MCAD activation by empagliflozin promotes fatty acid oxidation and reduces lipid deposition in NASH.

Medium-chain acyl-CoA dehydrogenase (MCAD) is one of the significant enzymes involved in the ß-oxidation of mitochondrial fatty acids. MCAD deficiency affects the ß-oxidation of fatty acid and leads to lipid deposition in multiple organs, but little is known about its importance in nonalcoholic steatohepatitis (NASH). Empagliflozin is revealed to effectively improve NASH by increasing research, whereas the specific mechanism still has to be explored. Human liver tissues of patients with or without NASH were obtained for proteomic analysis to screen proteins of interest. db/db mice were given empagliflozin by gavage for 8 weeks. The expression of MCAD and signaling molecules involved in hepatic lipid metabolism was evaluated in human liver, mice and HL7702 cells. We found that the MCAD levels in the liver were significantly reduced in NASH patients compared to patients without NASH. Protein-protein interaction network analysis showed that MCAD was highly correlated with forkhead box A2 (FOXA2) and protein kinase AMP-activated catalytic subunit alpha (PRKAA). AMPK/FOXA2/MCAD signaling pathway was detected to be inhibited in the liver of NASH patients. Decreased expression of MCAD was also observed in the livers of db/db mice and hepatocyte treated with palmitic acid and glucose. Of note, empagliflozin could upregulate MCAD expression by activating AMPK/FOXA2 signaling pathway, reduce lipid deposition and improve NASH in vivo and in vitro. This research demonstrated that MCAD is a key player of hepatic lipid deposition and its targeting partially corrects NASH. MCAD thus may be a potential therapeutic target for the treatment of NASH.

Current understanding of the role of Adipose-derived Extracellular Vesicles in Metabolic Homeostasis and Diseases: Communication from the distance between cells/tissues.

Extracellular vesicles (EVs) including exosomes, microvesicles (MVs), and apoptotic bodies, are small membrane vesicular structures that are released during cell activation, senescence, or programmed cell death, including apoptosis, necroptosis, and pyroptosis. EVs serve as novel mediators for long-distance cell-to-cell communications and can transfer various bioactive molecules, such as encapsulated cytokines and genetic information from their parental cells to distant target cells. In the context of obesity, adipocyte-derived EVs are implicated in metabolic homeostasis serving as novel adipokines. In particular, EVs released from brown adipose tissue or adipose-derived stem cells may help control the remolding of white adipose tissue towards browning and maintaining metabolic homeostasis. Interestingly, EVs may even serve as mediators for the transmission of metabolic dysfunction across generations. Also, EVs have been recognized as novel modulators in various metabolic disorders, including insulin resistance, diabetes mellitus, and non-alcoholic fatty liver disease. In this review, we summarize the latest progress from basic and translational studies regarding the novel effects of EVs on metabolic diseases. We also discuss EV-mediated cross-talk between adipose tissue and other organs/tissues that are relevant to obesity and metabolic diseases, as well as the relevant mechanisms, providing insight into the development of new therapeutic strategies in obesity and metabolic diseases.

Inhibition of microRNA-124a attenuates non-alcoholic fatty liver disease through upregulation of adipose triglyceride lipase and the effect of liraglutide intervention.

AIM: Glucagon-like peptide-1 receptor agonists (GLP-1Ras) have been reported to prevent non-alcoholic fatty liver disease (NAFLD), but the potential mechanisms are still debated. MicroRNAs (miRNAs) play a prominent role in the field of metabolic disorders, including NAFLD. Our study was designed to further evaluate the effect of GLP-1Ra liraglutide on NAFLD in terms of miRNAs. METHODS: MicroRNA expression was evaluated by clustering analysis of microRNA arrays in high fat diet-fed mice. The luciferase reporter assay was carried out to validate the cross-talk between adipose triglyceride lipase (ATGL) and miR-124a. MicroRNA-124a mimics and inhibitor plasmids were transfected to study the role of miR-124a in palmitate-treated normal human liver cell line (HL-7702). Liraglutide treatment was used to observe the effect of GLP-1Ra on the miR-124a/ATGL pathway. RESULTS: Expression of ATGL decreased and miR-124a expression increased in hepatosteatosis in vivo and in vitro. Mechanistically, miR-124a interacted with the 3'-untranslated region of ATGL mRNA and induced its degradation. MicroRNA-124a overexpression antagonized the effect of liraglutide on NAFLD by inhibiting ATGL expression, whereas miR-124a knockdown led to elevated ATGL and sirtuin 1 (Sirt1) expression, and subsequently decreased lipid accumulation and inflammation in cells. CONCLUSIONS: MicroRNA-124a overexpression contributes to the progression of NAFLD through reduction of ATGL expression, whereas miR-124a knockdown can reverse this trend, suggesting that miR-124a and its downstream target ATGL can be novel therapeutic targets of NAFLD. We reveal a novel mechanism by which liraglutide attenuates NAFLD by the miR-124a/ATGL/Sirt1 pathway.

Liraglutide prevents ß-cell apoptosis via inactivation of NOX2 and its related signaling pathway.

AIMS: High glucose (HG)-induced pancreatic ß-cell apoptosis may be a major contributor to the progression of diabetes mellitus (DM). NADPH oxidase (NOX2) has been considered a crucial regulator in ß-cell apoptosis. This study was designed to evaluate the impact of GLP-1 receptor agonist (GLP-1Ra) liraglutide on pancreatic ß-cell apoptosis in diabetes and the underlying mechanisms involved. METHODS: The diabetic rat models induced by streptozotocin (STZ) and a high fat diet (HFD) received 12 weeks of liraglutide treatment. Hyperglycemic clamp test was carried out to evaluate ß-cell function in vivo. Flow cytometry analysis was used to measure apoptosis rates in vitro. DCFH-DA method was used to detected ROS level in vivo and in vitro. RESULTS: Liraglutide significantly improved islet function and morphology in diabetic rats and decreased cell apoptosis rates. Thr183/Thr185 p-JNK1/2 and NOX2 levels reduced in diabetic rats and HG-induced INS-1 cell following liraglutide treatment. In addition, liraglutide upregulated the phosphorylation of AMPKα (p-AMPKα), which prevented NOX2 activation and alleviated HG-induced ß-cell apoptosis. CONCLUSION: The p-AMPKα/NOX2/JNK1/2 pathway is essential for liraglutide to attenuate HG-induced ß-cell apoptosis, which further proves that GLP-1Ras may become promising therapeutics for diabetes mellitus.

Serum adipocyte fatty acid-binding protein levels are associated with peripheral arterial disease in women, but not men, with type 2 diabetes mellitus.

BACKGROUND: Adipocyte fatty acid-binding protein (A-FABP) has been recognized as an important player in macrophage cholesterol trafficking and inflammation, and may promote the development of atherosclerosis. To further elucidate the role of A-FABP in atherosclerosis in diabetes, we investigated the relationship between serum A-FABP concentrations and peripheral arterial disease (PAD) in patients with type 2 diabetes mellitus (T2DM). METHODS: In all, 488 inpatients with T2DM were enrolled in the study (254 men, 234 women; mean (±SD) age 57.3 ± 13.0 years). The severity of peripheral arterial stenosis was assessed by ultrasound examination. Serum A-FABP concentrations were determined by ELISA. RESULTS: Serum A-FABP concentrations were significantly higher in patients with than without PAD (8.0 ± 3.3 vs 6.2 ± 1.6 ng/mL, respectively; P < 0.05). Interestingly, there was an obvious gender-related difference in PAD patients with T2DM, with the stenosis rate being higher for female than male T2DM patients in the third A-FABP tertile. Logistic regression analysis revealed that serum A-FABP concentrations were an independent risk factor for PAD in female T2DM patients (odds ratio 1.890, 95% confidence interval 1.041-3.432; P = 0.036), but not in male T2DM patients. Correlation analyses revealed that A-FABP concentrations were correlated with body mass index (BMI), diastolic blood pressure, urinary microalbumin, and serum creatinine in male patients, and with BMI, duration of T2DM, fasting blood glucose, and serum creatinine in female patients. CONCLUSIONS: Serum A-FABP concentrations are closely associated with PAD in Chinese women with T2DM. The study findings suggest that A-FABP may be a more specific marker of PAD in diabetic women than men.

Saxagliptin Induces ß-Cell Proliferation through Increasing Stromal Cell-Derived Factor-1α In Vivo and In Vitro.

Dipeptidyl peptidase-4 inhibitors, such as saxagliptin, have been reported to have beneficial effects on ß-cell function, but the specific underlying mechanism remains unclear. Stromal cell-derived factor-1α (SDF-1α), a chemokine produced in multiple organs, has been considered as a crucial regulator in promoting ß-cell survival. Here, we speculate that SDF-1α might mediate the effect of saxagliptin on improving ß-cell function. After 12-week saxagliptin treatment in high-fat diet/streptozotocin-induced diabetic rats, significant improvement in pancreas insulin secretion capacity evaluated by hyperglycemia clamp and increased ß-cell to α-cell areas ratio were observed. Saxagliptin significantly induced ß-cell proliferation and upregulated the expression of proliferation-related factors including c-myc and cyclind D1 determined with western blotting from the isolated islets. The expression/activity of DPP-4 was significantly reduced and paralleled with the restoration of SDF-1α levels in the saxagliptin-treated diabetic rats, subsequently the key WNT-signaling regulators, ß-catenin, and AKT were activated. However, the effect of saxagliptin inducing ß-cell proliferation was attenuated when we silenced the SDF-1α receptor (CXCR4) with RNAi in INS cell lines. Collectively, our data indicate that SDF-1α mediates the protective effect of saxagliptin on ß-cell proliferation, suggesting that DPP-4 inhibitors have the potential role on delaying ß-cell failure and SDF-1α could be a therapeutic target of ß-cell regeneration.