FGF21-FGFR1 Coordinates Phospholipid Homeostasis, Lipid Droplet Function, and ER Stress in Obesity.
The antiobese and antidiabetic fibroblast growth factor 21 (FGF21) regulates lipid metabolism and energy homeostasis by targeting the βKlotho-FGFR1 (fibroblast growth factor receptor 1) binary complex in adipose tissue adipocytes. Because lipid droplet is the organelle responsible for storing lipid energy in adipocytes, it is the plausible target of FGF21 action. However, the impact of the FGF21-βKlotho-FGFR1 signaling pathway on the functions of the lipid droplet is not clearly understood. Using our mouse models of adipocyte-specific FGFR1 ablation and hepatic overexpression of FGF21 with diet-induced obesity established previously, we analyzed the alterations of the pathways involved in energy and substrate metabolism that is attributable to the dynamic functions of the lipid droplet. In addition to the previous reports showing that FGFR1 deficiency abrogated lipolysis, fatty acid oxidation, and energy expenditure promoted by the elevated FGF21 signal, we observed that the deficiency up-regulated the biosynthesis and remodeling of membrane phospholipids that are important for the biogenesis and expansion of the droplet, whereas the enhanced FGF21 signal constrained the biosynthesis of phospholipids. As a result, the loss of adipose FGFR1 led to a sustained droplet expansion and endoplasmic reticulum (ER) stress, whereas the enhanced FGF21 signal suppressed them in obesogenesis. These new findings reveal that the FGF21-βKlotho-FGFR1 signaling axis plays roles in maintaining phospholipid homeostasis and the dynamic functions of the lipid droplet, whereas protecting against ER stress, and suggest a potential link of phospholipid biosynthesis, lipid droplet dynamics, ER stress, and energy homeostasis in adipose tissue coordinated by this signaling axis.
Center for Cancer and Stem Cell Biology (M.Y., C.W., Y.L.) and Proteomics and Nanotechnology Laboratory (Y.L.), Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030-3303; Department of Gastrointestinal Medical Oncology (W.L., J.L.A.), University of Texas MD Anderson Cancer Center, Texas 77030; School of Pharmaceutical Science (X.W., C.W., G.L., X.L., Y.L.), Wenzhou Medical University and Center for Collaborative Translational Biomedical Research (X.L., Y.L.), Wenzhou University, Wenzhou, Zhejiang 325035, China; and Centeer BioTherapeutics Ltd Co (Y.L.), Houston, Texas 77584.
Min
M
Ye
Center for Cancer and Stem Cell Biology (M.Y., C.W., Y.L.) and Proteomics and Nanotechnology Laboratory (Y.L.), Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030-3303; Department of Gastrointestinal Medical Oncology (W.L., J.L.A.), University of Texas MD Anderson Cancer Center, Texas 77030; School of Pharmaceutical Science (X.W., C.W., G.L., X.L., Y.L.), Wenzhou Medical University and Center for Collaborative Translational Biomedical Research (X.L., Y.L.), Wenzhou University, Wenzhou, Zhejiang 325035, China; and Centeer BioTherapeutics Ltd Co (Y.L.), Houston, Texas 77584.
Weiqin
W
Lu
Center for Cancer and Stem Cell Biology (M.Y., C.W., Y.L.) and Proteomics and Nanotechnology Laboratory (Y.L.), Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030-3303; Department of Gastrointestinal Medical Oncology (W.L., J.L.A.), University of Texas MD Anderson Cancer Center, Texas 77030; School of Pharmaceutical Science (X.W., C.W., G.L., X.L., Y.L.), Wenzhou Medical University and Center for Collaborative Translational Biomedical Research (X.L., Y.L.), Wenzhou University, Wenzhou, Zhejiang 325035, China; and Centeer BioTherapeutics Ltd Co (Y.L.), Houston, Texas 77584.
Xiaojie
X
Wang
Center for Cancer and Stem Cell Biology (M.Y., C.W., Y.L.) and Proteomics and Nanotechnology Laboratory (Y.L.), Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030-3303; Department of Gastrointestinal Medical Oncology (W.L., J.L.A.), University of Texas MD Anderson Cancer Center, Texas 77030; School of Pharmaceutical Science (X.W., C.W., G.L., X.L., Y.L.), Wenzhou Medical University and Center for Collaborative Translational Biomedical Research (X.L., Y.L.), Wenzhou University, Wenzhou, Zhejiang 325035, China; and Centeer BioTherapeutics Ltd Co (Y.L.), Houston, Texas 77584.
Cong
C
Wang
Center for Cancer and Stem Cell Biology (M.Y., C.W., Y.L.) and Proteomics and Nanotechnology Laboratory (Y.L.), Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030-3303; Department of Gastrointestinal Medical Oncology (W.L., J.L.A.), University of Texas MD Anderson Cancer Center, Texas 77030; School of Pharmaceutical Science (X.W., C.W., G.L., X.L., Y.L.), Wenzhou Medical University and Center for Collaborative Translational Biomedical Research (X.L., Y.L.), Wenzhou University, Wenzhou, Zhejiang 325035, China; and Centeer BioTherapeutics Ltd Co (Y.L.), Houston, Texas 77584.
James L
JL
Abbruzzese
Center for Cancer and Stem Cell Biology (M.Y., C.W., Y.L.) and Proteomics and Nanotechnology Laboratory (Y.L.), Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030-3303; Department of Gastrointestinal Medical Oncology (W.L., J.L.A.), University of Texas MD Anderson Cancer Center, Texas 77030; School of Pharmaceutical Science (X.W., C.W., G.L., X.L., Y.L.), Wenzhou Medical University and Center for Collaborative Translational Biomedical Research (X.L., Y.L.), Wenzhou University, Wenzhou, Zhejiang 325035, China; and Centeer BioTherapeutics Ltd Co (Y.L.), Houston, Texas 77584.
Guang
G
Liang
Center for Cancer and Stem Cell Biology (M.Y., C.W., Y.L.) and Proteomics and Nanotechnology Laboratory (Y.L.), Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030-3303; Department of Gastrointestinal Medical Oncology (W.L., J.L.A.), University of Texas MD Anderson Cancer Center, Texas 77030; School of Pharmaceutical Science (X.W., C.W., G.L., X.L., Y.L.), Wenzhou Medical University and Center for Collaborative Translational Biomedical Research (X.L., Y.L.), Wenzhou University, Wenzhou, Zhejiang 325035, China; and Centeer BioTherapeutics Ltd Co (Y.L.), Houston, Texas 77584.
Xiaokun
X
Li
Center for Cancer and Stem Cell Biology (M.Y., C.W., Y.L.) and Proteomics and Nanotechnology Laboratory (Y.L.), Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030-3303; Department of Gastrointestinal Medical Oncology (W.L., J.L.A.), University of Texas MD Anderson Cancer Center, Texas 77030; School of Pharmaceutical Science (X.W., C.W., G.L., X.L., Y.L.), Wenzhou Medical University and Center for Collaborative Translational Biomedical Research (X.L., Y.L.), Wenzhou University, Wenzhou, Zhejiang 325035, China; and Centeer BioTherapeutics Ltd Co (Y.L.), Houston, Texas 77584.
Yongde
Y
Luo
D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D000090265:Klotho Proteins; D066292:Lipid Droplets / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
C418622:Klb protein, mouse; D008565:Membrane Proteins; D010743:Phospholipids; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D000090265:Klotho Proteins