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Principal Investigator: Yu-Hua Tseng
Organization: JOSLIN DIABETES CENTER
Fiscal Year: 2024
Award: $526,732
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <Adipocytes><Adipose Cell><Adipose tissue><Adult-Onset Diabetes Mellitus><Autocrine Systems><Automobile Driving><BAT uncoupling protein><Blood Vessels><Brown Adipose Tissue><Brown Fat><CEK2><Calories><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Fraction><Cell Growth in Number><Cell Isolation><Cell Multiplication><Cell Proliferation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cell to Cell Communication and Signaling><Cell-Cell Signaling><Cellular Proliferation><Chromatin><Chromatin Remodeling Complex><Chromatin Remodeling Factor><Complex><DNA Methylation><DNA Synthesis Factor><Data><Diabetes Mellitus><Disease><Disorder><Dissociation><Endocrine><Endothelial Cell Growth Factor><Endothelial Cells><Endothelium><Energy Expenditure><Energy Metabolism><Epidemic><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><FGF><FGF-6><FGF-9 protein><FGF9><FGF9 gene><FGFR-3><FGFR3><FGFR3 gene><Fat Cells><Fats><Fatty Tissue><Fatty acid glycerol esters><Fibroblast Growth Factor><Fibroblast Growth Factor Gene Family><Fibroblast Growth Regulatory Factor><Gene Expression><Gene Transcription><Genes><Genetic Transcription><Glia-Activating Factor><Goals><Grant><Growth Agents><Growth Factor><Growth Substances><HBFG-9><HBGF-6><HSFGFR3EX><Health><Heat Production><Hibernating Gland><In Vitro><Intracellular Communication and Signaling><JTK4><KO mice><Ketosis-Resistant Diabetes Mellitus><Knock-out Mice><Knockout Mice><Knowledge><Ligands><Lipids><Lipocytes><Mammalia><Mammals><Maps><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Mediating><Metabolic Diseases><Metabolic Disorder><Metabolic syndrome><Mice><Mice Mammals><Mitochondria><Modeling><Murine><Mus><NIDDM><Nanotechnology><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nuclear Receptors><Null Mouse><Obesity><Pathology><Pathway interactions><Physiologic><Physiological><Play><Progenitor Cells><Protein Engineering><Proteins><Proteins Growth Factors><RNA Expression><Receptor Protein><Regulation><Research><Rodent><Rodentia><Rodents Mammals><Role><Scheme><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Stimulus><System><T2 DM><T2D><T2DM><Therapeutic><Thermogenesis><Thesaurismosis><Transcription><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Tyrosine Kinase JTK4><United States><Vascular Endothelial Cell><Vascularization><adipocytokines><adipogenesis><adipokines><adipose><adipose derived stem cell><adipose progenitor><adipose stem cell><adiposity><adult onset diabetes><angiogenesis><autocrine><biological signal transduction><brown adipose tissue uncoupling protein><cell sorting><cellular differentiation><chromatin modifier><co-morbid><co-morbidity><combat><comorbidity><corpulence><delivery vector><delivery vehicle><diabetes><driving><epigenetic regulation><epigenetically><fibroblast growth factor 6><fibroblast growth factor 9><fibroblast growth factor receptor 3><gain of function><genetic protein engineering><glial activating factor><glucose tolerance><hFGFR3><histone modification><improved><in vivo><innovate><innovation><innovative><insulin sensitivity><intercellular communication><ketosis resistant diabetes><lipid biosynthesis><lipogenesis><loss of function><maturity onset diabetes><metabolism disorder><mitochondrial><mouse model><murine model><nano particle><nano tech><nano technology><nano-sized particle><nano-technological><nanoparticle><nanosized particle><nanotech><nanotechnological><neovascularization><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><obesity prevention><pathway><precursor cell><prevent obesity><programs><protein design><receptor><recruit><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stem cells><success><thermogenin><type 2 DM><type II DM><type two diabetes><uncoupling protein 1><vascular><white adipose tissue><yellow adipose tissue>