Searching for alternative thermogenic pathways : lessons from uncoupling protein 1 knockout mice

Abstract

Obesity is one of the most prevalent diseases among the 21st century. Moreover, it is a major risk factor leading to many other illnesses such as diabetes mellitus and cardiovascular diseases. The medical community have made so many endeavors to find effective ways to treat obesity. A protein named uncoupling protein 1 (UCP1) in the brown adipose tissue (BAT) of human was found and put under the spotlight in recent decades. UCP1 can dissipate energy stored in the body as heat. Therefore, it is very likely an intervening target for obesity treatment. In our project, we evaluate the role of UCP1 in mice metabolism by the comparison of different metabolic parameters between UCP1-knockout and wild-type (WT) mice under standard chow diet and high-fat diet. Mechanisms behind those differences are determined by the investigation of mitochondria and other related proteins in both groups of mice. The weight of UCP1-knockout mice is less than that of WT mice under prolonged high-fat diet. This indicates that there is an alternative energy dissipation pathway being activated when UCP1 is absent. The lesser weight mainly comes from the decrease in subcutaneous white adipose tissue (scWAT). Mitochondria and the thermogenic agent glycerol-3-phosphate dehydrogenase (GPD2) in the scWAT of UCP1-knockout mice are probably the units of the alternative thermogenic pathway that trigger the weight loss. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) might be the mediator of the change of mitochondria in scWAT of UCP1-knockout mice. Several thermogenic agents such as uncoupling protein 2 & 3 and creatine kinase, mitochondrial 2 are found to increase in the BAT of UCP1-knockout mice. The roles of them in the alternative thermogenic pathway are still unknown. This study provides some understanding of the alternative energy dissipation pathway induced by UCP1 deletion in mice and it is an important stepping stone for the future anti-obesity studies.