| Nuclear receptors are a large class of ligand-activated transcription factors that regulate a diverse array of biological functions encompassing development, metabolism, and homeostasis. Peroxisome proliferator activated receptor γ (PPARγ) is a nuclear receptor that has previously been shown to play prominent roles in the control of adipocyte differentiation and systemic insulin signaling. A subtractive hybridization screen to identify the biologically relevant target genes of PPARγ yielded a novel gene encoding the protein PGAR (for PPARγ angiopoietin related), that belongs to the angiopoietin family of secreted proteins. The PGAR gene is rapidly induced within hours by PPARγ ligands in the absence of protein synthesis. The expression of PGAR is dramatically increased early in adipocyte differentiation and is predominantly localized to adipose tissues in vivo. Genetic models of obesity and leptin treatment are associated with alterations in PGAR expression. Moreover, PGAR mRNA levels in vivo are increased on an acute basis by dietary deprivation, suggesting a possible function as a component of a blood-borne homeostatic mechanism. These results define PGAR as a novel candidate regulator of systemic lipid and glucose metabolism.; Nuclear receptors interact with a group of proteins known as coactivators and corepressors that serve to potentiate or inhibit their transcriptional activity. PPARγ coactivator-1 (PGC-1) is a nuclear coactivator that can interact with a wide range of transcription factors, including PPARγ, and has previously been noted for its tissue-selective distribution, cold inducibility, and regulation of a specific physiological process, namely cellular respiration and adaptive thermogenesis. While the study of PGC-1 has thus far focused primarily on the thermogenic tissues, it is also present at substantial levels in several non-thermogenic tissues where it may be subject to regulation by physiological stimuli. It is now demonstrated that PGC-1 gene expression is increased in liver in vivo during a fast, a physiological state associated with enhanced hepatic glucose output resulting from a fall in insulin and a rise in counter-regulatory hormones. In agreement with the known liver physiology, PGC-1 is induced in cultured hepatocytes by CAMP and glucocorticoids acting synergistically. The endogenous PGC-1 expression in the liver is increased in animal models of insulin deficiency. Ectopic expression of PGC1 in hepatocytes strongly activates a program of key gluconeogenic enzymes, including PEPCK and glucose-6-phosphatase, leading to increased glucose output. The transcriptional activation of the PEPCK promoter requires PGC-1 binding to and coactivating the liver-enriched transcription factor HNF-4. Taken together, these results implicate PGC-1 as a key hormone-regulated modulator of hepatic gluconeogenesis. |
