REV-ERBα Agonist SR9009 Promotes a Negative Energy Balance in Goldfish.

Nuria Saiz,Esther Isorna,María Jesús Delgado,Marta Conde-Sieira,Nuria De Pedro,José Luis Soengas,Lisbeth Herrera-Castillo

doi:10.3390/ijms23062921

Nuria Saiz, Esther Isorna + Show 5 more

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https://doi.org/10.3390/ijms23062921

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Abstract

REV-ERBα (nr1d1, nuclear receptor subfamily 1 group D member 1) is a transcriptional repressor that in mammals regulates nutrient metabolism, and has effects on energy homeostasis, although its role in teleosts is poorly understood. To determine REV-ERBα’s involvement in fish energy balance and metabolism, we studied the effects of acute and 7-day administration of its agonist SR9009 on food intake, weight and length gain, locomotor activity, feeding regulators, plasma and hepatic metabolites, and liver enzymatic activity. SR9009 inhibited feeding, lowering body weight and length gain. In addition, the abundance of ghrelin mRNA decreased in the intestine, and abundance of leptin-aI mRNA increased in the liver. Hypocretin, neuropeptide y (npy), and proopiomelanocortin (pomc) mRNA abundance was not modified after acute or subchronic SR9009 administration, while hypothalamic cocaine- and amphetamine-regulated transcript (cartpt-I) was induced in the subchronic treatment, being a possible mediator of the anorectic effects. Moreover, SR9009 decreased plasma glucose, coinciding with increased glycolysis and a decreased gluconeogenesis in the liver. Decreased triglyceride levels and activity of lipogenic enzymes suggest a lipogenesis reduction by SR9009. Energy expenditure by locomotor activity was not significantly affected by SR9009. Overall, this study shows for the first time in fish the effects of REV-ERBα activation via SR9009, promoting a negative energy balance by reducing energetic inputs and regulating lipid and glucose metabolism.

Highlights

REV-ERBα is a nuclear receptor belonging to the REV-ERB family, which comprisesREV-ERBα and REV-ERBβ [1]
Carbohydrate metabolism in mammals is regulated by this nuclear receptor, since a chronic treatment with the agonist SR9009 induces the expression of the glycolytic enzymes hexokinase (HK) and pyruvate kinase (PK) in muscle, together with a reduction in plasma glucose levels [24]
REV-ERBα suppresses gluconeogenesis by repressing the expression of enzymes phosphoenolpyruvate carboxykinase (PECPK), glucose 6-phosphatase (G6Pase), and fructose 1,6-biphosphatase (FBPase) in the liver, reducing glucose production [7,26]

Summary

Introduction

REV-ERBα is a nuclear receptor belonging to the REV-ERB family, which comprisesREV-ERBα and REV-ERBβ [1]. REV-ERBα can bind to two adjacent ROREs and recruit the corepressors NCOR1 (nuclear receptor co-repressor 1) and HDAC3 (histone deacetylase 3) to repress transcription [3–5]. Apart from this direct regulation, REV-ERBα regulates indirectly gene transcription by interacting with other transcription factors [3]. REV-ERBα influences carbohydrate metabolism [11–14], adipogenesis and thermoregulation [1,8,15,16], lipid metabolism [11,12,17,18], cholesterol and bile acid metabolism [19], myogenesis [20], oxidative functions [21], and behavior [22,23], among other processes [1]. This is probably because most REV-ERBα targets are involved in the metabolism of lipids and lipoproteins, highlighting the importance of this receptor in this metabolic function [11]. REV-ERBα suppresses gluconeogenesis by repressing the expression of enzymes phosphoenolpyruvate carboxykinase (PECPK), glucose 6-phosphatase (G6Pase), and fructose 1,6-biphosphatase (FBPase) in the liver, reducing glucose production [7,26]

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