Acquirement of brown fat cell features by human white adipocytes

Obesity, i.e. an excess of white adipose tissue (WAT), predisposes to the development of type 2 diabetes and cardiovascular disease. Brown adipose tissue is present in rodents but not in adult humans. It expresses uncoupling protein 1 (UCP1) that allows dissipation of energy as heat. Peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgamma coactivator 1alpha (PGC-1alpha) activate mouse UCP1 gene transcription. We show here that human PGC-1alpha induced the activation of the human UCP1 promoter by PPARgamma. Adenovirus-mediated expression of human PGC-1alpha increased the expression of UCP1, respiratory chain proteins, and fatty acid oxidation enzymes in human subcutaneous white adipocytes. Changes in the expression of other genes were also consistent with brown adipocyte mRNA expression profile. PGC-1alpha increased the palmitate oxidation rate by fat cells. Human white adipocytes can therefore acquire typical features of brown fat cells. The PPARgamma agonist rosiglitazone potentiated the effect of PGC-1alpha on UCP1 expression and fatty acid oxidation. Hence, PGC-1alpha is able to direct human WAT PPARgamma toward a transcriptional program linked to energy dissipation. However, the response of typical white adipocyte targets to rosiglitazone treatment was not altered by PGC-1alpha. UCP1 mRNA induction was shown in vivo by injection of the PGC-1alpha adenovirus in mouse white fat. Alteration of energy balance through an increased utilization of fat in WAT may be a conceivable strategy for the treatment of obesity.