CALL FOR PAPERS Novel Aspects of Adipocyte Biology The nuclear retinoid-related orphan receptor- regulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis

Kadiri S, Monnier C, Ganbold M, Ledent T, Capeau J, Antoine B. The nuclear retinoid-related orphan receptorregulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis. Am J Physiol Endocrinol Metab 309: E105–E114, 2015. First published May 26, 2015; doi:10.1152/ajpendo.00518.2014.—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) 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 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 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 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.