FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases

Abstract

Abstract:Fibroblast growth factor 21 (FGF21) analogs and FGF21 receptor agonists (FGF21RAs) that mimic FGF21 ligand activity constitute the new "FGF21-class" of anti-obesity and anti-diabetic molecules that improve insulin sensitivity, ameliorate hepatosteatosis and promote weight loss. The metabolic actions of FGF21-class proteins in obese mice are attributed to stimulation of brown fat thermogenesis and increased secretion of adiponectin. The therapeutic utility of this class of molecules is being actively investigated in clinical trials for the treatment of type 2 diabetes and non-alcoholic steatohepatitis (NASH). This review is focused on various FGF21-class molecules, their molecular designs and the preclinical and clinical activities. These molecules include modified FGF21 as well as agonistic antibodies against the receptor for FGF21, namely the complex of FGF receptor 1 (FGFR1) and the obligatory coreceptor βKlotho (KLB). In addition, a novel approach to increase endogenous FGF21 activity by inhibiting the FGF21-degrading protease fibroblast activation protein (FAP) is discussed.

Adipocyte epigenetic alterations and potential therapeutic targets in transgenerationally inherited lean and obese phenotypes following ancestral exposures

“…The NCOA1 gene in adipocytes has also been shown to be associated with metabolic disease [87][88][89]. The KSR2 gene [60,90,91] and FGF21 [92][93][94] are also integrated genes in the network associated with obesity, Figure 7 and S3. Therefore, a number of the genes and pathways identified in Figure 7 and S3 provide potential therapeutic targets for adipocytes associated with obesity and metabolic disease.…”

Preemptive Activation of the Integrated Stress Response Protects Mice From Diet‐Induced Obesity and Insulin Resistance by Fibroblast Growth Factor 21 Induction

“…FGF21 is a hepatokine that has multiple metabolic activities, including improvement of obesity, hyperglycemia, dyslipidemia, and HS . Accordingly, FGF21 signaling has received significant attention as a therapeutic target for antiobesity and antidiabetes drugs . Various approaches have been utilized to develop FGF21‐based therapeutic molecules, including long‐acting FGF21 analogs and agonist antibodies for FGF21 receptor complex .…”

“…(37)(38)(39) Accordingly, FGF21 signaling has received significant attention as a therapeutic target for antiobesity and antidiabetes drugs. (40,41) Various approaches have been utilized to develop FGF21-based therapeutic molecules, including long-acting FGF21 analogs and agonist antibodies for FGF21 receptor complex. (40,41) Targeting ISR represents a strategy to increase endogenous FGF21 expression.…”

“…(40,41) Various approaches have been utilized to develop FGF21-based therapeutic molecules, including long-acting FGF21 analogs and agonist antibodies for FGF21 receptor complex. (40,41) Targeting ISR represents a strategy to increase endogenous FGF21 expression. It is notable that plasma FGF21 level in CReP LKO mice is comparable to fasting-induced FGF21 level in WT mice, which might be beneficial in minimizing potential side effects of using supraphysiological doses of FGF21 mimetics.…”

CNS-targeting pharmacological interventions for the metabolic syndrome

“…It mediates its weight-lowering effect mainly by acting on the CNS as a satiety signal to reduce food intake and by increasing energy expenditure and thermogenesis (132). Accordingly, it was hypothesized that glucagon would increase the weight-lowering effect of GLP-1, while the insulino- (159). A single dose of FGF1 injected into the hypothalamus was further shown to induce a sustained and full remission of diabetic hyperglycemia in rodents (160,161), which highlights the potential of FGF-based drugs in the fight against the MetS.…”