Rev‐erbα modulates the hypothalamic orexinergic system to influence pleasurable feeding behaviour in mice

Abstract

The drive to eat is regulated by two compensatory brain pathways termed as homeostatic and hedonic. Hypothalamic orexinergic (ORX) neurons regulate metabolism, feeding and reward, thus controlling physiological and hedonic appetite. Circadian regulation of feeding, metabolism and rhythmic activity of ORX cells are driven by the brain suprachiasmatic clock. How the circadian clock impacts on ORX signalling and feeding-reward rhythms is, however, unknown. Here we used mice lacking the nuclear receptor REV-ERBα, a transcription repressor and a key component of the molecular clockwork, to study food-reward behaviour. Rev-Erbα mutant mice showed highly motivated behaviours to obtain palatable food, an increase in the intake and preference for tasty diets, and in the expression of the ORX protein in the hypothalamus. Palatable food intake was inhibited in animals treated with the ORX1R antagonist. Analyzing the Orx promoter, we found Retinoic acid-related Orphan receptor Response Element binding sites for Rev-Erbα. Furthermore, Rev-Erbα dampened the activation of Orx in vitro and in vivo. Our data provide evidence for a possible repressive role of Rev-Erbα in the regulation of ORX signalling, highlighting an implication of the circadian clockwork in modulating food-reward behaviours with an important impact for the central regulation of overeating.

Interplay between the endocrine and circadian systems in fishes

“…Moreover, in situ hybridisation studies in this teleost have revealed that some of the brain regions that exhibit day/night differences in per1b expression (Sánchez-Bretaño et al 2015c) also possess orexin receptors (Facciolo et al 2012). In this sense, recent data in mammals have suggested that the REV-ERBs may be involved in the repression of orexinergic gene expression (Feillet et al 2015, Amador et al 2016. However, to date,…”

Central regulation of food intake in fish: an evolutionary perspective

“…Recent studies (Delezie et al 2016) show that Rev-Erbα, a nuclear receptor expressed rhythmically in the SCN and peripheral clocks, involved in the regulation of glucose and lipid metabolism (Everett & Lazar 2014), is required for neural network-based prediction of food availability. Moreover, Rev-Erbα seems to modulate hypothalamic orexinergic system to influence food reward behaviour in mice (Feillet et al 2017), highlighting the molecular link among circadian rhythms, metabolism and feeding behaviour. Some hormones that participate as internal synchronizers may also provide signals to inform central oscillators about the timing of food intake.…”

Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice

“…Our understanding of the physiological functions of REV-ERBs has mainly been derived from phenotypic and molecular analysis of mice lacking REV-ERBa in all tissues as REV-ERBb appears to be less important but provides redundancy for metabolic and behavioral rhythms 10,11 . REV-ERBa whole body knockout mice exhibit metabolic disorders including abnormal blood glucose level, increased adiposity, steatosis and increased thermogenic capacity 10,12,13 , as well as circadian behavioral changes such as reduction in locomotor activity period 14 , alteration of sleep homeostasis 15 , mood disorders 16,17 and altered feeding behaviors 18,19 .…”