Fibroblast Growth Factor-16 Is a Growth Factor for Embryonic Brown Adipocytes

Konishi, Morichika; Mikami, Tadahisa; Yamasaki, Masahiro; Miyake, Ayumi; Itoh, Nobuyuki

doi:10.1074/jbc.275.16.12119

Cited by 71 publications

(50 citation statements)

References 20 publications

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“…Although previous studies identified Fgf16 as a potent BAT mitogen during embryogenesis (27), we were unable to find published data describing a role for Fgf16 in adult BAT or WAT. Thus, because of the profile of Fgf16 from the high content cell-based screen, and the previously known role for Fgf16 in embryogenesis, we sought to more closely examine Fgf16 in the adult DIO mouse model and evaluate whether overexpression of Fgf16 in this context could induce metabolic effects via an iBAT-mediated mechanism.…”

Section: An In Vitro High Content Screen Identifies Fgf16 As Ancontrasting

confidence: 46%

“…In contrast to the adult expression profile, the examination of rat embryos at different stages of embryogenesis revealed Fgf16 expression in classical BAT depots during the latter stages of development, reaching the highest expression around stage embryonic day 20.5 and then tapering off by postnatal day 1 (27). During this time frame, maximal expression of Fgf16 was inversely correlated with Ucp1, with Ucp1 being strongly expressed at postnatal day 1.…”

mentioning

confidence: 94%

“…Furthermore, 8-week-old rats exposed to cold temperatures for a week exhibited increased Ucp1 expression in BAT tissue, whereas expression of Fgf16 was virtually absent. Thus, along with data demonstrating the mitogenic capacity of recombinant Fgf16 on primary rat adipocytes, the authors concluded Fgf16 was a potent embryonic BAT mitogen, with no significant post-natal role in BAT (27). However, the potential of increased expression of FGF16 to induce iBAT in adult mice has not been reported.…”

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confidence: 95%

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In Vitro and in Vivo Analyses Reveal Profound Effects of Fibroblast Growth Factor 16 as a Metabolic Regulator

Rulifson¹,

Collins

Li³

et al. 2017

Journal of Biological Chemistry

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Edited by George M. CarmanThe discovery of brown adipose tissue (BAT) as a key regulator of energy expenditure has sparked interest in identifying novel soluble factors capable of activating inducible BAT (iBAT) to combat obesity. Using a high content cell-based screen, we identified fibroblast growth factor 16 (FGF16) as a potent inducer of several physical and transcriptional characteristics analogous to those of both "classical" BAT and iBAT. Overexpression of Fgf16 in vivo recapitulated several of our in vitro findings, specifically the significant induction of the Ucp1 gene and UCP1 protein expression in inguinal white adipose tissue (iWAT), a common site for emergent active iBAT. Despite significant UCP1 up-regulation in iWAT and dramatic weight loss, the metabolic improvements observed due to Fgf16 overexpression in vivo were not the result of increased energy expenditure, as measured by indirect calorimetric assessment. Instead, a pattern of reduced food and water intake, combined with feces replete with lipid and bile acid, indicated a phenotype more akin to that of starvation and intestinal malabsorption. Gene expression analysis of the liver and ileum indicated alterations in several steps of bile acid metabolism, including hepatic synthesis and reabsorption. Histological analysis of intestinal tissue revealed profound abnormalities in support of this conclusion. The in vivo data, together with FGF receptor binding analysis, indicate that the in vivo outcome observed is the likely result of both direct and indirect mechanisms and probably involves multiple receptors. These results highlight the complexity of FGF signaling in the regulation of various metabolic processes.

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Section: An In Vitro High Content Screen Identifies Fgf16 As Ancontrasting

confidence: 46%

mentioning

confidence: 94%

mentioning

confidence: 95%

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In Vitro and in Vivo Analyses Reveal Profound Effects of Fibroblast Growth Factor 16 as a Metabolic Regulator

Rulifson¹,

Collins

Li³

et al. 2017

Journal of Biological Chemistry

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“…It will be interesting to clarify whether the binding of FGF-16 to CS-E can stimulate cellular growth or the signal transduction cascade in vivo. FGF-16 is expressed predominantly in the brown adipocytes of rat embryos during embryonic days 17.5-19.5 and appears to be a unique growth factor involved in the proliferation of embryonic brown adipose tissue (65). It also induces hepatocellular proliferation and increases liver weight in vivo (34).…”

Section: Discussionmentioning

confidence: 99%

Specific Molecular Interactions of Oversulfated Chondroitin Sulfate E with Various Heparin-binding Growth Factors

Deepa

Umehara

Higashiyama

et al. 2002

Journal of Biological Chemistry

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309

254

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We previously observed that the cortical neuronal cell adhesion mediated by midkine (MK), a heparin (Hep)-binding growth factor, is specifically inhibited by oversulfated chondroitin sulfate-E (CS-E) (Ueoka, C., Kaneda, N., Okazaki, I., Nadanaka, S., Muramatsu, T., and Sugahara, K. Proteoglycans (PGs)1 that bear heparan sulfate (HS) glycosaminoglycan side chains have attracted much attention because of the demonstration of the involvement of HS in the developmental processes and specific signaling pathways (for review, see Refs. 1-3). Although the chondroitin sulfate (CS) glycosaminoglycan side chains of CS-PGs have attracted less attention until recently, accumulating evidence suggests the importance of these molecules in various biological functions (2, 4). CS-PGs are also ubiquitous components of the extracellular matrix of connective tissues and are also found at the surfaces of many cell types and in intracellular secretory granules (for review, see Refs. 5 and 6). Developmentally regulated expression of CS epitopes in the rodent fetus has been demonstrated by immunological studies (7), especially during central nervous system development (8 -10). CS is a rich component in the extracellular matrix of the brain (11). Developmentally regulated expression and tissue-specific distribution of CS variants suggest that CS chains differing in the degree and profile of sulfation perform distinct functions during development (12).Among variant forms of CS chains, oversulfated CS chains, such as CS-E and CS-D, are of special interest. The presence of E (GlcUA␤1-3GalNAc(4S,6S)) and D (GlcUA(2S)␤1-3GalNAc(6S)) units in bovine brain (13) and E18 rat brain (14) has been reported (GlcUA stands for D-glucuronic acid whereas 2S, 4S, and 6S represent 2-O-, 4-O-, and 6-O-sulfate, respectively). These units are present in appreciable proportions in chick brains, and their expression is regulated developmentally (15). Faissner et al. (16) demonstrated that the neurite outgrowth-stimulating capacity of DSD-1-PG, derived from neonatal mouse brains, is strongly reduced by the monoclonal antibody 473HD, which recognizes a CS epitope, and the interaction is inhibited by shark cartilage CS-C. We have shown that CS-D, an oversulfated CS also derived from shark cartilage, inhibits the interactions between the monoclonal antibody 473HD and DSD-1-PG and also promotes neurite outgrowth of E18 hippocampal neurons (17,18) and that the DSD-1-PG contains the D disaccharide unit, which is a rich and poor component in CS-D and CS-C, respectively. We have further observed that another oversulfated variant CS-E, derived from squid cartilage, also exhibits neurite outgrowth promoting activity, which is not inhibited by 473HD, suggesting a

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“…It is expressed mainly in embryonic brown adipose tissue and adult heart and, once secreted, has a mitogenic effect on primary brown adipocytes, which it exerts by binding to and activating FGFR-4 on the plasma membrane (22). In the present study, we investigated the mechanism and structural requirements for the secretion of FGF-16.…”

mentioning

confidence: 99%