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Organ Cross-Talk Regulates (Brain) Insulin Action
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
The function and induction of FGF21 are complex. After the discovery of the Fgf21 gene in 2000 (76), FGF21 was proposed to be a potential anti-diabetic drug due to its positive regulation of glucose uptake in adipocytes (67). Over the following years, FGF21 has been widely considered a fasting-induced hormone with the peroxisome proliferator-activated receptor-alpha (PPARα), which becomes activated by fatty acids (89), as the underlying mechanism. Discovered by multiple groups, FGF21 mediates the adaptive fasting response to induce lipolysis, lipid β-oxidation, ketogenesis, and gluconeogenesis in animal models (70, 71, 90). Consistent with observations in rodents, in humans, circulating levels of FGF21 are also induced during seven days of fasting (91, 92). However, in Fgf21-KO mice, no impaired response to fasting could be observed, suggesting that FGF21 is not necessary for the physiological response to caloric restriction (93).
Adipose Tissue (Adipokinome), Skeletal Muscle (Myokinome), and Liver (Hepatokinome) as Endocrine Regulators During Exercise
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Logan K. Townsend, Greg L. McKie, Hesham Shamshoum, David C. Wright
FGF21 is predominantly expressed in the liver, but is also present in white and brown adipose tissue, skeletal muscle, and the pancreas to lesser extents (97). Despite expression in other tissues, most, if not all, circulating FGF21 is from the liver (82), whereas FGF21 in other tissues most likely works in a paracrine/autocrine manner (26, 50). In both rodents and humans, circulating FGF21 is increased by acute exercise (41). In humans, moderate-to-intense aerobic exercise leads to transient increases in circulating FGF21 (41, 42, 120), and this has been shown to be derived from the liver and not contracting skeletal muscle (41). There has been little research on the effects of chronic aerobic exercise training on FGF21 or how FGF21 contributes to chronic training adaptations, and the results so far are conflicting; some studies show that chronic aerobic exercise training reduces circulating FGF21 in overweight and elderly people, whereas others show no effect or that daily physical activity is associated with increased circulating FGF21 (20).
Fibroblast growth factor (FGF)-21 based therapies: A magic bullet for nonalcoholic fatty liver disease (NAFLD)?
Published in Expert Opinion on Investigational Drugs, 2020
Michael Ritchie, Ibrahim A. Hanouneh, Mazen Noureddin, Timothy Rolph, Naim Alkhouri
While the KLB and FGFR bestow tissue-specific targeting of the FGF21 molecule, the intracellular pathway induced by the activation of the FGFR varies depending on tissue type [22]. Consequently in adipocytes, activation of the FGFR1c triggers a MAPK/ERK pathway that increases insulin sensitivity through increased adiponectin transcription [22]. Interestingly in vivo mice studies have shown increased insulin sensitivity but on a time scale that implies post-translational effect rather than transcriptional regulation which implies multiple mechanisms toward one goal of increased insulin sensitivity and glucose uptake [23]. In hepatocytes, the FGFR/KLB/FGF21 complex triggers a phosphoinositol3 Kinase (PI3K), mTOR, and IGF-1 signaling that effectively decreases lipid production and inhibits growth hormone effect on the liver [24,25]. Given the pleiotropic effects on lipid and glucose metabolism and the tissue specificity, FGF21 represents an appealing therapeutic target for not just fatty liver disease but the underlying metabolic syndrome.
Pegbelfermin (BMS-986036): an investigational PEGylated fibroblast growth factor 21 analogue for the treatment of nonalcoholic steatohepatitis
Published in Expert Opinion on Investigational Drugs, 2020
Cristy R.C. Verzijl, Ivo P. Van De Peppel, Dicky Struik, Johan W. Jonker
FGF21 is another member of the FGF-family and exerts its biological effects by binding to FGF receptors (FGFRs) in complex with the transmembrane protein β Klotho (KLB), resulting in the activation of various canonical signaling pathways such as mitogen-activated protein kinase (MAPK) and phosphoinositide-3-kinase–protein kinase B/AKT (PI3K-PKB/AKT) [28]. FGF21 is primarily produced by the liver in response to metabolic stress, such as fasting or a ketogenic diet [29]. In mice, the induction of Fgf21 is associated with changes in lipolysis, ketogenesis, growth, torpor, and female reproduction, all responses related to the adaptive starvation response [29]. Whether FGF21 regulates similar functions in humans is still unclear. However, the identification of an FGF21 gene variant that is associated with increased sugar intake suggests that it has a role in the central regulation of carbohydrate consumption [30]. Association studies have provided additional evidence that FGF21 might play a role in metabolic regulation in humans as well. Increased plasma levels of FGF21 are associated with various obesity-related diseases, including T2D, coronary heart disease, and NAFLD/NASH [31,32]. Although it has been speculated that chronically elevated FGF21 levels reflect a state of FGF21 resistance, pharmacologic FGF21 administration has been shown to improve metabolic health in mice, non-human primates, and humans [33].
Obesity medications in development
Published in Expert Opinion on Investigational Drugs, 2020
Candida J. Rebello, Frank L. Greenway
PF-05231023 is a long-acting FGF21 analog consisting of two molecules linked to a humanized immunoglobulin 1 monoclonal antibody backbone. In overweight or obese subjects with type 2 diabetes, PF-05231023 therapy at 100 mg and 140 mg doses intravenously administered twice weekly significantly reduced body weight over 4 weeks compared to the placebo. There was no change in glycemic control and significant changes in markers of bone turnover [52]. However, intravenous administration of PF-05231023 at 100 mg and 150 mg doses once weekly had no effect on body weight with minimal effects on markers of bone turnover [58]. Novo Nordisk recently completed a safety, tolerability, and pharmacokinetic study of an FGF21 analog (NCT03479892, ClinicalTrials.gov), but no results have been posted. Whether FGF21 analogs will prove to be effective in the treatment of obesity remains to be established.