Mechanistic insights into the role of USP14 in adipose tissue macrophage recruitment and insulin resistance in obesity.

Diet-induced obesity can cause metabolic syndromes. The critical link in disease progression is adipose tissue macrophage (ATM) recruitment, which drives low-level inflammation, triggering adipocyte dysfunction. It is unclear whether ubiquitin-specific proteinase 14 (USP14) affects metabolic disorders by mediating adipose tissue inflammation. In the present study, we showed that USP14 is highly expressed in ATMs of obese human patients and diet-induced obese mice. Mouse USP14 overexpression aggravated obesity-related insulin resistance by increasing the levels of pro-inflammatory ATMs, leading to adipose tissue inflammation, excessive lipid accumulation, and hepatic steatosis. In contrast, USP14 knockdown in adipose tissues alleviated the phenotypes induced by a high-fat diet. Co-culture experiments showed that USP14 deficiency in macrophages led to decreased adipocyte lipid deposition and enhanced insulin sensitivity, suggesting that USP14 plays an important role in ATMs. Mechanistically, USP14 interacted with TNF receptor-associated 6, preventing K48-linked ubiquitination as well as proteasome degradation, leading to increased pro-inflammatory polarization of macrophages. In contrast, the pharmacological inhibition of USP14 significantly ameliorated diet-induced hyperlipidemia and insulin resistance in mice. Our results demonstrated that macrophage USP14 restriction constitutes a key constraint on the pro-inflammatory M1 phenotype, thereby inhibiting obesity-related metabolic diseases.

Knowledge, attitude, and practice toward weight management among diabetic patients in Qidong City, Jiangsu Province.

BACKGROUND: Weight management is an effective prevention and treatment strategy for diabetes mellitus. This study aimed to assess the knowledge, attitude, and practice (KAP) of diabetic patients towards weight management. METHODS: Diabetic patients treated at Qidong City, Jiangsu Province, between January 2023 and June 2023 were included in this cross-sectional study. A self-designed questionnaire was used to collect their demographic characteristics and KAP toward weight management. Structural equation modeling (SEM) was employed to examine the inter-relationships among KAP scores. RESULTS: Among a total of 503 valid questionnaires that were collected, 55.07% were filled out by men and 54.67% by those aged < 60 years. The mean scores for knowledge, attitude, and practice were 8.03 ± 3.525 (possible range: 0-13), 31.88 ± 3.524 (possible range: 10-50), and 22.24 ± 3.318 (possible range: 9-45), respectively. Pearson's correlation analysis revealed the knowledge was positively associated with attitude (r = 0.295, P < 0.001) and practice (r = 0.131, P < 0.001), and attitude was positively associated with practice (r = 0.140, P = 0.002). SEM demonstrated positive associations between knowledge and attitude (ß = 0.28, P < 0.001), and attitude and practice (ß = 0.09, P = 0.019). Moreover, older age was negatively associated with knowledge (ß=-0.04, P = 0.001), while higher education (ß = 1.220, P < 0.001), increased monthly income (ß = 0.779, P < 0.001), diagnosis of fatty liver (ß = 1.03, P = 0.002), and screening for excess visceral fat (ß = 1.11, P = 0.002) were positively associated with knowledge. CONCLUSION: Diabetic patients showed moderate knowledge, neutral attitudes, and inappropriate practices toward weight management. Knowledge was positively associated with attitude and practice. These findings provided valuable directions for healthcare interventions targeting improved KAP status of weight management among diabetic patients.

Impact of a high dietary fiber cereal meal intervention on body weight, adipose distribution, and cardiovascular risk among individuals with type 2 diabetes.

Objective: This study sought to examine the impacts of a high dietary fiber cereal meal in comparison to conventional dietary management for diabetes on body weight, distribution of adipose tissue, and cardiovascular risk among individuals diagnosed with type 2 diabetes (T2DM). Methods: A cohort of 120 patients diagnosed with T2DM was enlisted as the study population and divided into two groups using a ratio of 2:1-namely, the W group (n=80) and the U group (n=40). The U group (control) received usual diet, while the W group (intervention) incorporated a high dietary fiber cereal meal in place of their regular staple food in addition to adhering to conventional diabetes dietary recommendations. The high dietary fiber cereal meal was based on whole grains, traditional Chinese medicinal foods, and prebiotics. A subsequent follow-up period of 3 months ensued, during which diverse parameters such as body mass index (BMI),waist-hip ratio (WHR), glycated hemoglobin (HbA1c),fasting blood glucose(FBG),C-peptide levels, blood pressure, blood lipids, high-sensitivity C-reactive protein (hsCRP),10-year cardiovascular disease (CVD) risk, and Lifetime CVD risk were assessed before and after the intervention. Results: Among the participants, a total of 107 successfully completed the intervention and follow-up, including 72 individuals from the W group and 35 from the U group. Following the intervention, both cohorts exhibited decrease in BMI, WHR, HbA1c, FBG, blood pressure, and blood lipid levels in contrast to their initial measurements. Remarkably, the improvements in BMI, WHR, HbA1c, FBG, total cholesterol (TC), triglycerides(TG), low-density lipoprotein cholesterol (LDL-C), the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C), and the ratio of 2-hour C-peptide (2hCP) to fasting C-peptide (FCP) were more marked within the W group, exhibiting statistically significant disparities (P<0.05) in comparison to the U group. Furthermore, the levels of hsCRP declined among individuals in the W group, while the U group experienced an elevation.10-year CVD risk reduction were similar in the two groups. While, Lifetime CVD risk only decreased significantly in the W group. Conclusion: The intervention centred on a cereal-based dietary approach showcased favourable outcomes with regard to body weight, adipose distribution, and cardiovascular risk in overweight individuals grappling with T2DM.

USP14 governs CYP2E1 to promote nonalcoholic fatty liver disease through deubiquitination and stabilization of HSP90AA1.

Nonalcoholic fatty liver disease (NAFLD) begins with excessive triglyceride accumulation in the liver, and overly severe hepatic steatosis progresses to nonalcoholic steatohepatitis (NASH), which is characterized by lipid peroxidation, inflammation, and fibrosis. Ubiquitin-specific proteinase 14 (USP14) regulates inflammation, hepatocellular carcinoma and viral infection, but the effect of USP14 on NAFLD is unknown. The aim of this study was to reveal the role of USP14 in the progression of NAFLD and its underlying mechanism. We demonstrated that hepatic USP14 expression was significantly increased in NAFLD in both humans and mice. Hepatic USP14 overexpression exacerbated diet-induced hepatic steatosis, inflammation and fibrosis in mice, in contrast to the results of hepatic USP14 knockdown. Furthermore, palmitic/oleic acid-induced lipid peroxidation and inflammation in hepatocytes were markedly increased by USP14 overexpression but decreased by USP14 knockdown. Notably, in vivo or in vitro data show that USP14 promotes NAFLD progression in a cytochrome p4502E1 (CYP2E1)-dependent manner, which exacerbates hepatocyte oxidative stress, impairs the mitochondrial respiratory chain and inflammation by promoting CYP2E1 protein levels. Mechanistically, we demonstrated by immunoprecipitation and ubiquitination analysis that USP14 inhibits the degradation of heat shock protein 90 alpha family class A member 1 (HSP90AA1) by decreasing its lysine 48-linkage ubiquitination. Meanwhile, upregulation of HAP90AA1 protein promotes CYP2E1 protein accumulation. Collectively, our data indicate that an unknown USP14-HSP90AA1-CYP2E1 axis contributes to NAFLD progression, and we propose that inhibition of USP14 may be an effective strategy for NASH treatment.

Adipose Tissue Macrophage-Mediated Inflammation in Obesity: A Link to Posttranslational Modification.

Adipose tissue macrophages (ATM) are an essential type of immune cells in adipose tissue. Obesity induces the inflammation of adipose tissues, as expressed by ATM accumulation, that is more likely to become a source of systemic metabolic diseases, including insulin resistance. The process is characterized by the transcriptional regulation of inflammatory pathways by virtue of signaling molecules such as cytokines and free fatty acids. Notably, posttranslational modification (PTM) is a key link for these signaling molecules to trigger the proinflammatory or anti-inflammatory phenotype of ATMs. This review focuses on summarizing the functions and molecular mechanisms of ATMs regulating inflammation in obese adipose tissue. Furthermore, the role of PTM is elaborated, hoping to identify new horizons of treatment and prevention for obesity-mediated metabolic disease.

Melatonin relieves hepatic lipid dysmetabolism caused by aging via modifying the secondary bile acid pattern of gut microbes.

It has been reported that aging-generated gut microecosystem may promote host hepatic lipid dysmetabolism through shaping the pattern of secondary bile acids (BAs). Then as an oral drug, melatonin (Mel)-mediated beneficial efforts on the communication between gut microbiota and aging host are still not clearly. Here, we show that aging significantly shapes the pattern of gut microbiota and BAs, whereas Mel treatment reverses these phenotypes (P < 0.05), which is identified to depend on the existence of gut microbiota. Mechanistically, aging-triggered high-level expression of ileac farnesoid X receptor (FXR) is significantly decreased through Mel-mediated inhibition on Campylobacter jejuni (C. jejuni)-induced deconjugation of tauroursodeoxycholic acid (TUDCA) and glycoursodeoxycholic acid (GUDCA) (P < 0.05). The aging-induced high-level of serum taurine chenodeoxycholic acid (TCDCA) activate trimethylamine-N-oxide (TMAO)-triggered activating transcriptional factor 4 (ATF4) signaling via hepatic FXR, which further regulates hepatic BAs metabolism, whereas TUDCA inhibits aging-triggered high-level of hepatic ATF4. Overall, Mel reduces C. jejuni-mediated deconjugation of TUDCA to inhibit aging-triggered high-level expression of hepatic FXR, which further decreases hepatic TMAO production, to relieve hepatic lipid dysmetabolism.

Arginine promotes testicular development in boars through nitric oxide and putrescine.

The present work aimed to explore the influence and underlying mechanisms involving arginine in testicular development in boars. To this end, thirty 30-day-old male Duroc piglets (7.00 ± 0.30 kg) were randomly sorted into two groups, maintained on either a basal diet (CON, n = 15) or a diet supplemented with 0.8% arginine (ARG, n = 15). Blood and testicular samples were collected during the experimental period to analyse amino acid composition and arginine metabolite levels. The results showed that dietary supplementation with arginine increased number of spermatogonia and height of the seminiferous epithelium (p < 0.05). Sperm density, total number and effective number of sperm of the boars in the ARG group increased significantly compared with those in the CON group (p < 0.05). Although arginine supplementation did not affect plasma amino acid levels, testicular arginine levels in 150-day-old boars exhibited a significant increase (p < 0.05). The level of serum nitric oxide (NO) and activity of nitric oxide synthase (NOS) also increased in 150-day-old boars in the ARG group (p < 0.05). Interestingly, dietary supplementation with arginine increased testicular levels of putrescine in 150-day-old boars (p < 0.05). These results indicated that arginine supplementation increased serum NO levels and testicular arginine and putrescine abundance, thereby improving testicular development and semen quality in boars.

Leptin Reduces Plin5 m6A Methylation through FTO to Regulate Lipolysis in Piglets.

Perilipin5 (Plin5) is a scaffold protein that plays an important role in lipid droplets (LD) formation, but the regulatory effect of leptin on it is unclear. Our study aimed to explore the underlying mechanisms by which leptin reduces the N6-methyladenosine (m6A) methylation of Plin5 through fat mass and obesity associated genes (FTO) and regulates the lipolysis. To this end, 24 Landrace male piglets (7.73 ± 0.38 kg) were randomly sorted into two groups, either a control group (Control, n = 12) or a 1 mg/kg leptin recombinant protein treatment group (Leptin, n = 12). After 4 weeks of treatment, the results showed that leptin treatment group had lower body weight, body fat percentage and blood lipid levels, but the levels of Plin5 mRNA and protein increased significantly in adipose tissue (p < 0.05). Leptin promotes the up-regulation of FTO expression level in vitro, which in turn leads to the decrease of Plin5 M6A methylation (p < 0.05). In in vitro porcine adipocytes, overexpression of FTO aggravated the decrease of M6A methylation and increased the expression of Plin5 protein, while the interference fragment of FTO reversed the decrease of m6A methylation (p < 0.05). Finally, the overexpression in vitro of Plin5 significantly reduces the size of LD, promotes the metabolism of triglycerides and the operation of the mitochondrial respiratory chain, and increases thermogenesis. This study clarified that leptin can regulate Plin5 M6A methylation by promoting FTO to affect the lipid metabolism and energy consumption, providing a theoretical basis for treating diseases related to obesity.

Proteomic analysis reveals key proteins involved in arginine promotion of testicular development in boars.

In order to study the effect of l-arginine on testicular development in boars and its underlying mechanism, thirty 30-day-old Duroc boars (7.0 ± 0.3 kg) were randomly allocated to either a basal diet (CON, n = 15) or a 0.8% arginine diet (ARG, n = 15). Blood samples were collected and weight measurements were done regularly to every pig during the experimental period. Testes were collected for histological and proteomic analysis from 150-day-old boars. Results showed that dietary supplementation with arginine significantly increased testicular weight, the number of spermatogonia, and the height of the seminiferous epithelium (P < 0.05). The serum levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were also significantly increased in the ARG group (P < 0.05). A total of 154 differentially expressed proteins (DEPs) were identified, 76 of them were upregulated and 78 were downregulated. Mainly enriched metabolic pathways were the mTOR and Wnt signaling pathways. Functional annotation suggested that 18 DEPs were related to male reproduction. Western blotting results further validated the results from proteomics. This study may provide new insights into the molecular mechanisms by which arginine promotes male testicular development.

Interpretation of Fiber Supplementation on Offspring Testicular Development in a Pregnant Sow Model from a Proteomics Perspective.

To study the effects of maternal fiber supplementation during pregnancy on the testicular development of male offspring and its possible mechanisms, 36 sows (Landrace × Yorkshire) were allocated to either a control diet (n = 18) or a fiber diet (the control diet supplemented with 22.60 g/kg inulin and 181.60 g/kg cellulosic; n = 18) during pregnancy. The body and testes weight of the offspring, 7-day-old piglets, was recorded. Testes were collected for further analyses. Results showed that the testicular organ index and the number of spermatogonia in single seminiferous tubule were higher in piglets from the fiber group than from the control group (p < 0.05). In addition, a significant increase in the concentration of glucose, lactate, and lipids in the testes was found in the fiber group (p < 0.05). Proteomic analysis suggested that there were notable differences in glucolipid transport and metabolism, oxidation, and male reproduction-related proteins expression between the two groups (p < 0.05). Results revealed that the most enriched signaling pathways in the fiber group testes included starch and sucrose metabolism, fatty acid metabolism, glutathione metabolism, and the renin-angiotensin system. mRNA expression analyzes further confirmed the importance of some signaling pathways in maternal fiber nutrition regulating offspring testicular development. Our results shed new light on the underlying molecular mechanisms of maternal fiber nutrition on offspring testicular development and provided a valuable insight for future explorations of the effect of maternal fiber nutrition on man reproduction.