FGF-21 as a novel metabolic regulator

Kharitonenkov, Alexei; Shiyanova, Tatiyana; Köester, Anja; Ford, Amy; Micanovic, Radmila; Galbreath, Elizabeth; Sandusky, George E.; Hammond, Lisa J.; Moyers, Julie S.; Owens, Rebecca A.; Gromada, Jesper; Brozinick, Joseph T.; Hawkins, Eric D.; Wroblewski, Victor J.; Li, De Shan; Mehrbod, Farrokh; Jaskunas, S R; Shanafelt, Armen B.

doi:10.1172/jci23606

Cited by 1,804 publications

(2,213 citation statements)

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“…In addition, acidic glycosaminoglycans in the form of heparan sulfate proteoglycans function to retain these FGFs in the vicinity of FGF-producing sites, such that they primarily act in a paracrine manner. By contrast, the hFGFs have low-affinity heparin-binding sites and have been found to act in an endocrine manner (Tomlinson et al, 2002;Lundasen et al, 2006;Kharitonenkov et al, 2005Kharitonenkov et al, , 2007Fukumoto and Yamashita, 2007;Liu and Quarles, 2007).…”

Section: Identification Of the Mouse Fgf Gene Familymentioning

confidence: 99%

“…In addition, acidic glycosaminoglycans limit the diffusion of FGFs, localizing their activity to the vicinity of FGF-producing cells (Flaumenhaft et al, 1990). In contrast, hFGFs have poor heparin-binding affinity and act on target cells far from their site of production in an endocrine manner (Tomlinson et al, 2002;Lundasen et al, 2006;Kharitonenkov et al, 2005Kharitonenkov et al, , 2007Fukumoto et al, 2007;Liu et al, 2007). In addition, FGF15, FGF21, and FGF23 require co-receptors, Klotho or ␤Klotho, to activate FGFRs (Ogawa et al, 2007;Urakawa et al, 2006).…”

Section: Perspectivesmentioning

confidence: 99%

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Functional evolutionary history of the mouse Fgf gene family

Itoh

Ornitz

2007

Developmental Dynamics

346

313

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Section: Identification Of the Mouse Fgf Gene Familymentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

Functional evolutionary history of the mouse Fgf gene family

Itoh

Ornitz

2007

Developmental Dynamics

346

313

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“…Pharmacological treatment with FGF21 ameliorates age‐related metabolic disorders such as insulin resistance, dyslipidemia, and obesity in rodents (Coskun et al, 2008; Kharitonenkov et al, 2005), and pilot studies in humans indicate that treatment with an FGF21‐analog has beneficial effects on hyperlipidemia and body weight (Gaich et al, 2013). Sustained increases in FGF21 levels attained by transgenic overexpression of FGF21 extend the lifespan of mice (Zhang et al, 2012), suggesting that FGF21 is a pro‐longevity hormone.…”

mentioning

confidence: 99%

Aging is associated with increased FGF21 levels but unaltered FGF21 responsiveness in adipose tissue

et al. 2018

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Fibroblast growth factor 21 (FGF21) has been proposed to be an antiaging hormone on the basis of experimental studies in rodent models. However, circulating FGF21 levels are increased with aging in rodents and humans. Moreover, despite the metabolic health‐promoting effects of FGF21, the levels of this hormone are increased under conditions such as obesity and diabetes, an apparent incongruity that has been attributed to altered tissue responsiveness to FGF21. Here, we investigated serum FGF21 levels and expression of genes encoding components of the FGF21‐response molecular machinery in adipose tissue from healthy elderly individuals (≥70 years old) and young controls. Serum FGF21 levels were increased in elderly individuals and were positively correlated with insulinemia and HOMA‐IR, indices of mildly deteriorated glucose homeostasis. Levels of β‐Klotho, the coreceptor required for cellular responsiveness to FGF21, were increased in subcutaneous adipose tissue from elderly individuals relative to those from young controls, whereas FGF receptor‐1 levels were unaltered. Moreover, total ERK1/2 protein levels were decreased in elderly individuals in association with an increase in the ERK1/2 phosphorylation ratio relative to young controls. Adipose explants from aged and young mice respond similarly to FGF21 “ex vivo”. Thus, in contrast to what is observed in obesity and diabetes, high levels of FGF21 in healthy aging are not associated with repressed FGF21‐responsiveness machinery in adipose tissue. The lack of evidence for impaired FGF21 responsiveness in adipose tissue establishes a distinction between alterations in the FGF21 endocrine system in aging and chronic metabolic pathologies.

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“…These factors (or hepatokines) include fetuin A [51], adropin [52], angiopoietin-like protein [53], fibroblast growth factor-21 [54], and selenoprotein [55]. All of these hepatokines have been suggested as potential endocrine mediators of insulin resistance and/or glucose intolerance in NAFLD.…”

Section: Secreted Hepatokines and The Role Of Incretins And Glucagonmentioning

confidence: 99%

Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: Causal association or epiphenomenon?

Targher

Marchesini

Byrne

2016

Diabetes & Metabolism

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Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide, causing considerable liverrelated mortality and morbidity. Over the last 10 years, it has also become increasingly evident that NAFLD is a multisystem disease, affecting many extra-hepatic organ systems and interacting with the regulation of multiple metabolic pathways. NAFLD is potentially involved in the aetiology and pathogenesis of type 2 diabetes via its direct contribution to hepatic/peripheral insulin resistance and the systemic release of multiple hepatokines that may adversely affect glucose metabolism and insulin action and secretion. In this updated review, we discuss the rapidly expanding body of clinical and epidemiological evidence that supports a strong link between NAFLD and the risk of developing type 2 diabetes. We also briefly examine the conventional and the more innovative pharmacological approaches for the treatment of NAFLD that may influence the risk of developing type 2 diabetes. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 AbstractNonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide, causing considerable liver-related mortality and morbidity. Over the last 10 years, it has also become increasingly evident that NAFLD is a multisystem disease, affecting many extra-hepatic organ systems and interacting with the regulation of multiple metabolic pathways. NAFLD is potentially involved in the aetiology and pathogenesis of type 2 diabetes via its direct contribution to hepatic/peripheral insulin resistance and the systemic release of multiple hepatokines that may adversely affect glucose metabolism and insulin action and secretion. In this updated review, we discuss the rapidly expanding body of clinical and epidemiological evidence that supports a strong link between NAFLD and the risk of developing type 2 diabetes. We also briefly examine the conventional and the more innovative pharmacological approaches for the treatment of NAFLD that may influence the risk of developing type 2 diabetes.

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FGF-21 as a novel metabolic regulator

Cited by 1,804 publications

References 49 publications

Functional evolutionary history of the mouse Fgf gene family

Functional evolutionary history of the mouse Fgf gene family

Aging is associated with increased FGF21 levels but unaltered FGF21 responsiveness in adipose tissue

Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: Causal association or epiphenomenon?

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