Childhood and adult obesity and their associated metabolic complications is a public health problem. In the United States alone, more than 67% of adults and 33% of children are currently overweight or obese, which can cause both immediate and long-term health problems. If this epidemic is uncorrected it will lead to a range of ensuing metabolic disorders such as heart disease, diabetes, atherosclerosis, and cancer. Adipose or fat tissues appear to be at the nexus of the obesity crisis. However, very little is known about the cells and molecular mechanisms that oversee the formation and the expansion of adipocytes and adipose tissues. Our recent findings using genetic mouse models demonstrate that there are two progenitor populations that give rise to adipocytes: developmental progenitors, for adipose development, and adult progenitors, for adipose homeostasis. In established adult adipose depots, not developmental adipose depots, adipocytes fate-map from a perivascular residing progenitor cell pool. Contrary to adult adipose tissue, even less is known about the cellular origin of developmental progenitor cells and the signals that control their cellular dynamics including pattern, proliferation, migration and formation. The central focus of this proposal aims to use our genetic tools to identify novel regulatory mechanisms important for adipose tissue development compared to adult adipose tissue homeostasis and expansion. Previous studies have suggested that platelet derived growth factor receptor ? (PDGFR?) is an important potential source of developmental adipose progenitor cells. Furthermore, PDGFR?+ cells contribute to adipose tissue expansion in respond to high fat diet feeding. However, few studies have examined if PDGFR?, gene function, is critical for adipose tissue development or adult regulation. Based on our preliminary data, I hypothesize that PDGFR? signaling is a central regulator of adipose tissue development by establishing the adipose lineage. Thus the specific aims of this study are focused on:
Aim 1 : Determine if PDGFR? is necessary for adipose tissue development (organogenesis).
Aim 2 : Determine the mechanisms by which PDGFR? controls adipose tissue development.
Aim 3 : Determine if PDGFR? is necessary for adult adipose tissue obesogenic expansion. Based on preliminary data, PDGFR? is critical for the development of adipose tissue but not for maintaining it. It appears that PDGFR? regulates adipose progenitor cell fate promoting adipose tissue organogenesis. These findings will be of great importance for three reasons: 1) how embryonic cells adopt an adipose tissue cell fate, 2) the molecular underpinning that govern this developmental cell fate, and 3) how adipose tissue expands in response to caloric excess compared to adult adipose tissue homeostasis. These important findings may lead to novel discrete therapeutic targets for childhood and adult obesity.
In the United States, more than one third of children are considered overweight or obese, which causes both immediate and long-term health problems including heart disease, type 2 diabetes, hypertension, and cancer. Fat or adipose tissue appears to be at the core of this epidemic; yet, our understanding of adipose tissue development, formation and expansion is very limited. This project aims to elucidate how targeting platelet derived growth factor alpha (PDGFR?) alters adipose progenitor cell fate and cell dynamics in turn regulating adipose tissue development and expansion. Further this projects aims to identify how PDGFR? mechanically governs adipose progenitor lineage fate, tissue morphogenesis and specification. The findings from this proposal will enhance our understanding of adipose tissue organogenesis and expansion, which could lead to novel discrete therapeutic targets for childhood and adult obesity.
| 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: |
