Adipose tissue exerts two important functions involved in the regulation of lipid metabolism and insulin sensitivity: 1 ) storage of FFA as triglycerides (TG) into adipocytes and their disposal by lipolysis, and 2 ) secretion of adipokines and cytokines that could promote either insulin sensitivity or resistance in target tissues. Type 2 diabetes has been shown to be associated with disturbances in glucose and lipid metabolism, with modifi cations in systemic levels of adipokines, cytokines, and FFAs, partly as a consequence of adipose tissue dysfunction and infl ammation. In particular, dysregulation of FFA metabolism would be an essential cause of metabolic anomalies because a defect in their storage into adipocytes could lead to their ectopic depot in the liver, muscles, heart, and pancreas, where they play an important role in dyslipidemia, insulin resistance, and altered glucose tolerance ( 1 ). Recently, the antiretroviral drugs given to patients to control human immunodeficiency virus (HIV) infection were recognized as responsible for metabolic alterations and abnormal adipose tissue distribution, together with modifi cations in adipokines, cytokines, and FFAs, and with ectopic depots of lipids in nonfat tissues, arguing for mechanisms common to those reported in diabetes ( 2, 3 ).We recently highlighted, in human adipose tissue, the importance of the metabolic pathway, glyceroneogenesis (GNG), which is able to limit FFA release to blood under physiological fasting situations and which is a new target of thiazolidinedione action ( 4-6 ). FFA re-esterifi cation via GNG was fi rst described by Ballard et al. ( 7 )

Circadian rhythms have an essential role in feeding behavior and metabolism. ROR␣ is a nuclear receptor involved in the interface of the circadian system and metabolism. The adipocyte glyceroneogenesis pathway derives free fatty acids (FFA) liberated by lipolysis to reesterification into triglycerides, thus regulating FFA homeostasis and fat mass. Glyceroneogenesis shares with hepatic gluconeogenesis the key enzyme phosphoenolpyruvate carboxykinase c (PEPCKc), whose gene is a ROR␣ target in the liver. ROR␣-deficient mice (staggerer, ROR sg/sg ) have been shown to exhibit a lean phenotype and fasting hypoglycemia for unsolved reasons. In the present study, we investigated whether adipocyte glyceroneogenesis might also be a target pathway of ROR␣, and we further evaluated the role of ROR␣ in hepatocyte gluconeogenesis. In vivo investigations comparing ROR sg/sg mice with their wild-type (WT) littermates under fasting conditions demonstrated that, in the absence of ROR␣, the release of FFA into the bloodstream was altered and the rise in glycemia in response to pyruvate reduced. The functional analysis of each pathway, performed in adipose tissue or liver explants, confirmed the impairment of adipocyte glyceroneogenesis and liver gluconeogenesis in the ROR sg/sg mice; these reductions of FFA reesterification or glucose production were associated with decreases in PEPCKc mRNA and protein levels. Treatment of explants with ROR␣ agonist or antagonist enhanced or inhibited these pathways, respectively, in tissues isolated from WT but not ROR sg/sg mice. Our results indicated that both adipocyte glyceroneogenesis and hepatocyte gluconeogenesis were regulated by ROR␣. This study demonstrates the physiological function of ROR␣ in regulating both glucose and FFA homeostasis. glyceroneogenesis; phosphoenolpyruvate carboxykinase c; nuclear retinoid-related orphan receptor-␣; adipose tissue RETINOID-RELATED ORPHAN RECEPTORS (RORs) are members of the nuclear receptor family. The ROR family comprises three members: ROR␣ (NR1F1), ROR␤ (NR1F2), and ROR␥ (NR1F3), with ROR␣ being the most abundant isoform present in the adipose tissue (18). RORs regulate gene transcription by binding to specific DNA response elements (RORE) consisting of the consensus RGGTCA core motif. Reciprocally, the nuclear receptor Rev-erb␣ (NR1D1) acts as a transcriptional repressor by competing with RORs for RORE binding and thereby antagonizes ROR action. Indeed, both receptors are often coexpressed in the same tissues (14).ROR␣ and Rev-erb␣ are involved in many pathways implicated in various physiological functions, including immune function, circadian rhythms, and metabolism. They appear to be pivotal players at the interface between the circadian system and metabolism (49). Among the direct target genes of ROR␣ and Rev-erb␣ are several clock genes such as Bmal1, thus ensuring a fine tuning of circadian rhythms, as well as some metabolic genes involved in the control of cholesterol and bile acid metabolism (11, 29) apolipoprotein synthesis (39), lipogene...