Obesity is of epidemic proportions and adipose tissue (fat) is central to the manifestation of the accompanying metabolic dysfunction (diabetes, cardiovascular disease, atherosclerosis, and hypertension). The global prevalence of obesity is approximately 15% and in the United States more than two thirds of the population is considered overweight. Fat mass can expand from 2?3% to 60?70% of overall body weight in response to caloric excess. Adipose tissue is comprised of two cell types: the cells that store lipids, adipocytes, and the cells that can divide and have the potential to make new adipocytes, fat progenitor cells. Fat accumulation occurs in two ways, one is to expand lipid storage in existing adipocytes and the second is to increase (proliferate) the fat stem cell population in turn creating new adipocytes. Despite the important health implications of obesity our understanding about the adipocyte stem compartment and its niche (the specialized microenvironment that controls all aspects of stem/progenitor cell biology) remains undefined. Our recent studies have identified and localized fat stem cells to the blood vessel wall in the adipose tissue thus serving as the niche. Much remains unknown about how these progenitor cells divide and migrate, how they adhere to the blood vessel, how they are retained at the vasculature, and how these cells undergo adipocyte differentiation. Furthermore, it is unclear how disrupting these two compartments alter adiposity and systemic metabolism. This proposal aims to explore these questions using cell culture and mouse models to address the interaction between adipose stem cells and their niche. An important regulator of this biology is platelet derived growth factor receptor ? (PDGFR?), which I found to be upregulated in vascular residing adipose progenitor cells.
Aim 1 of this proposal uses cell culture modeling to manipulate PDGFR? expression and monitor adipose stem cell function (proliferation migration and differentiation) and niche interaction. My preliminary data suggest that PDGFR? is a critical regulator of adipose progenitor cell proliferation, migration and adipocyte formation.
Aim 2 addresses the physiological consequence of deleting PDGFR? in adipose stem cells on adiposity and glucose metabolism. Preliminary studies show that deleting PDGFR in the adipose lineage results in adipose stem cell?niche mis?localization in turn leading to fat loss Aim 3 takes a clinical approach to address if pharmacologically targeting PDGFR alters adipose stem cells locality thereby blocking adiposity and improving glucose sensitivity. Preliminary data mirror the genetic deletion studies of PDGFR?, highlighting clinical utility. These findings will e of great importance for two reasons: 1) they address significant biological questions into how adipose stem cells interact with their niche, communicate with their niche and expand their niche and 2) they will show that pharmacologically targeting this communication network between adipose progenitor cells and the niche reduces adiposity but improves glucose sensitivity, a highly sought?after therapy to combat obesity.
In the United States, obesity and its associated metabolic disorders are a leading cause of mortality; however, adipose progenitor cells within white adipose depots may hold clues critical for development of targeted therapies to alleviate this public health scourge. This project investigates how altering adipose progenitor cell?niche locality and communication via genetically and pharmacologically targeting platelet derived growth factor ? (PDGFR?) regulates adipose tissue mass, tissue homeostasis and systemic metabolism. The findings from this proposal will build our understanding of adipose progenitor cell function and their niche and may provide a therapeutic entry to combat excess fat mass
| Jiang, Yuwei; Berry, Daniel C; Jo, Ayoung et al. (2017) A PPAR? transcriptional cascade directs adipose progenitor cell-niche interaction and niche expansion. Nat Commun 8:15926 |
| Jiang, Yuwei; Berry, Daniel C; Graff, Jonathan M (2017) Distinct cellular and molecular mechanisms for ?3 adrenergic receptor-induced beige adipocyte formation. Elife 6: |
| Berry, Daniel C; Jiang, Yuwei; Arpke, Robert W et al. (2017) Cellular Aging Contributes to Failure of Cold-Induced Beige Adipocyte Formation in Old Mice and Humans. Cell Metab 25:166-181 |
| Berry, Daniel C; Jiang, Yuwei; Graff, Jonathan M (2016) Emerging Roles of Adipose Progenitor Cells in Tissue Development, Homeostasis, Expansion and Thermogenesis. Trends Endocrinol Metab 27:574-585 |
