Adipose tissue stromal vascular fraction (SVF) is a source of multipotent mesenchymal stem cells that can be isolated from brown and white adipose tissue. While it is accepted that the precursor cells that give rise to mature adipose tissue reside in the SVF, multipotent adipose stem cells capable of self-renewal have not been molecularly defined. Our preliminary data show that mouse telomerase reverse transcriptase expression (mTert) marks a population of brown and white adipose SVF cells expressing putative adipogenic precursor cell surface markers that are capable of self-renewal and adipogenic differentiation in vitro. Further, the mTert cellular lineage is quiescent in brown and white adipose tissue in vivo from 3 weeks of age until 6 months, however high fat diet caused an increase in mTert lineage proliferation in 8-month old animals. Based on these findings, this project is designed to test the novel hypothesis that mTert expressing cells are multipotent adipose stem cells capable of responding to high fat diet and beta-adrenergic stimulation that serve as differentiation cues. There are two specific aims: 1) Functional and molecular characterization of mTert- expressing cells in vitro comparing these putative adipose stem cells to committed progenitor cells;2) Determine the effects of differentiation cues on mTert cell proliferation and differentiation in adipose in vivo compared to committed progenitor cells from PDGFr?-CreERT2 mice. Identifying adipose tissue stem cells and the mechanisms that govern their proliferation and differentiation will have important significance in the understanding of adipose tissue development and obesity and this knowledge may be applicable in autologous tissue transplants in human disease or injury.

Public Health Relevance

Obesity, driven by increased adiposity is a major public health concern and telomerase expression has been shown to be marker of tissue resident stem cells in several adult tissues, suggesting it may play a role in adipose tissue stem cell maintenance, proliferation and differentiation. The goal of this research proposal is to characterize brown and white adipose tissue telomerase-expressing cells and determine the inductive cues that govern their function and fate. This will lead to a better understanding of adipose tissue development and homeostasis and could help to identify novel strategies for autologous cell transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK102320-01
Application #
8718295
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Castle, Arthur
Project Start
2014-06-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02215
Lynes, Matthew D; Shamsi, Farnaz; Sustarsic, Elahu Gosney et al. (2018) Cold-Activated Lipid Dynamics in Adipose Tissue Highlights a Role for Cardiolipin in Thermogenic Metabolism. Cell Rep 24:781-790
Bartelt, Alexander; Widenmaier, Scott B; Schlein, Christian et al. (2018) Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity. Nat Med 24:292-303
Gao, Fei; McDaniel, Justice; Chen, Emily Y et al. (2018) Adapted MS/MSALL Shotgun Lipidomics Approach for Analysis of Cardiolipin Molecular Species. Lipids 53:133-142
Sustarsic, Elahu G; Ma, Tao; Lynes, Matthew D et al. (2018) Cardiolipin Synthesis in Brown and Beige Fat Mitochondria Is Essential for Systemic Energy Homeostasis. Cell Metab 28:159-174.e11
Lynes, Matthew D; Tseng, Yu-Hua (2018) Deciphering adipose tissue heterogeneity. Ann N Y Acad Sci 1411:5-20
Ramirez, Alfred K; Lynes, Matthew D; Shamsi, Farnaz et al. (2017) Integrating Extracellular Flux Measurements and Genome-Scale Modeling Reveals Differences between Brown and White Adipocytes. Cell Rep 21:3040-3048
Lynes, Matthew D; Leiria, Luiz O; Lundh, Morten et al. (2017) The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat Med 23:631-637
Gao, Fei; McDaniel, Justice; Chen, Emily Y et al. (2016) Monoacylglycerol Analysis Using MS/MS(ALL) Quadruple Time of Flight Mass Spectrometry. Metabolites 6:
Xue, Ruidan; Lynes, Matthew D; Dreyfuss, Jonathan M et al. (2015) Clonal analyses and gene profiling identify genetic biomarkers of the thermogenic potential of human brown and white preadipocytes. Nat Med 21:760-8
Lynes, Matthew D; Schulz, Tim J; Pan, Andrew J et al. (2015) Disruption of insulin signaling in Myf5-expressing progenitors leads to marked paucity of brown fat but normal muscle development. Endocrinology 156:1637-47

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