The regulation of FGF21 gene expression by metabolic factors and nutrients

Abstract

Fibroblast growth factor 21 (FGF21) gene expression is altered by a wide array of physiological, metabolic, and environmental factors. Among dietary factors, high dextrose, low protein, methionine restriction, short-chain fatty acids (butyric acid and lipoic acid), and all-trans-retinoic acid were repeatedly shown to induce FGF21 expression and circulating levels. These effects are usually more pronounced in liver or isolated hepatocytes than in adipose tissue or isolated fat cells. Although peroxisome proliferator-activated receptor α (PPARα) is a key mediator of hepatic FGF21 expression and function, including the regulation of gluconeogenesis, ketogenesis, torpor, and growth inhibition, there is increasing evidence of PPARα-independent transactivation of the FGF21 gene by dietary molecules. FGF21 expression is believed to follow the circadian rhythm and be placed under the control of first order clock-controlled transcription factors, retinoic acid receptor-related orphan receptors (RORs) and nuclear receptors subfamily 1 group D (REV-ERBs), with FGF21 rhythm being anti-phase to REV-ERBs. Key metabolic hormones such as glucagon, insulin, and thyroid hormone have presumed or clearly demonstrated roles in regulating FGF21 transcription and secretion. The control of the FGF21 gene by glucagon and insulin appears more complex than first anticipated. Some discrepancies are noted and will need continued studies. The complexity in assessing the significance of FGF21 gene expression resides in the difficulty to ascertain (i) when transcription results in local or systemic increase of FGF21 protein; (ii) if FGF21 is among the first or second order genes upregulated by physiological, metabolic, and environmental stimuli, or merely an epiphenomenon; and (iii) whether FGF21 may have some adverse effects alongside beneficial outcomes.

In vivo protective effect of adipsin-deficiency on spontaneous knee osteoarthritis in aging mice

“…Although a relationship between the expression of adipsin and FGF-21 has been reported [62], the regulatory factors at play still remain to be determined. FGF-21 is known to be regulated by a number of metabolic factors, nutrients, and oxidative stress [58,63,64], and involved in the regulation of glucose and lipid metabolism [65][66][67][68]. This could suggest that the lack of adipsin impacted these metabolic factors.…”

Regulation of Ketone Body Metabolism and the Role of PPARα

“…The chief player in this process is fibroblast growth factor 21 (FGF21). The studies on mice revealed that FGF21 is mainly produced in the liver and its expression is strongly upregulated by PPARα [44,45], but additional PPARα -independent transactivation mechanisms also exist, and involve retinoid orphan receptors (RORs) [46]. FGF21 activates hepatic lipolysis and ketogenesis in hepatocytes, and in various mammalian species is the chief endocrine factor driving metabolic reprogramming during torpor, which includes inhibition of cell growth in size and cell proliferation to preserve energy reserves [47].…”

Circulating FGF21 Levels in Human Health and Metabolic Disease

“…FGF21 has also been detected in human cerebrospinal fluid, indicating that circulating FGF21 may enter the brain to act on the central nervous system [19]. Recent reviews have summarized the production and secretion sites of FGF21 [20,21], the expression of its receptor components as well as FGF21 signaling pathway [22,23], and the metabolic [20,24] and pharmacological [25,26] effects FGF21 in mice and men. Thus, in this review we will focus on FGF21 levels in the blood of healthy, obese and metabolically unhealthy individuals to provide an overview on the concentration levels in human blood.…”