TRC150094 attenuates progression of nontraditional cardiovascular risk factors associated with obesity and type 2 diabetes in obese ZSF1 rats

Shitalkumar P Zambad¹, Siralee Munshi², Amita Dubey³, Ram Gupta¹, Rosa Anna Busiello⁴, Antonia Lanni⁵, Fernando Goglia⁶, Ramesh C Gupta⁷, Vijay Chauthaiwale⁸, Chaitanya Dutt^9
1Pharmacology, ²Cellular and Molecular Biology, ³Pre-clinical and Safety Evaluation, Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, India; ⁴Dipartimento di Biologia, Universita degli Studi di Napoli Federico II, Naples, Italy; ⁵Dipartimento di Scienze della Vita, Seconda Universita di Napoli, Caserta, Italy; ⁶Dipartimento di Scienze Biologiche ed Ambientali, Universita del Sannio, Benevento, Italy; ⁷Medicinal Chemistry, ⁸Discovery Research, ⁹Clinical Research, Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, India

Abstract: Chronic overnutrition and consequential visceral obesity is associated with a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus. Moreover, individuals who have a triad of hypertension, dysglycemia, and elevated triglycerides along with reduced high-density lipoprotein cholesterol have a greater residual cardiovascular risk even after factoring for the traditional risk factors such as age, smoking, diabetes, and elevated low-density lipoprotein cholesterol. In our previous study we demonstrated that TRC150094, when administered to rats receiving a high-fat diet, stimulated mitochondrial fatty acid oxidation (FAO) and reduced visceral adiposity, opening an interesting perspective for a possible clinical application. In the present study, oral administration of TRC150094 to obese Zucker spontaneously hypertensive fatty rats (obese ZSF1) improved glucose tolerance and glycemic profile as well as attenuated a rise in blood pressure. Obese ZSF1 rats treated with TRC150094 also showed reduced hepatic steatosis, reduced progression of nephropathy, and improved skeletal muscle function. At the cellular level, TRC150094 induced a significant increase in mitochondrial respiration as well as an increased FAO in liver and skeletal muscle, ultimately resulting in reduced hepatic as well as total body fat accumulation, as evaluated by magnetic resonance spectroscopy and magnetic resonance imaging, respectively. If reproduced in humans, these results could confirm that TRC150094 may represent an attractive therapeutic agent to counteract multiple residual cardiovascular risk components.

Keywords: CV risk factors, energy expenditure, fatty acid oxidation, obesity, TRC150094, type 2 diabetes