Fibroblast Growth Factor and Energy Metabolism

Information

  • Research Project
  • 10220487
  • ApplicationId
    10220487
  • Core Project Number
    R01DK102898
  • Full Project Number
    2R01DK102898-06A1
  • Serial Number
    102898
  • FOA Number
    PA-20-185
  • Sub Project Id
  • Project Start Date
    7/3/2015 - 8 years ago
  • Project End Date
    3/31/2025 - 9 months from now
  • Program Officer Name
    HAFT, CAROL R
  • Budget Start Date
    4/29/2021 - 3 years ago
  • Budget End Date
    3/31/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    06
  • Suffix
    A1
  • Award Notice Date
    4/29/2021 - 3 years ago

Fibroblast Growth Factor and Energy Metabolism

Project Summary/Abstract Obesity is growing at epidemic rates worldwide and leads to a broad spectrum of other disorders, which collectively form metabolic syndrome. Central to these pathologies is the adipose tissue. In mammals, there are two functionally distinct types of fat: white adipose tissue, which stores excess calories, and brown and its related beige adipose tissue, which dissipates energy for thermogenesis. Numerous studies in rodents have demonstrated that increasing the amount or activity of brown or beige fat holds excellent therapeutic potential for obesity-related metabolic diseases. Adipose tissue undergoes dramatic remodeling in response to environmental challenges. Cold exposure is an effective way to increase brown fat mass and activity. as well as to induce browning of white adipose tissue. While it has long been postulated that growth factors produced by the adipose niche play a critical role in the remodeling of brown and white fat upon cold challenge, the identity of such factors have remained mostly unidentified. Recently, we discovered that fibroblast growth factor (FGF) 9 is a cold-induced adipokine and can induce UCP1 expression independent of brown adipogenesis. In addition to adipose progenitors, FGF9 also stimulates thermogenic program in mature adipocytes. Importantly, expression of FGF receptor 3 (FGFR3), the receptor that mediates FGF9?s effects, is also induced by cold in both the stromal vascular fraction (SVF) cells and adipocytes, suggesting that FGF9 functions as an autocrine/endocrine factor within the adipose niche. Using single-cell RNA sequencing of the adipose SVF, we identify FGFR3?s abundant expression in the vascular endothelial cells. Based on these exciting findings, we hypothesize that FGF9, produced by adipocytes, functions as a niche factor to promote brown and white adipose tissue remodeling and modulate thermogenic program in mature adipocytes, in response to cold challenge. The primary goals of this grant are to 1) determine the role of FGF9 in regulation of thermogenic program in mature adipocytes and delineate the underlying transcriptional and epigenetic mechani, 2) determine the role of FGF9-induced angiogenesis in adipose remodeling, and 3) use both gain- and loss-of-function mouse models and nanotechnology to define the in vivo role of the FGF9-FGFR3 axis in energy metabolism and explore the potential of targeting this pathway to develop new therapies to treat obesity and its many related co-morbidities. Completion of the proposed studies will lead to a new understanding of adipose remodeling and could provide potential therapeutic approaches for obesity, type 2 diabetes, and other related metabolic diseases.

IC Name
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
  • Activity
    R01
  • Administering IC
    DK
  • Application Type
    2
  • Direct Cost Amount
    364927
  • Indirect Cost Amount
    241928
  • Total Cost
    606855
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    847
  • Ed Inst. Type
  • Funding ICs
    NIDDK:606855\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    CADO
  • Study Section Name
    Cellular Aspects of Diabetes and Obesity Study Section
  • Organization Name
    JOSLIN DIABETES CENTER
  • Organization Department
  • Organization DUNS
    071723084
  • Organization City
    BOSTON
  • Organization State
    MA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    022155306
  • Organization District
    UNITED STATES