saroglitazar and Obesity

Higher global prevalence of non-alcoholic fatty liver disease (NAFLD) is associated with obesity, steatosis, and insulin resistance (IR), and often progresses to steatohepatitis (NASH). Even after more than twenty years of research, there is still no FDA approved therapy for the treatment of fatty liver disease/NASH though, Saroglitazar - a dual PPAR α/γ agonist has been recently approved as a therapeutic option for the fatty liver disease in India. Hepatoprotective Ayurvedic formulations are widely used and are considered safe. In the present study, C57BL/6 male mice on HFHF diet for four weeks were treated with vehicle, Saroglitazar (3 mg/kg/po), and Hepano - a formulation of five herbs (200 mg/kg/po), at the human equivalent therapeutic doses for additional eight weeks. These animals were evaluated after 12 weeks for obesity, body mass index (BMI), systemic insulin resistance, hyperglycaemia, dyslipidaemia, and hepatic lipid accumulation. Differential liquid chromatography-mass spectrometry (LC-MS/MS) based lipidomics analysis demonstrated significant changes in the different class of lipids [phospholipids, sphingolipids, diglycerides and triglycerides (TG)] in HFHF fed group. The protective effects of both Saroglitazar and Hepano were evident against IR, obesity and in the modulation of different class of lipids in the circulation and hepatic tissue. Saroglitazar reduced TG as well as modulated phospholipids levels, while Hepano modulated only phospholipids, ceramides, oxidised lipids, and had no effect on hepatic or circulating TG levels in HFHF fed mice. In addition, in vitro studies using HepG2, THP1 and LX2 cells demonstrated safety of both the test substances where Hepano possess better anti-inflammatory as well as anti-fibrotic potential. Overall, Saroglitazar seems to be more efficacious than Hepano in the regimen used against HFHF induced IR, obesity, and dyslipidaemia.

Topics: Animals; Cell Line; Diet; Diet, High-Fat; Fatty Liver; Fructose; Humans; Hypolipidemic Agents; Insulin Resistance; Lipid Metabolism; Lipidomics; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Phenylpropionates; Pyrroles

Topics: Animals; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Aorta, Thoracic; Disease Models, Animal; Endothelium, Vascular; Male; NADPH Oxidases; Nitric Oxide Synthase Type III; Obesity; Phenylpropionates; PPAR alpha; PPAR gamma; Proto-Oncogene Proteins c-akt; Pyrroles; Rats, Wistar; Signal Transduction; Vasodilation

Prevailing knowledge links chronic low-grade inflammation in the adipose tissue to obesity and its associated metabolic complications. In this study, we evaluated immunometabolic effects of a recently launched dual peroxisome proliferator-activated receptor (PPAR) α & γ agonist 'Saroglitazar' in a mouse model of diet-induced obesity (DIO). Body composition analysis revealed that saroglitazar treatment promoted hepatic weight gain, while attenuated epididymal white adipose tissue (eWAT) mass in DIO. In the eWAT of saroglitazar treated mice, histological analysis showed reduced adipocyte hypertrophy and matrix deposition (picrosirius red staining). Immunological profiling of stromal vascular fraction isolated from eWAT showed decreased pro-inflammatory cells (M1 macrophages, CD4 and CD8 T-cells) and increased anti-inflammatory M2 macrophages. Gene expression and western blot analysis suggested that saroglitazar promoted energy expenditure machinery and attenuated inflammatory as well as fibrotic markers in eWAT during DIO. In conclusion, for the first time we are reporting immunometabolic effects of dual PPARα & γ agonist saroglitazar in DIO and insulin resistance (IR). Saroglitazar exerted its beneficial effects on adipose tissue by limiting, diet-induced adipose tissue dysfunction, adipocyte hypertrophy, adipocyte cell damage and extracellular matrix deposition in obesity.

Topics: Adipose Tissue; Animals; Energy Metabolism; Glucose; Homeostasis; Hypertrophy; Inflammation; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Specificity; Phenylpropionates; Pyrroles