Trends in Endocrinology & Metabolism
ReviewFGF21-based pharmacotherapy – potential utility for metabolic disorders
Section snippets
Discovery and characterization of FGF21 as a metabolic regulator
FGF21 was identified as a potential metabolic factor in a screen for proteins that induce glucose uptake in adipocytes [1]. Subsequent in vivo evaluation of recombinant FGF21 uncovered a wide variety of metabolic effects. In mouse models of diabetes and obesity, FGF21 administration lowers glucose and improves insulin sensitivity, decreases body weight, and lowers serum triglyceride and cholesterol as well as hepatic triglyceride levels 1, 2, 3, 4, 5, 6. The effects of FGF21 on glucose are
FGF21 receptors and FGF21-induced signaling
The metabolic effects of FGF21 observed in animal models prompted efforts to characterize its receptor complex and downstream signaling pathways. It is now clear that FGF21 requires the cofactor β-Klotho (KLB) for signaling both in vitro 9, 10 and in vivo 11, 12. The C-terminus of FGF21 binds with high affinity to KLB [13], which is present in a complex with FGF receptors (FGFRs) on the surface of cells [10] (Figure 1). Binding of FGF21 to KLB enables its interaction with the FGFR, thus
Gene expression in mice
The metabolic effects of exogenously administered FGF21 and its potential target tissues are summarized in Figure 2. initial clues to target tissues and more specific in vivo mechanisms were evident from gene expression changes following FGF21 administration. Within 2 h of FGF21 injection, the glucose transporter GLUT1 is upregulated in white adipose tissue 1, 20, and several target genes in the liver are induced within 1–4 h 18, 23. Three days of FGF21 treatment induces a prominent thermogenic
Physiological functions of endogenous FGF21
Pharmacological or overexpression studies achieve circulating levels of FGF21 which significantly exceed endogenous levels. A crucial issue to be addressed concerns the physiologic role of endogenous FGF21. FGF21 is primarily expressed in pancreas, liver and adipose tissue [34]; it is still unclear to what extent these tissues contribute to the circulating levels of FGF21. Another important question is the relative importance of FGF21 as an autocrine/paracrine versus endocrine factor. Different
Are there connections to human disease?
As described above, the discovery and characterization of FGF21 as a potential metabolic regulator was based largely on studies conducted in preclinical model systems. To date, no clear genetic associations between known components of the FGF21 pathway and inherited human disorders (including polygenic forms of T2D) have been reported. Although the potential role(s) of FGF21 biology in human disease are not well characterized, some important clues – based largely on measurements of circulating
FGF21-based therapeutics – potential approaches
Significant effort is being expended to identify therapeutic agents that mimic the potential beneficial effects of native FGF21, while addressing its shortcomings, namely poor biophysical properties and a short half-life in vivo (Table 2). An analog, LY2405319, was designed to achieve improved biophysical properties along with biological effects that are indistinguishable from native FGF21 in vitro. LY2405319 shows glucose-, bodyweight-, and lipid-lowering activity in diabetic rodent or monkey
Initial human proof-of-concept
The pharmacologic effects of exogenous FGF21 in humans have only recently begun to be explored. We recently tested the clinical effects of LY2405319, an analog of human FGF21. Initial Phase I studies indicated that subcutaneous injections of LY2405319 were well tolerated across a broad dose range (0.6–30 mg) and produced systemic drug levels that were in the range achieved in preclinical animal models [68]. A subsequent 28 day Phase IB study was conducted in obese subjects with T2D [76].
Potential concerns
Safety is paramount in the development of new agents for metabolic disorders. Although our clinical study with LY2405319 did not identify obvious safety concerns (apart from immune-mediated effects of the molecule), ongoing investigation of the biological functions of FGF21 in rodents has identified areas of concern that need to be taken into consideration. Mitogenicity represents a theoretical concern. However, unlike canonical FGFs, FGF21 does not induce cell proliferation in vitro [1], and
Concluding remarks and future perspectives
Despite recent advances in healthcare delivery for patients with metabolic disease, many patients remain at risk of developing debilitating cardiovascular (CV) and microvascular complications. A compelling need for better therapies is evident, and disease-modifying approaches that could directly address aspects of underlying pathophysiology are particularly desirable. These might include new agents with insulin-sensitizing activity along with mechanisms that can potentiate lipid oxidation and
Acknowledgments
We would like to thank Craig Dickinson for modeling the FGF21 signaling complex and Andrew Adams and Alexei Kharitonenkov for critical reading of this manuscript.
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