Implantation of CPT1AM-expressing adipocytes reduces obesity and glucose intolerance in mice

• Published in: Metabolic engineering Vol. 77; pp. 256 - 272
• Main Authors: Soler-Vázquez, M Carmen, Romero, María del Mar, Todorcevic, Marijana, Delgado, Katia, Calatayud, Carles, Benitez -Amaro, Aleyda, La Chica Lhoëst, Maria Teresa, Mera, Paula, Zagmutt, Sebastián, Bastías-Pérez, Marianela, Ibeas, Kevin, Casals, Núria, Escolà-Gil, Joan Carles, Llorente-Cortés, Vicenta, Consiglio, Antonella, Serra, Dolors, Herrero, Laura
• Format: Journal Article
• Language: English
• Published: Belgium Elsevier Inc 01-05-2023
• Subjects: Adipocytes - metabolism; Adipose tissue; Adipose Tissue - metabolism; Adipose tissue-derived mesenchymal stem cells; Animals; Carnitine palmitoyltransferase 1A; Glucose Intolerance - genetics; Glucose Intolerance - metabolism; Inflammation - metabolism; Mice; Obesity; Obesity - drug therapy; Obesity - genetics; Obesity - metabolism; Type 2 diabetes; Type 2 diabetes; Obesity; Carnitine palmitoyltransferase 1A; Adipose tissue; Adipose tissue-derived mesenchymal stem cells
• ISSN: 1096-7176; 1096-7184
• DOI: 10.1016/j.ymben.2023.04.010

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.
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•AT-MSCs could be isolated from different fat depots of lean and obese mice.•Implantation of CPT1AM-expressing AT-MSC-derived adipocytes improves obesity.•Implantation of CPT1AM-expressing AT-MSC-derived adipocytes reduces hyperglycemia.•CPT1AM-implanted mice showed improved HFD-induced adipose tissue derangements.•Novel pre-clinical cell-based gene therapy for obesity and associated diseases.