammation in all three brain regions and visceral adipose tissue along with upregulation of microgliosis/astrogliosis and suppression of neurotrophic/neuroprotective factors in all brain regions, denoting the duration of obesity as a critical risk factor for neurodegenerative diseases. Importantly, when female mice were older (i.e., mature adult), even the intermediate duration of obesity induced similar adverse effects in all brain regions. Taken together, our findings suggest that (1) both age and duration of obesity have a significant impact on obesity-associated comorbidities and (2) early interventions to end obesity are critical to preserving brain health.

Wingless-type inducible signaling pathway protein-1 (WISP1) is a newly recognized adipokine, associated with obesity and type 2 diabetes (T2DM). This study aimed to investigate the effect of metabolic and bariatric surgery (MBS) on WISP1 circulating (serum) levels and tissue expression using rat models. We initially investigated whether WISP1 circulating levels were altered between the T2DM and normal rats. After confirmation, Sprague-Dawley (SD) rats were obtained and randomly divided as follows: Roux-en-Y gastric bypass (RYGB) group (n = 10), sleeve gastrectomy (SG) group (n = 10), SHAM group (n = 10), and normal control (NC) group (n = 10). Rats were followed for 8 weeks postoperatively. Preoperative and postoperative WISP1 circulating (serum) levels, glucose tolerance test (OGTT), insulin tolerance test (ITT), postoperative WISP1 expression (visceral adipose tissue, VAT; and skeletal muscle, SM), body weight, food intake, and fasting blood glucose levels were recorded. MBS significantly induced glucose control and weight loss. At postoperative week 8, WISP1 serum levels decreased in the MBS groups (P < 0.05); furthermore, WISP1 expression in VAT and SM significantly decreased in the RYGB and SG groups than SHAM (P < 0.05, and P < 0.05, respectively). Whereas the difference in the expression level between SG and RYGB did not amount to statistical significance (P > 0.05). MBS significantly decreased WISP1 serum levels, tissue expression in the VAT, and SM. As WISP1 is a regulator of low-grade inflammation associated with obesity and T2DM, further studies are needed to explore its relevance in MBS.

Obesity is a major public health problem and is a major contributor to the development of insulin resistance. In previous studies we observed that single-wavelength red or infrared photobiomodulation (PBM) improved insulin signaling in adipocytes and skeletal muscle of mice fed a high-fat diet, but information about the combination of different wavelengths, as well as the effect of different light doses (J/cm2) is lacking. Therefore, the aim of this study was to investigate the effects of different doses of dual-wavelength PBM on insulin signaling in muscle cell, and explore potential mechanisms involved. Mouse myoblasts (C2C12) were differentiated into myotubes and cultured in palmitic acid, sodium oleate and l-carnitine (PAL) to induce insulin resistance high or in glucose medium (CTRL). Then, they received SHAM treatment (lights off, 0 J/cm2) or PBM (660 + 850 nm; 2, 4 or 8 J/cm2). PAL induced insulin resistance (assessed by Akt phosphorylation at ser473), attenuated maximal citrate synthase activity, and increased the phosphorylation of c-Jun NH(2) terminal kinase (JNK) (T183/Y185). PBM at doses of 4 or 8 J/cm2 reversed these PAL-induced responses. Furthermore, at doses of 2, 4 or 8 J/cm2, PBM reversed the increase in mitofusin-2 content induced by PAL. In conclusion, the combination of dual-wavelength red and infrared PBM at doses of 4 and 8 J/cm2 improved intracellular insulin signaling in musculoskeletal cells, and this effect appears to involve the modulation of mitochondrial function and the attenuation of the activation of stress kinases.

Among members of the mitogen-activated protein kinase (MAPK) family, c-Jun N-terminal kinases (JNKs) are vital for cellular responses to stress, inflammation, and apoptosis. Recent advances have highlighted their important implications in cancer biology, where dysregulated JNK signalling plays a role in the growth, progression, and metastasis of tumors. The present understanding of JNK kinase and its function in the etiology of cancer is summarized in this review. By modifying a number of downstream targets, such as transcription factors, apoptotic regulators, and cell cycle proteins, JNKs exert diverse effects on cancer cells. Apoptosis avoidance, cell survival, and proliferation are all promoted by abnormal JNK activation in many types of cancer, which leads to tumor growth and resistance to treatment. JNKs also affect the tumour microenvironment by controlling the generation of inflammatory cytokines, angiogenesis, and immune cell activity. However, challenges remain in deciphering the context-specific roles of JNK isoforms and their intricate crosstalk with other signalling pathways within the complex tumor environment. Further research is warranted to delineate the precise mechanisms underlying JNK-mediated tumorigenesis and to develop tailored therapeutic strategies targeting JNK signalling to improve cancer management. The review emphasizes the role of JNK kinases in cancer biology, as well as their potential as pharmaceutical targets for precision oncology therapy and cancer resistance. Also, this review summarizes all the available promising JNK inhibitors that are suggested to promote the responsiveness of cancer cells to cancer treatment.

Obesity is associated with a low-grade chronic inflammatory process characterized by higher circulating TNFα levels, thus contributing to insulin resistance. This study evaluated the effect of silybin, the main bioactive component of silymarin, which has anti-inflammatory properties, on TNFα levels and its impact on glucose uptake in the adipocyte cell line 3T3-L1 challenged with two different inflammatory stimuli, TNFα or lipopolysaccharide (LPS). Silybin's pre-treatment effect was evaluated in adipocytes pre-incubated with silybin (30 or 80 µM) before challenging with the inflammatory stimuli (TNFα or LPS). For the post-treatment effect, the adipocytes were first challenged with the inflammatory stimuli and then post-treated with silybin. After treatments, TNFα production, glucose uptake, and GLUT4 protein expression were determined. Both inflammatory stimuli increased TNFα secretion, diminished GLUT4 expression, and significantly decreased glucose uptake. Silybin 30 µM only reduced TNFα secretion after the LPS challenge. Silybin 80 µM as post-treatment or pre-treatment decreased TNFα levels, improving glucose uptake. However, glucose uptake enhancement induced by silybin did not depend on GLUT4 protein expression. These results show that silybin importantly reduced TNFα levels and upregulates glucose uptake, independently of GLUT4 protein expression.

Obesity is a chronic inflammatory disorder, which promotes the progression of metabolic disorders. MicroRNA (miR)-6838-5p is dysregulated and participates in the progression of several disorder models.

To explore the role and mechanism of miR-6838-5p in insulin resistance.

Mice were fed with high-fat diet (HFD) to construct an obesity animal model. The role of miR-6838-5p was evaluated by insulin tolerance test (ITT), glucose tolerance test (GTT), homeostasis model assessment of insulin resistance (HOMA-IR) analysis, enzyme-linked immunosorbent assay (ELISA) and western blot assays. The potential target of miR-6838-5p was screened through the starBase online website and confirmed by the luciferase assay.

HFD supply induced a prominent increase in the body weight, white adipose tissue (WAT) weight, the area under the curve (AUC) of GTT and ITT, HOMA-IR, the serum level of insulin and the serum concentrations and relative protein levels of interleukin (IL)-1β, IL-6 and monocyte chemoattractant protein-1 (MCP-1) accompanied with reduced levels of IL-10 in mice. The level of miR-6838-5p was reduced in HFD-fed mice. Upregulation of miR-6838-5p partly reversed the above-mentioned indicators. Moreover, miR-6838-5p directly targeted to β-site amyloid precursor protein cleaving enzyme1 (BACE1) and negatively regulated the BACE1 expression. Downregulation of BACE1 improved insulin sensitivity and inflammatory mediators release involving in AKT/GSK3β signaling pathway in HFD-fed mice. Besides, overexpression of BACE1 counteracted the depressant role of miR-6838-5p overexpression in insulin resistance and inflammatory factors release in HFD-fed mice.

MiR-6838-5p/BACE1 axis regulated insulin resistance and inflammatory factors release in HFD-fed mice.

Altered hepatic glucose fluxes are critical during the pathogenesis of type 2 diabetes. G protein-coupled receptors represent important regulators of hepatic glucose production. Recent studies have shown that hepatocytes express GPCRs that can couple to G12/13, a subfamily of heterotrimeric G proteins that has attracted relatively little attention in the past. Here we show, by analyzing several mutant mouse strains, that selective activation of hepatocyte G12/13 signaling leads to pronounced hyperglycemia and that this effect involves the stimulation of the ROCK1-JNK signaling cascade. Using both mouse and human hepatocytes, we also show that activation of endogenous sphingosine-1-phosphate type 1 receptors strongly promotes glucose release in a G12/13-dependent fashion. Studies with human liver samples indicate that hepatic GNA12 (encoding Gα12) expression levels positively correlate with indices of insulin resistance and impaired glucose homeostasis, consistent with a potential pathophysiological role of enhanced hepatic G12/13 signaling.

Expansion of white adipose tissue causes systemic inflammation and increased risk of metabolic diseases due to its endocrine function. Resveratrol was suggested to be able to prevent obesity-related disorders by mimicking caloric restriction; however, its structure-activity relationships and molecular targets are still unknown. We aimed to compare the effects of resveratrol and its analogues on adipocyte metabolism and lipid accumulation in vitro.

Mouse embryonic fibroblasts were differentiated to adipocytes in the absence or presence of resveratrol or its derivatives (oxyresveratrol, monomethylated resveratrol, or trimethylated resveratrol). Intracellular lipid content was assessed by Oil Red O staining. Glucose uptake and its response to insulin were estimated by 2-NBDG, and mitochondrial activity was assayed via resazurin reduction. Involvement of potential molecular pathways was investigated by concurrent treatment with their inhibitors.

Although lipid accumulation was significantly reduced by all analogues without altering protein content, oxyresveratrol was the most potent (IC50 = 4.2 μM), while the lowest potency was observed with trimethylated resveratrol (IC50 = 27.4 μM). Increased insulin-stimulated glucose uptake was restored by each analogue with comparable efficiency. The enhanced mitochondrial activity was normalized by resveratrol and its methylated derivatives, while oxyresveratrol had a minor impact on it. Among the examined pathways, inhibition of SIRT1, PGC-1α, and JNK diminished the lipid-reducing effect of the compounds. Autophagy appeared to play a key role in the effect of all compounds but oxyresveratrol.

Resveratrol and its analogues can mimic caloric restriction with complex mechanisms, including activation of SIRT1, PGC-1α, and JNK, making them possible drug candidates to treat obesity-related diseases.

Radix scutellariae (the root of Scutellaria baicalensis Georgi) is a traditional Chinese medicine (TCM) used to treat a wide range of inflammation-related diseases, such as obesity, diabetes, diabetic kidney disease, and COVID-19-associated inflammatory states in the lung and kidney. Baicalin is the major anti-inflammatory component of Radix scutellariae and has shown the potential to inhibit inflammation in metabolic disorders. In this study, we explored the ability and underlying mechanisms of baicalin to modulate the macrophage to mitigate insulin resistance in obesity.

Obese mice were administered baicalin (50 mg/kg/day) intraperitoneally for 3 weeks. RAW264.7 and BMDM cells were stimulated with LPS and treated with baicalin for 24 h, while 3T3-L1 and primary white adipocytes were treated with the supernatants from baicalin-treated RAW264.7 cells for 24 h.

The results showed that baicalin significantly improved glucose and insulin tolerance as well as decreased fat and adipose tissue macrophage levels in obese mice. Besides, baicalin significantly reduced serum and adipose tissue IL-1β, TNF-α and IL-6 levels in obese mice, as well as suppressed LPS-induced IL-1β, TNF-α and IL-6 expression and release in macrophages. Furthermore, treatment with the supernatant from baicalin-treated RAW264.7 cells increased the levels of PGC-1α, SIRT1, p-IRS-1 and p-AKT in adipocytes. Moreover, baicalin treatment dramatically downregulated macrophage p-p38, p-JNK, and Ac-p65Lys310 levels while increasing SIRT1 both in vivo and in vitro. Importantly, JNK inhibitor SP600125 blocked most of the effects of baicalin on SIRT1, Ac-p65Lys310 and pro-inflammatory factors in macrophages.

Therefore, these results demonstrated for the first time that baicalin exerts its anti-inflammatory effects in obese adipose tissue macrophages mainly through suppressing JNK/SIRT1/p65 signaling. These findings amplified the mechanisms of baicalin and its potential to attenuate insulin resistance.

The ancient Ginkgo biloba tree grows across various regions, with distinctive leaves emitting a unique fragrance. Its extract contains flavonoids, organic acids, and terpenoids. Ginkgolide and bilobalide, which are G. biloba leaf extracts, offer diverse pharmaceutical benefits, including antioxidant, anti-inflammatory, and neuroprotective properties. The antioxidant and anti-inflammatory properties of these compounds are crucial for mitigating neurodegeneration, particularly in diseases such as Alzheimer's disease. Additionally, their effectiveness in countering oxidative stress and inflammation highlights their potential to prevent cardiovascular ailments. This study also suggests that these compounds have a promising impact on lipid metabolism, suggesting their significance in addressing obesity-related metabolic disorders. In conclusion, ginkgolides and bilobalide exhibit promising effects in sustaining the integrity of the nervous and endocrine systems, along with the modulation of lipid metabolism. The diverse health benefits suggest that these compounds could serve as promising therapeutic interventions for various conditions, including neurological, cardiovascular, and metabolic diseases.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder associated with insulin resistance (IR) and hyperandrogenaemia (HA). Metabolic inflammation (MI), characterized by a chronic low-grade inflammatory state, is intimately linked with chronic metabolic diseases such as IR and diabetes and is also considered an essential factor in the development of PCOS. Insulin-like growth factor 1 (IGF-1) plays an essential role in PCOS pathogenesis through its multiple functions in regulating cell proliferation metabolic processes and reducing inflammatory responses. This review summarizes the molecular mechanisms by which IGF-1, via MI, participates in the onset and progression of PCOS, aiming to provide insights for studies and clinical treatment of PCOS.

Extracellular signal-regulated kinase (ERK) signaling is essential to regulated cell behaviors, including cell proliferation, differentiation, and apoptosis. The influence of cell-cell contacts on ERK signaling is central to epithelial cells, yet few studies have sought to understand the same in cancer cells, particularly with single-cell resolution. To acquire same-cell measurements of both phenotypic (cell-contact state) and targeted-protein (ERK phosphorylation) profiles, we prepend high-content, whole-cell imaging prior to end-point cellular-resolution Western blot analyses for each of hundreds of individual HeLa cancer cells cultured on that same chip, which we call contactBlot. By indexing the phosphorylation level of ERK in each cell or cell cluster to the imaged cell-contact state, we compare the ERK signaling between isolated and in-contact cells. We observe attenuated (∼2×) ERK signaling in HeLa cells that are in-contact versus isolated. Attenuation is sustained when the HeLa cells are challenged with hyperosmotic stress. Our findings show the impact of cell-cell contacts on ERK activation with isolated and in-contact cells while introducing a multi-omics tool for control and scrutiny of cell-cell interactions.

This review presents current knowledge related to the voltage-dependent anion channel-1 (VDAC1) as a multi-functional mitochondrial protein that acts in regulating both cell life and death. The location of VDAC1 at the outer mitochondrial membrane (OMM) allows control of metabolic cross-talk between the mitochondria and the rest of the cell, and also enables its interaction with proteins that are involved in metabolic, cell death, and survival pathways. VDAC1's interactions with over 150 proteins can mediate and regulate the integration of mitochondrial functions with cellular activities. To target these protein-protein interactions, VDAC1-derived peptides have been developed. This review focuses specifically on cell-penetrating VDAC1-based peptides that were developed and used as a "decoy" to compete with VDAC1 for its VDAC1-interacting proteins. These peptides interfere with VDAC1 interactions, for example, with metabolism-associated proteins such as hexokinase (HK), or with anti-apoptotic proteins such as Bcl-2 and Bcl-xL. These and other VDAC1-interacting proteins are highly expressed in many cancers. The VDAC1-based peptides in cells in culture selectively affect cancerous, but not non-cancerous cells, inducing cell death in a variety of cancers, regardless of the cancer origin or genetics. They inhibit cell energy production, eliminate cancer stem cells, and act very rapidly and at low micro-molar concentrations. The activity of these peptides has been validated in several mouse cancer models of glioblastoma, lung, and breast cancers. Their anti-cancer activity involves a multi-pronged attack targeting the hallmarks of cancer. They were also found to be effective in treating non-alcoholic fatty liver disease and diabetes mellitus. Thus, VDAC1-based peptides, by targeting VDAC1-interacting proteins, offer an affordable and innovative new conceptual therapeutic paradigm that can potentially overcome heterogeneity, chemoresistance, and invasive metastatic formation.

Obesity has shown a global epidemic trend. The high-lipid state caused by obesity can maintain the heart in a prolonged low-grade inflammatory state and cause ventricular remodeling, leading to a series of pathologies, such as hypertrophy, fibrosis, and apoptosis, which eventually develop into obese cardiomyopathy. Therefore, prolonged low-grade inflammation plays a crucial role in the progression of obese cardiomyopathy, making inflammation regulation an essential strategy for treating this disease. Cyy-272, an indazole derivative, is an anti-inflammatory compound independently synthesized by our laboratory. Our previous studies revealed that Cyy-272 can exert anti-inflammatory effects by inhibiting the phosphorylation and activation of C-Jun N-terminal kinase (JNK), thereby alleviating lipopolysaccharide (LPS)-induced acute lung injury (ALI). The current study aimed to evaluate the potential of Cyy-272 to mitigate the occurrence and progression of obese cardiomyopathy through the inhibition of the JNK signaling pathway. Our results indicate that the compound Cyy-272 has encouraging therapeutic effects on obesity-induced cardiac injury. It significantly inhibits inflammation in cardiomyocytes and heart tissues induced by high lipid concentrations, further alleviating the resulting hypertrophy, fibrosis, and apoptosis. Mechanistically, the protective effect of Cyy-272 on obese cardiomyopathy can be attributed to its direct inhibition of JNK protein phosphorylation. In conclusion, we identified a novel compound, Cyy-272, capable of alleviating obese cardiomyopathy and confirmed that its effect is achieved through direct inhibition of JNK.

Reactive oxygen species (ROS) are well-established signaling molecules implicated in a wide range of cellular processes, including both oxidative stress and intracellular redox signaling. In the context of insulin action within its target tissues, ROS have been reported to exert both positive and negative regulatory effects. However, the precise molecular mechanisms underlying this duality remain unclear. This Review examines the complex role of ROS in insulin action, with a particular focus on skeletal muscle. We aim to address three critical aspects: (a) the proposed intracellular pro-oxidative redox shift elicited by insulin, (b) the evidence supporting that redox-sensitive cysteine modifications impact insulin signaling and action, and (c) cellular mechanisms underlying how ROS can paradoxically act as both enhancers and inhibitors of insulin action. This Review underscores the urgent need for more systematic research to identify specific reactive species, redox targets, and the physiological significance of redox signaling in maintaining insulin action and metabolic health, with a particular emphasis on human skeletal muscle.

Nutrient metabolism is regulated by several factors. Social determinants of health with or without genetics are the primary regulator of metabolism, and an unhealthy lifestyle affects all modulators and mediators, leading to the adaptation and finally to the exhaustion of cellular functions. Hepatic steatosis is defined by presence of fat in more than 5% of hepatocytes. In hepatocytes, fat is stored as triglycerides in lipid droplet. Hepatic steatosis results from a combination of multiple intracellular processes. In a healthy individual nutrient metabolism is regulated at several steps. It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component. Several hormones, peptides, and genes have been described that participate in nutrient metabolism. Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP. As of now several publications have revealed very intricate regulation of nutrient metabolism, where most of the regulatory factors are tied to each other bidirectionally, making it difficult to comprehend chronological sequence of events. Insulin hormone is the primary regulator of all nutrients' metabolism both in prandial and fasting states. Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes; metabolic, inflammation and repair, and cell growth and regeneration. Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands, adiponectin, leptin, and adiponutrin. Insulin hormone has direct effect on these final modulators. Whereas blood glucose level, serum lipids, incretin hormones, bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle. The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) that help us understand the disease natural course, risk stratification, role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine. PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states; MASLD, cardiovascular disease and cancer. More than 1000 publications including original research and review papers were reviewed.

Hepatocellular carcinoma (HCC) is an increasingly prevalent disease that is associated with high and continually rising mortality rates. Lipid metabolism holds a crucial role in the pathogenesis of HCC, in which abnormalities pertaining to the delicate balance of lipid synthesis, breakdown, and storage, predispose for the pathogenesis of the nonalcoholic fatty liver disease (NAFLD), a disease precursor to HCC. If caught early enough, HCC treatment may be curative. In later stages, treatment is only halting the inevitable outcome of death, boldly prompting for novel drug discovery to provide a fighting chance for this patient population. In this review, we begin by providing a summary of current local and systemic treatments against HCC. From such we discuss hepatic lipid metabolism and highlight novel targets that are ripe for anti-cancer drug discovery. Lastly, we provide a targeted summary of current known risk factors for HCC pathogenesis, providing key insights that will be essential for rationalizing future development of anti-HCC therapeutics.

Diets leading to caloric overload are linked to metabolic disorders and reproductive function impairment. Metabolic and hormonal abnormalities stand out as defining features of metabolic disorders, and substantially affect the functionality of the testis. Metabolic disorders induce testicular metabolic dysfunction, chronic inflammation and oxidative stress. The disruption of gastrointestinal, pancreatic, adipose tissue and testicular hormonal regulation induced by metabolic disorders can also contribute to a state of compromised fertility. In this Review, we will delve into the effects of high-fat diets and metabolic disorders on testicular metabolism and spermatogenesis, which are crucial elements for male reproductive function. Moreover, metabolic disorders have been shown to influence the epigenome of male gametes and might have a potential role in transmitting phenotype traits across generations. However, the existing evidence strongly underscores the unmet need to understand the mechanisms responsible for transgenerational paternal inheritance of male reproductive function impairment related to metabolic disorders. This knowledge could be useful for developing targeted interventions to prevent, counteract, and most of all break the perpetuation chain of male reproductive dysfunction associated with metabolic disorders across generations.

There is growing evidence suggesting a relationship between periostin levels, inflammation, and ovarian dysfunction. In this prospective case-control study, we aimed to investigate serum periostin levels and their relationship with metabolic parameters in patients with polycystic ovary syndrome.

We conducted a prospective case-control study involving 45 polycystic ovary syndrome patients and 45 control subjects, matched in a 1:1 ratio. Serum samples collected from both study and control groups were analyzed using enzyme-linked immunosorbent assay.

The demographic characteristics were similar between the polycystic ovary syndrome and control groups (p>0.05). Periostin levels were significantly higher in patients with polycystic ovary syndrome compared with the control group (4.67±2.46 vs. 2.60±1.41 ng/mL, respectively; p=0.000).

Our study revealed a significant elevation in periostin levels among polycystic ovary syndrome patients compared with controls. These findings suggest that periostin could serve as a potential marker for assessing disease severity in polycystic ovary syndrome patients.

Unhealthy lifestyles, obesity, and environmental pollutants are strongly correlated with the development of nonalcoholic fatty liver disease (NAFLD). Haloacetaldehyde-associated disinfection byproducts (HAL-DBPs) at various multiples of concentrations found in finished drinking water together with high-fat (HF) were examined to gauge their mixed effects on hepatic lipid metabolism. Using new alternative methods (NAMs), studying effects in human cells in vitro for risk assessment, we investigated the combined effects of HF and HAL-DBPs on hepatic lipid metabolism and lipotoxicity in immortalized LO-2 human hepatocytes. Coexposure of HAL-DBPs at various multiples of environmental exposure levels with HF increased the levels of triglycerides, interfered with de novo lipogenesis, enhanced fatty acid oxidation, and inhibited the secretion of very low-density lipoproteins. Lipid accumulation caused by the coexposure of HAL-DBPs and HF also resulted in more severe lipotoxicity in these cells. Our results using an in vitro NAM-based method provide novel insights into metabolic reprogramming in hepatocytes due to coexposure of HF and HAL-DBPs and strongly suggest that the risk of NAFLD in sensitive populations due to HAL-DBPs and poor lifestyle deserves further investigation both with laboratory and epidemiological tools. We also discuss how results from our studies could be used in health risk assessments for HAL-DBPs.

The rapidly evolving field of immunometabolism explores how changes in local immune environments may affect key metabolic and cellular processes, including that of adipose tissue. Importantly, these changes may contribute to low-grade systemic inflammation. In turn, chronic low-grade inflammation affecting adipose tissue may exacerbate the outcome of metabolic diseases. Novel advances in our understanding of immunometabolic processes may critically lead to interventions to reduce disease severity and progression. An important example in this regard relates to obesity, which has a multifaceted effect on immunity, activating the proinflammatory pathways such as the inflammasome and disrupting cellular homeostasis. This multifaceted effect of obesity can be investigated through study of downstream conditions using cellular and systemic investigative techniques. To further explore this field, the National Institutes of Health P30 Nutrition Obesity Research Center at Harvard, in partnership with Harvard Medical School, assembled experts to present at its 24th Annual Symposium entitled "Adiposity, Immunity, and Inflammation: Interrelationships in Health and Disease" on 7 June, 2023. This manuscript seeks to synthesize and present key findings from the symposium, highlighting new research and novel disease-specific advances in the field. Better understanding the interaction between metabolism and immunity offers promising preventative and treatment therapies for obesity-related immunometabolic diseases.

Myostatin (MSTN) has long been recognized as a critical regulator of muscle mass. Recently, there has been increasing interest in its role in metabolism. In our study, we specifically knocked out MSTN in brown adipose tissue (BAT) from mice (MSTNΔUCP1) and found that the mice gained more weight than did controls when fed a high-fat diet, with progressive hepatosteatosis and impaired skeletal muscle activity. RNA-Seq analysis indicated signatures of mitochondrial dysfunction and inflammation in the MSTN-ablated BAT. Further studies demonstrated that Kruppel-like factor 4 (KLF4) was responsible for the metabolic phenotypes observed, whereas fibroblast growth factor 21 (FGF21) contributed to the microenvironment communication between adipocytes and macrophages induced by the loss of MSTN. Moreover, the MSTN/SMAD2/3-p38 signaling pathway mediated the expression of KLF4 and FGF21 in adipocytes. In summary, our findings suggest that brown adipocyte-derived MSTN regulated BAT thermogenesis via autocrine and paracrine effects on adipocytes or macrophages, ultimately regulating systemic energy homeostasis.

Metabolic inflammation (metaflammation) in obesity is primarily initiated by proinflammatory macrophage infiltration into adipose tissue. SelenoM contributes to the modulation of antioxidative stress and inflammation in multiple pathological processes; however, its roles in metaflammation and the proinflammatory macrophage (M1)-like state in adipose tissue have not been determined.

We hypothesize that SelenoM could effectively regulate metaflammation via the Hippo-YAP/TAZ-ROS signaling axis in obesity derived from a high-fat diet.

Morphological changes in adipose tissue were examined by hematoxylin-eosin (H&E) staining and fluorescence microscopy. The glucose tolerance test (GTT) and insulin tolerance test (ITT) were used to evaluate the impact of SelenoM deficiency on blood glucose levels. RNA-Seq analysis, LC-MS analysis, Mass spectrometry analysis and western blotting were performed to detect the levels of genes and proteins related to glycolipid metabolism in adipose tissue.

Herein, we evaluated the inflammatory features and metabolic microenvironment of mice with SelenoM-deficient adipose tissues by multi-omics analyses. The deletion of SelenoM resulted in glycolipid metabolic disturbances and insulin resistance, thereby accelerating weight gain, adiposity, and hyperglycemia. Mice lacking SelenoM in white adipocytes developed severe adipocyte hypertrophy via impaired lipolysis. SelenoM deficiency aggravated the generation of ROS by reducing equivalents (NADPH and glutathione) in adipocytes, thereby promoting inflammatory cytokine production and the M1-proinflammatory reaction, which was related to a change in nuclear factor kappa-B (NF-κB) levels in macrophages. Mechanistically, SelenoM deficiency promoted metaflammation via Hippo-YAP/TAZ-ROS-mediated transcriptional regulation by targeting large tumor suppressor 2 (LATS2). Moreover, supplementation with N-acetyl cysteine (NAC) to reduce excessive oxidative stress partially rescued adipocyte inflammatory responses and macrophage M1 activation.

Our data indicate that SelenoM ameliorates metaflammation mainly via the Hippo-YAP/TAZ-ROS signaling axis in obesity. The identification of SelenoM as a key regulator of metaflammation presents opportunities for the development of novel therapeutic interventions targeting adipose tissue dysfunction in obesity.