Fibroblast growth factor-21, energy balance and obesity
Introduction
It is generally agreed that the seminal publication by Kharitonenkov and collaborators in The Journal of Clinical Investigation (2005) was the first description of fibroblast growth factor-21 (FGF21) as an endocrine factor relevant for the control of metabolism. These authors reported that FGF21 was a powerful anti-diabetic agent, promoting glucose lowering in rodent models of type 2 diabetes (T2DM) and exerting other relevant beneficial effects on dyslipidemia. Ten years on, extensive studies have confirmed that FGF21 constitutes the central component of an entire endocrine/autocrine system with multi-organ actions and a complex profile of synthesis in distinct cells and tissues. Moreover, the FGF21 endocrine system is emerging as a powerful therapeutic target in the design of novel treatments for diabetes, dyslipidemias and perhaps obesity.
Previous reviews have provided excellent summaries on the current knowledge on the multifaceted roles of FGF21 in physiopathology and metabolism. The current review will focus specifically on the role of FGF21 in energy balance and its involvement in obesity as a pathogenic process that develops as a consequence of energy balance dysregulation.
Section snippets
FGF21 synthesis and action
The fibroblast growth factor (FGF) superfamily comprises 22 secreted polypeptides that were initially described as mitogenic factors (Gospodarowicz et al., 1974). They actually exert a wide range of functions, from the promotion of cell proliferation and differentiation to systemic effects. Most members of the FGF family act as autocrine/paracrine factors; once secreted, they are retained in the surrounding extracellular matrix owing to their high affinity for heparan sulfate. There are also
FGF21 lowers body weight through induction of energy expenditure
The first reports of FGF21's profound beneficial metabolic effects on hyperglycemia and hyperlipidemia also indicated direct body weight-reducing effects of FGF21. FGF21 induces glucose consumption and energy expenditure, improving insulin sensitivity (Coskun et al., 2008). There are direct effects of FGF21 on target cells that may account for promotion of glucose uptake, such as the induction of glucose transporter-1 (GLUT1) expression (Kharitonenkov et al., 2005, Ge et al., 2011).
FGF21: activator of brown adipose tissue and “browning”
Studies on the role of the FGF21 surge that occurs in neonates raised awareness of the BAT activation-based physiological mechanism by which FGF21 promotes energy expenditure. It was found that the initiation of suckling and the sudden availability of milk lipids to the liver activate FGF21 synthesis and release into the circulation. FGF21 targets BAT and thereby contributes to the induction of heat production that is critical for temperature homeostasis in the neonate (Hondares et al., 2010).
Peripheral versus central effects of FGF21 on energy metabolism homeostasis
Despite evidence that FGF21 can directly induce activation and recruitment of brown adipocytes in mice, the known major role of sympathetic nervous system (SNS) activity in controlling BAT activity has led researchers to consider the possibility that FGF21 may act centrally, modulating BAT activity and browning indirectly via central effects.
FGF21 is not expressed in the central nervous system but can cross the blood–brain barrier (Hsuchou et al., 2007) and there are reports of FGF21 in human
Is obesity an FGF21-resistant state?
As mentioned above, rodent models evidenced the paradoxical finding that FGF21 levels are not decreased relative to lean controls, but instead are systematically increased (Coskun et al., 2008, Kharitonenkov et al., 2005, Zhang et al., 2008). On the basis of impaired FGF21-induced gene expression and metabolic effects in high-fat-diet–fed obese mice, and the observation that liver and adipose tissues were the targets of these alterations, Fisher et al. (2010) proposed that obesity is a
FGF21 and human BAT
The extensive evidence for a role for FGF21 in promoting energy expenditure through BAT activation developed in animal models has been translated to human studies. Moreover, research on FGF21 action in recent years has coincided with a re-appraisal of the role of BAT in human physiopathology. Although the existence of BAT in humans has long been known, the recognition that active BAT plays a relevant role in human adults is very recent, first emerging less than a decade ago (Nedergaard et al.,
FGF21 and human obesity
As discussed above, despite the multiple beneficial effects of FGF21 on insulin sensitivity and glucose and lipid homeostasis reported in animal studies, serum FGF21 levels are elevated in obese/diabetic rodent models (Coskun et al., 2008, Kharitonenkov et al., 2005). This paradox has also been reported in human subjects. Circulating FGF21 levels have consistently been found to correlate positively with body mass index (BMI), insulin levels and glycemia (Chavez et al., 2009, Dushay et al., 2010
Conclusions: towards an FGF21-based pharmacotherapy for obesity?
Despite the abnormal elevation of FGF21 levels in obese rodent models and in patients with obesity and T2DM, described above, evidence from preclinical models for multifaceted beneficial effects of experimental treatment with FGF21—from amelioration of hyperglycemia to weight loss—is prompting interest in exploiting these FGF21 properties for the development of new treatments for metabolic diseases. Moreover, the ability of FGF21 to activate BAT makes it an attractive molecule for the design of
Acknowledgments
This work was supported by MINECO (grants SAF2011-23636, SAF2014-55725-R), Instituto de Salud Carlos III (grants PI11-00376, PI14-00063), EU (FP7 project BETABAT, grant HEALTH-F2-2011-277713), and Generalitat de Catalunya (2014SGR-141).
References (115)
- et al.
Thyroid hormone regulates hepatic expression of fibroblast growth factor 21 in a PPARalpha-dependent manner
J. Biol. Chem.
(2010) - et al.
Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states
Cell Metab.
(2007) - et al.
FGF21 mediates the lipid metabolism response to amino acid starvation
J. Lipid Res.
(2013) - et al.
βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism
Cell Metab.
(2012) - et al.
Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease
Gastroenterology
(2010) - et al.
UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality
Cell Metab.
(2009) - et al.
The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes
Cell Metab.
(2013) - et al.
Fibroblast growth factor 21 induces glucose transporter-1 expression through activation of the serum response factor/Ets-like protein-1 in adipocytes
J. Biol. Chem.
(2011) - et al.
Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat
Cell Metab.
(2010) - et al.
Thermogenic activation induces FGF21 expression and release in brown adipose tissue
J. Biol. Chem.
(2011)