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Abstract Objectives The nuclear receptor superfamily is a potential target for the development of new treatments for obesity and metabolic diseases. Increasing evidence has pointed towards the retinoic acid-related orphan receptor-alpha (RORα) as an important nuclear receptor involved in several biological processes. RORα full body knockout mice display improved metabolic phenotypes on both chow and high fat (60% fat, 20% carbohydrate) diets, but also have severe behavioral abnormalities. Here we investigated the effect of hepatic RORα by generating mice with liver-specific RORα deletion to elucidate the role of this nuclear receptor on host metabolism. Methods 8 week-old mice with liver-specific RORα deletion and littermate controls were fed either chow or western-style diets (40% fat, 40% carbohydrate) for 12 weeks. Metabolic phenotyping was performed at the end of the dietary intervention. Results Here, we show that hepatic RORα deletion does not affect the metabolic susceptibility to either chow or western-style diet in terms of glucose metabolism and adiposity. Conclusions Our data indicate that liver deletion of RORα does not have a pivotal role in the regulation of hepatic glucose and lipid metabolism on chow or western-style diet. Highlights • Hepatic deletion of RORα does not affect host metabolism on chow diet. • Hepatic deletion of RORα does not affect host metabolism on western-style diet. • Similar phenotypes between male and female mice. [ABSTRACT FROM AUTHOR]

Summary The mammalian circadian system consists of a master clock in the brain that synchronizes subsidiary oscillators in peripheral tissues. The master clock maintains phase coherence in peripheral cells through systemic cues such as feeding-fasting and temperature cycles. Here, we examined the role of oxygen as a resetting cue for circadian clocks. We continuously measured oxygen levels in living animals and detected daily rhythms in tissue oxygenation. Oxygen cycles, within the physiological range, were sufficient to synchronize cellular clocks in a HIF1α-dependent manner. Furthermore, several clock genes responded to changes in oxygen levels through HIF1α. Finally, we found that a moderate reduction in oxygen levels for a short period accelerates the adaptation of wild-type but not of HIF1α-deficient mice to the new time in a jet lag protocol. We conclude that oxygen, via HIF1α activation, is a resetting cue for circadian clocks and propose oxygen modulation as therapy for jet lag. [ABSTRACT FROM AUTHOR]

Proanthocyanidins (PAs), a flavonoid sub-class, alter the expression of clock genes in the liver of lean and obese rats. The present study aimed to determine whether PAs could modulate the 24-hour rhythmicity of clock gene expression and to identify the molecular mechanism through which PAs could adjust the clock system in HepG2 cells. The 24-hour rhythmicity of core clock ( CLOCK and BMAL1 ) and clock-controlled ( CRY, PER2, RORα, REV-ERBα ) gene expression indicated that a grape seed proanthocyanidin extract (GSPE) shifted the acrophase of nearly all of them, but BMAL1 appeared as the most sensitive gene to GSPE. Specifically, GSPE increased BMAL1 expression strongly and very quickly. This effect was also reproduced by melatonin. The overexpression of BMAL1 was melatonin receptor 1 (MT1) dependent for melatonin but MT1 independent for GSPE. However, GSPE increased the transcriptional activity of RORα, suggesting that this nuclear receptor could be responsible for the modulation of BMAL1 by GSPE. [ABSTRACT FROM AUTHOR]