Implantation of CPT1AM-expressing adipocytes reduces obesity and glucose intolerance in mice
M. Carmen Soler‐Vázquez, María del Mar Romero, Marijana Todorčević, Katia Delgado, Carles Calatayud, Aleyda Benitez -Amaro, Maria Teresa La Chica Lhoëst, Paula Mera, Sebastián Zagmutt, Marianela Bastías‐Pérez, Kevin Ibeas, Núria Casals, Joan Carles Escolá‐Gil, Vicenta Llorente‐Cortés, Antonella Consiglio, Dolors Serra, Laura Herrero
Abstract
Obesity and its associated metabolic comorbidities are a rising global health and social issue, with novel therapeutic approaches urgently needed. Adipose tissue plays a key role in the regulation of energy balance and adipose tissue-derived mesenchymal stem cells (AT-MSCs) have gained great interest in cell therapy. Carnitine palmitoyltransferase 1A (CPT1A) is the gatekeeper enzyme for mitochondrial fatty acid oxidation. Here, we aimed to generate adipocytes expressing a constitutively active CPT1A form (CPT1AM) that can improve the obese phenotype in mice after their implantation. AT-MSCs were differentiated into mature adipocytes, subjected to lentivirus-mediated expression of CPT1AM or the GFP control, and subcutaneously implanted into mice fed a high-fat diet (HFD). CPT1AM-implanted mice showed lower body weight, hepatic steatosis and serum insulin and cholesterol levels alongside improved glucose tolerance. HFD-induced increases in adipose tissue hypertrophy, fibrosis, inflammation, endoplasmic reticulum stress and apoptosis were reduced in CPT1AM-implanted mice. In addition, the expression of mitochondrial respiratory chain complexes was enhanced in the adipose tissue of CPT1AM-implanted mice. Our results demonstrate that implantation of CPT1AM-expressing AT-MSC-derived adipocytes into HFD-fed mice improves the obese metabolic phenotype, supporting the future clinical use of this ex vivo gene therapy approach.