Amelioration of Type 2 Diabetes by Antibody-Mediated Activation of Fibroblast Growth Factor Receptor 1

Wu, Ai-Luen; Kolumam, Ganesh; Stawicki, Scott; Chen, Yongmei; Li, Jun; Zavala-Solorio, José; Phamluong, Khanhky; Feng, Bo; Li, Li; Marsters, Scot A.; Kates, Lance; Bruggen, Nicholas van; Leabman, Maya; Wong, Anne; West, David B.; Stern, Howard M.; Luis, Elizabeth; Kim, Hok Seon; Yansura, Daniel G.; Peterson, Andrew S.; Filvaroff, Ellen; Wu, Yan; Sonoda, Junichiro

doi:10.1126/scitranslmed.3002669

Cited by 157 publications

(188 citation statements)

References 32 publications

Supporting

Mentioning

174

Contrasting

Unclassified

Order By: Relevance

“…Mice lacking KLB are resistant to both acute and chronic effects of FGF21. However, the acute insulin-sensitizing effects of FGF21 are also absent in mice with specific deletion of adipose KLB (32) or FGFR1 (33), consistent with the notion that direct adipose tissue activation is required for FGF21 action (34).…”

supporting

confidence: 73%

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

Jager

Wang

Fang

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erb␣, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erb␣ for Rev-erb␣-binding sites identified ␤Klotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erb␣ in white adipose tissue but not liver. Rev-erb␣ ablation led to the robust elevated expression of ␤Klotho. Consequently, the effects of FGF21 were markedly enhanced in the white adipose tissue of mice lacking Reverb␣. A major Rev-erb␣-controlled enhancer at the Klb locus was also bound by the adipocytic transcription factor peroxisome proliferator-activated receptor (PPAR) ␥, which regulates its activity in the opposite direction. These findings establish Rev-erb␣ as a specific modulator of FGF21 signaling in adipose tissue.Adipose tissue is an important fat storage and endocrine organ whose dysfunction is closely associated with the development of obesity, diabetes mellitus, and cardiovascular disease (1-5). Nuclear receptors are DNA-binding proteins that directly regulate gene expression in response to ligands derived from endocrine glands, metabolism, diet, and the environment (6). They are widely believed to act as key regulators in various physiological processes, such as circadian rhythm, development, reproduction, energy homeostasis, and metabolism (7,8).The nuclear receptor Rev-erb␣ differs from other members of the nuclear receptor superfamily because it lacks a classical activation domain and thus functions as a constitutive repressor of transcription (9 -11). Acting in this repressive manner, Rev-erb␣ has been described as a core component of the mammalian biological clock (12) that links circadian rhythms to metabolism in diverse tissues. Indeed, studies from different groups have revealed Rev-erb␣ as a key regulator of multiple biological processes in various metabolic tissues, including liver (13-15), macrophages (16), muscle (17), brown fat (18), and brain (19). However, little is known about potential role in white adipose tissue (WAT). 3FGF21 is an atypical member of the FGF superfamily that, because of a lack of a heparin binding domain, is able to escape into the circulation, functioning as a hormone to regulate carbohydrate and lipid metabolism (20,21). In the metabolic context, FGF21 was first discovered to induce glucose uptake in 3T3L1 adipocytes (22). Subsequently it was demonstrated that FGF21 administration to obese rodents and non-human primates improves hyperglycemia, lowers elevated triglyceride levels, and reduces body weight (22)(23)(24)(25). In rodents, the mechanisms underlying FGF21 actions include improving whole-body insulin sensitivity and ␤ cell function, reducing hepatic lipogenesis, and enhancing brown fat thermogenic activity (22,23,(25)(26)(27). These effects identify FGF21 as an attractive therapeutic agent f...

show abstract

supporting

confidence: 73%

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

Jager

Wang

Fang

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Recent evidence suggests that these beneficial effects observed with FGF21 or FGF19 treatment are not mediated through FGFR4 but distinctly through the FGFR1c/ ␤ Klotho complex. For example, treatment of mice with an FGF molecule biased toward the FGFR1c/ ␤ Klotho receptor complex or FGFR1 agonist antibody can recapitulate metabolic phenotypes induced by FGF19 and FGF21, including improvement of hyperglycemia and hyperlipidemia ( 14,28 ). These effects were absent in lipoatrophic animals ( 28 ), suggesting FGFR1 in adipose tissue is the main target of FGF21 action.…”

Section: Discussionmentioning

confidence: 99%

Dual actions of fibroblast growth factor 19 on lipid metabolism

Baribault

et al. 2013

Journal of Lipid Research

View full text Add to dashboard Cite

hormone ( 3 ). In lieu of heparan sulfate binding, FGF19 requires a protein cofactor, ␤ Klotho, to effectively interact with and activate FGF receptors ( 4-6 ). The requirement for a co-receptor is a unique feature common to the FGF19 subfamily and is further exemplifi ed by another subfamily member, FGF21, which also lacks heparan sulfate affi nity and uses ␤ Klotho as its co-receptor ( 4 ). Consistent with their shared ability to use the same co-receptor for signaling, there is extensive overlap in the reported pharmacological effects of FGF19 and FGF21. FGF19 and FGF21 transgenic mice, as well as chronic administration of recombinant FGF19 or FGF21 proteins, similarly lowered serum glucose, triglyceride (TG), and cholesterol levels and improved insulin sensitivity and reduced body weight in high-fat diet-induced obesity models ( 7-9 ). Chronic treatment with FGF19 or FGF21 similarly reduced blood glucose levels and improved glucose disposal in ob/ob (B6.V-Lep ob /J) leptin-defi cient mice; however, plasma TG and cholesterol levels after treatment with FGF19 have not been reported in this model ( 8,9 ).The common co-receptor for FGF19 and FGF21, ␤ Klotho, is a single-pass transmembrane protein with two homologous extracellular domains that share sequence homology to ␤ -glucosidases in bacteria and plants ( 10 ). ␤ Klotho has a short intracellular domain and is unlikely to signal by itself. Its primary role is believed to mediate interactions between these two FGF molecules and FGF receptors (FGFR) to activate FGFR tyrosine kinase activity ( 11 ). ␤ Klotho interacts with only four of the seven major FGFRs, the "c" isoforms of FGFR1, -2, -3. and -4 ( 11 ). FGF19 and FGF21 can activate FGFR1c, -2c, and -3c complexed with ␤ Klotho in vitro ( 4, 6, 11-13 ). Recent results using an engineered FGF19 variant with altered receptor specifi city Abstract Elevated triglyceride (TG) and cholesterol levels are risk factors for cardiovascular disease and are often associated with diabetes and metabolic syndrome. Recent reports suggest that fi broblast growth factor (FGF)19 and FGF21 can dramatically improve metabolic dysfunction, including hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. Due to their similar receptor specifi cities and co-receptor requirements, FGF19 and FGF21 share many common properties and have been thought to be interchangeable in metabolic regulation. Here we directly compared how pharmacological administration of recombinant FGF19 or FGF21 proteins affect metabolism in B6.VLep ob /J leptin-defi cient mice. FGF19 and FGF21 equally improved glucose parameters; however, we observed increased serum TG and cholesterol levels after treatment with FGF19 but not with FGF21. Increases in serum TGs were also observed after a 4-day treatment with FGF19 in C57BL6/J mice on a high-fat diet. This is in contrast to many literature reports that showed signifi cant improvements in hyperlipidemia after chronic treatment with FGF19 or FGF21 in high-fat diet models. We propose that FGF19 has lipid-raising an...

show abstract

“…Besides, ablation of FGFR1 in adipose tissue resulted in impaired lipid profile [15]. Moreover, FGFR1 agonist treated diabetic mice exhibited improvement of hyperglycemia, hyperlipidemia, and hepatosteatosis [16]. Therefore, rescuing FGFR1 signaling would provide opportunity to reverse T2DM.…”

Section: Enzyme Linked Immunosorbent Assaymentioning

confidence: 99%

The effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats

et al. 2017

View full text Add to dashboard Cite

TYPE 2 DIABETES MELLITUS (T2DM) is associated with obesity and insulin resistance and has severe complications. As an effective and safe oral drug, metformin has been used to treat T2DM for almost fifty years. Possible mechanisms of metformin in improving glucose homeostasis are partially depended on the activation of adenosine monophosphate-activated protein kinase (AMPK) which then inhibits glucose output and increases insulin sensitivity in peripheral tissues [1].Fibroblast growth factor-19 (FGF19) and FGF21 belong to beta-klotho family, and recent studies showedThe effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats Yan Wang 1), 2) , Ningning Dang 3) , Pei Sun 2) , Jin Xia 2), 4) , Chunxue Zhang 2), 4) and Shuguang Pang 1), 2), 4) Abstract. To understand metformin's effects on fibroblast growth factors (FGFs) and fibroblast growth factor receptor 1 (FGFR1), we investigated circulating fibroblast growth factor-19 (FGF19), FGF21 levels, and FGFR1 in type 2 diabetes mellitus (T2DM). In addition, protein kinase B (Akt) signaling pathway was detected to explain the possible mechanisms. T2DM was induced by feeding rats with high-fat diet for 11 weeks, followed by a low dose of streptozotocin (STZ, 30-35 mg/kg, intraperitoneally). Control rats (Con) were fed on a normal chow; diabetic rats (DM) were fed on high-fat diet supplemented with or without metformin (METF) for 12 weeks (500 mg·kg -1 ·d -1 ). Biochemical parameters were detected at the end of 24th weeks. FGFR1 expression and protein kinase B (Akt) phosphorylation in the pancreas and visceral adipose tissues were detected using either Western blot (WB) or immunohistochemistry (IHC). Serum FGF19 and FGF21 were measured using enzyme-linked immune sorbent assay (ELISA). Metformin treated DM rats showed improved glucose, lipid and bile acid metabolism. Besides, significantly decreased FGF19 and increased FGF21 were observed in DM+METF rats. DM rats showed significantly increased FGFR1 both in the pancreas and visceral adipose tissues. While in DM+METF rats, FGFR1 was almost remained at a normal level in the pancreas and increased in the visceral adipose tissue compared to that in DM rats. Besides, metformin treatment restores Akt phosphorylation in both tissues. The altered glucose and lipid profiles by metformin treatment may be associated with the increased circulating FGF21 and tissue-specific expressions of FGFR1.Key words: Diabetes, FGF21, FGFR1, β cell, Visceral adipose that they were produced by the activation of Farnesoid X Receptor (FXR) in the ileum and liver, respectively [2,3]. FGF19 and FGF21 are emerging as endocrine hormones since they showed novel roles in bile acid, lipid, and glucose metabolism [4][5][6]. In obese or diabetic animal models, administration of FGF19 and FGF21 led to beneficial effects on metabolism through increasing insulin sensitivity, energy expenditure and white adipose browning [7][8][9][10].FGFs exert their roles by binding...

show abstract

Amelioration of Type 2 Diabetes by Antibody-Mediated Activation of Fibroblast Growth Factor Receptor 1

Cited by 157 publications

References 32 publications

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

Dual actions of fibroblast growth factor 19 on lipid metabolism

The effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats

Contact Info

Product

Resources

About