A futile metabolic cycle activated in adipocytes by antidiabetic agents

Thiazolidinediones (TZDs) are effective therapies for type 2 diabetes, which has reached epidemic proportions in industrialized societies. Peroxisome proliferator-activated receptor γ (PPARγ), an intensively studied nuclear receptor in diabetes for the last decade, is the master regulator of adipogenesis as well as the target of thiazolidinedione (TZD) antidiabetic drugs. TZD treatment reduces circulating free fatty acids, which oppose insulin actions in skeletal muscle and other insulin target tissues. Here we report that TZDs dramatically induce adipocyte glycerol kinase (GyK) gene expression. This is surprising, as standard textbooks indicate that adipocytes lack GyK and thereby avoid futile cycles of triglyceride breakdown and re-synthesis from glycerol and free fatty acids. By inducing GyK, TZDs markedly stimulate glycerol incorporation into TG and reduce free fatty acid (FFA) secretion from adipocytes. The futile fuel cycle resulting from expression of GyK in adipocytes is thus a novel mechanism contributing to reduced free fatty acid levels and perhaps insulin sensitization by antidiabetic agents. In adipocytes, many PPARγ target genes such as aP2 are induced robustly during adipogenesis, others, such as GyK, are expressed at low levels in adipocytes but are dramatically upregulated by TZDs. We have explored the mechanism whereby an exogenous PPARγ ligand is selectively required for adipocyte gene expression. The GyK gene contains a functional PPARγ-response element to which endogenous PPARγ is recruited in adipocytes. However, unlike the classic PPARγ-target gene aP2, which is constitutively associated with coactivators, the GyK gene is targeted by corepressors in adipocytes. TZDs trigger the dismissal of corepressors and histone deacetylase (HDAC) complex and the recruitment of coactivators to the GyK gene. TZDs also induce PPARγ-Coactivator 1α (PGC-1α), whose recruitment to the GyK gene is sufficient to release the corepressors. Thus, selective modulation of adipocyte PPARγ target genes by TZDs involves the dissociation of corepressors by direct and indirect mechanisms