Complementary effects of dapagliflozin and lobeglitazone on metabolism in a diet-induced obese mouse model.

Thiazolidinedione, an insulin sensitizer, has beneficial effects on glucose metabolism; however, there are concerns regarding weight gain and heart failure. Sodium-glucose co-transporter 2 (SGLT2) inhibitors can reduce body weight, increase diuresis, and play a protective role in heart failure. We examined the complementary effects of dapagliflozin, an SGLT2 inhibitor, and lobeglitazone, a thiazolidinedione, in high-fat diet (HFD)-induced obese mice. We treated HFD-induced obese mice with vehicle, dapagliflozin, lobeglitazone, and their combination for 12 weeks. Oral glucose tolerance and insulin tolerance tests were performed after 12-week treatment, and body composition was measured by dual-energy X-ray absorptiometry before and after treatment. We analyzed oxygen consumption rate (OCR) using 3T3-L1 cells after treatment of ß-hydroxybutyrate and/or lobeglitazone. Treatment with a combination of dapagliflozin and lobeglitazone resulted in a significant decrease in postprandial hyperglycemia compared with dapagliflozin monotherapy, but not compared with lobeglitazone monotherapy. The addition of dapagliflozin to lobeglitazone treatment did not attenuate weight gain compared with lobeglitazone monotherapy in this study. However, this combination prevented the increase of organ weight of liver and heart, and OCR in 3T3-L1 cells was increased after treatment with a combination of ß-hydroxybutyrate and lobeglitazone compared to lobeglitazone monotherapy. We confirmed the beneficial effect of lobeglitazone on glucose metabolism; however, we did not find any beneficial effect of dapagliflozin on body weight in HFD-induced obese mice. However, the protective effects of dapagliflozin and lobeglitazone combined therapy on the liver, heart, energy consumption, and ß-cell senescence are worth investigating in clinical trials.

Effect of atorvastatin on lipoxygenase pathway-related gene expression in an in vitro model of lipid accumulation in hepatocytes.

Lipid accumulation in hepatocytes can result from an imbalance between lipid acquisition and lipid catabolism. In recent years, it has been discovered that eicosanoids derived from arachidonic acid (AA) have the potential to create specialized pro-resolving lipid mediators to actively resolve inflammation, but it is not clear whether AA and lipoxygenases exert effects on hepatic inflammation. Here, the effects of atorvastatin on the expression of cytoplasmic phospholipase A2 (cPLA2) and lipoxygenase pathway genes (ALOX5, ALOX12, ALOX15, and ALOX15B) were evaluated in an in vitro model of palmitic acid (PA)-induced hepatocyte lipid accumulation in McA-RH7777 (McA) cells. Palmitic acid increased cPLA2 expression, intracellular AA levels, and ALOX12 expression (P < 0.05). Atorvastatin at various concentrations had no significant effects on AA levels or on cPLA2, ALOX15, and ALOX15B expressions. ALOX5 was not detected, despite multiple measurements. Pro-inflammatory IL-1ß expression levels were upregulated by PA (P < 0.01) and attenuated by atorvastatin (P < 0.001). TNFα did not differ among groups. The expression levels of anti-inflammatory IL-10 decreased in response to PA (P < 0.05), but were not affected by atorvastatin. In conclusion, in an in vitro model of lipid accumulation in McA cells, atorvastatin reduced IL-1ß; however, its effect was not mediated by AA and the lipoxygenase pathway at the established doses and treatment duration. Further research is required to investigate time-response data, as well as other drugs and integrated cell systems that could influence the lipoxygenase pathway and modulate inflammation in liver diseases.

Association Between Fat Mass or Fat Fibrotic Gene Expression and Polyneuropathy in Subjects With Obesity: A Korean Metabolic Bariatric Surgery Cohort.

Aim: We aimed to investigate the association between obesity-related parameters and polyneuropathy (PN) and to evaluate inflammatory and fibrotic gene expression of fat as a potential mediator in subjects scheduled to undergo metabolic bariatric surgery (MBS). Methods: This was a cross-sectional study of MBS cohort. Body composition and visceral fat area (VFA) were quantified by bioimpedance analysis and computed tomography scan. PN was defined by Michigan Neuropathy Screening Instrument-Physical Examination score was > 2. We measured mRNA expression level of FN1, TIMP1, CCL2, and CXCL8 in omental fat tissue. Results: Of 189 subjects (mean age, 39.4 years; 69 [36.5%] male; mean body mass index, 38.5 kg/m2), prevalence of PN was 9.1% in subjects without diabetes (n = 110) and 20.3% in those with diabetes (n = 79). Nondiabetic subjects with PN had higher homeostatic model assessment-insulin resistance (6.8 ± 3.5 vs 4.5 ± 2.8, p = 0.041), and increased fat mass (58.5 ± 12.5 kg vs 50.5 ± 10.7 kg, p = 0.034), and VFA (309.4 ± 117.6 cm2vs 243.5 ± 94.2 cm2, p = 0.046) compared to those without PN. These obesity-related parameters were significantly associated with the presence of PN after adjusting for conventional risk factors of PN only in subjects without diabetes. In contrast, a fibrotic gene such as TIMP1 was independently associated with PN (adjusted odds ratio of 1.56; 95% confidence interval 1.06, 2.30) only in subjects with diabetes. Conclusion: Increased adiposity was independently associated with PN in obese subjects without diabetes. In contrast, this association was not significant after adjusting conventional risk factors of PN in obese subjects with diabetes but increased fibrotic gene expression in fat was associated with PN in this group.

Liver fibrosis indices are related to diabetic peripheral neuropathy in individuals with type 2 diabetes.

The association between nonalcoholic fatty liver (NAFL) or liver fibrosis and diabetic peripheral neuropathy (DPN) has not been well studied. We aimed to investigate the association of NAFL or liver fibrosis indices and DPN in individuals with type 2 diabetes. In this observational study, we included 264 individuals with type 2 diabetes, and calculated non-alcoholic fatty liver disease (NAFLD) liver fat score, NAFLD fibrosis score, and Fibrosis-4 (FIB-4) index to evaluate the status of NAFLD or liver fibrosis. DPN was diagnosed when the Michigan Neuropathy Screening Instrument-Physical Examination score was ≥ 2.5. The NAFLD fibrosis score and FIB-4 index were significantly higher in individuals with DPN than in those without DPN. Logistic analyses showed that the NAFLD fibrosis score and FIB-4 index were associated with DPN after adjustment for covariates (adjusted odds ratio 1.474 and 1.961, respectively). In the subgroup analysis, this association was only significant in the group with a high NAFLD liver fat score (> - 0.640). Serum levels of fetuin-A, a hepatokine, were decreased in individuals with abnormal vibration perception or 10-g monofilament tests compared with their counterparts. The present study suggests that liver fibrosis might be associated with DPN in individuals with type 2 diabetes.

Antiinflammatory activity of ANGPTL4 facilitates macrophage polarization to induce cardiac repair.

Mesenchymal stem cells (MSCs) can suppress pathological inflammation. However, the mechanisms underlying the association between MSCs and inflammation remain unclear. Under coculture conditions with macrophages, MSCs highly expressed angiopoietin-like 4 (ANGPTL4) to blunt the polarization of macrophages toward the proinflammatory phenotype. ANGPTL4-deficient MSCs failed to inhibit the inflammatory macrophage phenotype. In inflammation-related animal models, the injection of coculture medium or ANGPTL4 protein increased the antiinflammatory macrophages in both peritonitis and myocardial infarction. In particular, cardiac function and pathology were markedly improved by ANGPTL4 treatment. We found that retinoic acid-related orphan receptor α (RORα) was increased by inflammatory mediators, such as IL-1ß, and bound to ANGPTL4 promoter in MSCs. Collectively, RORα-mediated ANGPTL4 induction was shown to contribute to the antiinflammatory activity of MSCs against macrophages under pathological conditions. This study suggests that the capability of ANGPTL4 to induce tissue repair is a promising opportunity for safe stem cell-free regeneration therapy from a translational perspective.