The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

Abstract

FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erb␣, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erb␣ for Rev-erb␣-binding sites identified ␤Klotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erb␣ in white adipose tissue but not liver. Rev-erb␣ ablation led to the robust elevated expression of ␤Klotho. Consequently, the effects of FGF21 were markedly enhanced in the white adipose tissue of mice lacking Reverb␣. A major Rev-erb␣-controlled enhancer at the Klb locus was also bound by the adipocytic transcription factor peroxisome proliferator-activated receptor (PPAR) ␥, which regulates its activity in the opposite direction. These findings establish Rev-erb␣ as a specific modulator of FGF21 signaling in adipose tissue.Adipose tissue is an important fat storage and endocrine organ whose dysfunction is closely associated with the development of obesity, diabetes mellitus, and cardiovascular disease (1-5). Nuclear receptors are DNA-binding proteins that directly regulate gene expression in response to ligands derived from endocrine glands, metabolism, diet, and the environment (6). They are widely believed to act as key regulators in various physiological processes, such as circadian rhythm, development, reproduction, energy homeostasis, and metabolism (7,8).The nuclear receptor Rev-erb␣ differs from other members of the nuclear receptor superfamily because it lacks a classical activation domain and thus functions as a constitutive repressor of transcription (9 -11). Acting in this repressive manner, Rev-erb␣ has been described as a core component of the mammalian biological clock (12) that links circadian rhythms to metabolism in diverse tissues. Indeed, studies from different groups have revealed Rev-erb␣ as a key regulator of multiple biological processes in various metabolic tissues, including liver (13-15), macrophages (16), muscle (17), brown fat (18), and brain (19). However, little is known about potential role in white adipose tissue (WAT). 3FGF21 is an atypical member of the FGF superfamily that, because of a lack of a heparin binding domain, is able to escape into the circulation, functioning as a hormone to regulate carbohydrate and lipid metabolism (20,21). In the metabolic context, FGF21 was first discovered to induce glucose uptake in 3T3L1 adipocytes (22). Subsequently it was demonstrated that FGF21 administration to obese rodents and non-human primates improves hyperglycemia, lowers elevated triglyceride levels, and reduces body weight (22)(23)(24)(25). In rodents, the mechanisms underlying FGF21 actions include improving whole-body insulin sensitivity and ␤ cell function, reducing hepatic lipogenesis, and enhancing brown fat thermogenic activity (22,23,(25)(26)(27). These effects identify FGF21 as an attractive therapeutic agent f...

REV-ERBα regulates Fgf21 expression in the liver via hepatic nuclear factor 6

“…S1 " type="url"/> ). This concept is also consistent with the observation that REV-ERBα can regulate FGF21 signaling in an adipose tissue-specific manner by directly regulating βKlotho, an essential co-receptor for FGF21 signaling ( Jager et al, 2016 ).…”

Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation

“…Conditional deletion of BMAL1 is widely used in experimental models, as this is the only core molecular element driving circadian cycles in which suppression of function leads to abolition of rhythmic transcriptional oscillations in the cell. In order to identify specific circadian-regulated proteins that directly couple to the regulation of immunity, we focused on the circadian REV-ERB transcription factors, which have been previously been identified as strong candidates for the regulation of diverse physiological functions, including rhythmic regulation of hepatic metabolism and adipose tissue ( 14 , 18 ). To identify the role of REV-ERBα in circadian control of lung inflammation, we first raised a monoclonal antibody that specifically detects REV-ERBα but not its paralog REV-ERBβ ( Supplemental Figure 1 ; supplemental material available online with this article; https://doi.org/10.1172/JCI93910DS1 ).…”

Integrated stress response stimulates FGF21 expression: Systemic enhancer of longevity

“…circadian regulator, are important repressors of β-klotho gene expression [64,103,104]. There is compelling evidence indicating that the liver coordinates global metabolism, both at rest and in times of stress, through multiorgan crosstalk by secreting FGF21 as well as some other hepatokines [105].…”