Liver-specific RORα deletion does not affect the metabolic susceptibility to western style diet feeding

Antonio Molinaro, Robert Caesar, Laurent L'homme, Ara Koh, Marcus Ståhlman, Bart Staels, Fredrik Bäckhed

The incidence of obesity and associated metabolic disorders increase worldwide. Accumulating evidence points towards nuclear receptor (NR) transcription factors as potential treatment targets. The retinoic acid-related orphan receptor α (RORα) is a NR that has been implicated in the regulation of a wide variety of metabolic pathways. Molinaro et al. generated a liver-specific RORα deficient mouse strain that was metabolically phenotyped on both chow and western-style diet (WSD). Their data show that the deletion of RORα in the liver does not affect glucose or lipid metabolism during WSD in mice. Further studies testing the role of liver RORα or the double RORα and RORγ deletion in different dietary settings are needed to further elucidate the role of RORα in obesity and metabolic disorders.

Objective: 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.