The nuclear retinoid-related orphan receptor-α regulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis

Abstract

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...

The nuclear retinoid-related orphan receptor RORα controls circadian thermogenic programming in white fat depots

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Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

“…The ROR family, which includes RORα, β, and γ, activates transcription at ROR response elements through recruitment of co-activators such as PGC-1α 212 and steroid receptor co-activator 2 (SRC2) 213 . Loss of RORα leads to fasting hypoglycemia and decreased expression of gluconeogenic genes in the liver 214 .…”

The hepatic circadian clock fine-tunes the lipogenic response to feeding through RORα/γ

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