Written by Charlotte Harrison, Science Writer.
A team of researchers, led by scientists at the University of Barcelona, have developed a gene-therapy strategy that combats obesity and diabetes in mouse models.
“This preclinical study could open the doors to future therapeutic strategies to address the treatment of obesity,” noted the authors in a press release.
Metabolic gatekeeper
The gene-therapy strategy aimed to deliver a copy of CPT1A (carnitine palmitoyltransferase 1A), which encodes an enzyme that is a gatekeeper for mitochondrial fatty acid oxidation and hence has a key role in metabolic activities.
First, mesenchymal stem cells were isolated from mouse adipose tissue, specifically from deposits of white adipose tissue, as this tissue type is more accessible in humans should the therapy reach clinical testing.
The stem cells were then differentiated into mature adipocytes and subjected to lentivirus-mediated expression of CPT1AM. Adipocytes expressing CPT1AM were implanted subcutaneously into mice fed a high-fat diet.
Improved phenotypes
The CPT1AM gene therapy reversed the diabetic and obese phenotypes of mice fed a high-fat diet. Mice that received the gene therapy had a lower body weight, less hepatic steatosis, lower serum insulin and cholesterol levels, and also better glucose tolerance.
Moreover, increases in adipose tissue hypertrophy, fibrosis and inflammation caused by the high-fat diet were reduced in treated mice. At a cellular level, CPT1AM-treated mice had lower levels of endoplasmic reticulum stress and apoptosis, and better expression of mitochondrial respiratory chain complexes.
Thinking about the clinic
The authors highlight that the improved obese metabolic phenotype seen in mice supports the future clinical use of the CPT1AM gene therapy. They note that if the therapy was trailed in humans, the adipose tissue-derived cells could be obtained during liposuction or bariatric surgery. These cells would then be genetically modified and implanted back into the same individual.
“To approximate the therapy in humans, we need to optimize several processes such as the quality and viability of stem cells from adipose tissue … the percentage of infection with lentivirus, and the number of cells used for transplantation”, concluded author Laura Herrero.
