The Nuanced Metabolic Functions of Endogenous FGF21 Depend on the Nature of the Stimulus, Tissue Source, and Experimental Model

Abstract

Fibroblast growth factor 21 (FGF21) is a hormone that is involved in the regulation of lipid, glucose, and energy metabolism. Pharmacological FGF21 administration promotes weight loss and improves insulin sensitivity in rodents, non-human primates, and humans. However, pharmacologic effects of FGF21 likely differ from its physiological effects. Endogenous FGF21 is produced by many cell types, including hepatocytes, white and brown adipocytes, skeletal and cardiac myocytes, and pancreatic beta cells, and acts on a diverse array of effector tissues such as the brain, white and brown adipose tissue, heart, and skeletal muscle. Different receptor expression patterns dictate FGF21 function in these target tissues, with the primary effect to coordinate responses to nutritional stress. Moreover, different nutritional stimuli tend to promote FGF21 expression from different tissues; i.e., fasting induces hepatic-derived FGF21, while feeding promotes white adipocyte-derived FGF21. Target tissue effects of FGF21 also depend on its capacity to enter the systemic circulation, which varies widely from known FGF21 tissue sources in response to various stimuli. Due to its association with obesity and non-alcoholic fatty liver disease, the metabolic effects of endogenously produced FGF21 during the pathogenesis of these conditions are not well known. In this review, we will highlight what is known about endogenous tissue-specific FGF21 expression and organ cross-talk that dictate its diverse physiological functions, with particular attention given to FGF21 responses to nutritional stress. The importance of the particular experimental design, cellular and animal models, and nutritional status in deciphering the diverse metabolic functions of endogenous FGF21 cannot be overstated.

Multi-organ FGF21-FGFR1 signaling in metabolic health and disease

“…FGF21 response in organs appears to be influenced by tissue-specific interactions ( 68 ), summarized in Figure 1 . FGF21 stimulates adiponectin secretion from adipocytes, which confers metabolic actions on the other cells/tissue, such as blood vessels ( 69 ).…”

FGF21 regulates alcohol intake: New hopes on the rise for alcohol use disorder treatment?

“… 2 Fibroblast growth factor 21 (FGF21) is a 181 amino acid peptide hormone, primarily released by the liver in response to physiological perturbations, with key functions in the homeostatic control of glucose and lipid metabolism. 3 Both preclinical and clinical studies recently found that alcohol consumption increases endogenous FGF21 levels. 4 , 5 Albeit preliminary, these findings suggest that elevated FGF21 following alcohol use may lead to reduced alcohol intake, potentially through acting on the co-receptor β-klotho (encoded by the KLB gene) expressed in the brain.…”

“…While the present study provided important mechanistic information, more research is needed to understand the bidirectional relationship between FGF21 and alcohol ( Figure 1 ). Previous studies found that acute and chronic alcohol consumption in rodents 3 and humans 4 induce hepatic FGF21 and may be dependent on the carbohydrate response element-binding protein (ChREBP) and/or the peroxisome proliferator-activated receptor (PPARα). 3 While ChREBP and PPARα mediate hepatic FGF21 production under fasting conditions, whether alcohol triggers these specific pathways remains unknown.…”

“…Previous studies found that acute and chronic alcohol consumption in rodents 3 and humans 4 induce hepatic FGF21 and may be dependent on the carbohydrate response element-binding protein (ChREBP) and/or the peroxisome proliferator-activated receptor (PPARα). 3 While ChREBP and PPARα mediate hepatic FGF21 production under fasting conditions, whether alcohol triggers these specific pathways remains unknown. Future studies should further investigate cellular mechanisms involved in the interplay between FGF21 and alcohol.…”

“…Future studies should further investigate cellular mechanisms involved in the interplay between FGF21 and alcohol. Hepatocytes secrete FGF21 in response to endoplasmic reticulum stress and oxidative stress 3 and alcohol induces these forms of cellular stress, 8 suggesting that FGF21 may be released as a protective mechanism to safeguard the damaged liver and as a signal to the brain to consume less alcohol. Altogether, the bidirectional relationship between FGF21 and alcohol consumption appears to play an important role in pushing a return from physiological stress toward homeostasis.…”