Access Type

Open Access Dissertation

Date of Award

January 2012

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pathology

First Advisor

JAMES G. GRANNEMAN

Second Advisor

TODD LEFF

Abstract

Nutritional and pharmacological stimuli can dramatically alter the cellular composition and phenotype of white adipose tissue (WAT). Nonetheless, the identity of progenitors that contribute to this cellular plasticity in vivo remains poorly understood. Utilizing genetic lineage tracing techniques in combination with in situ imunohistochemical analysis, we demonstrate that brown adipocytes (BA) that are induced by beta3-adrenergic receptor activation (ADRB3) in WAT arise from the proliferation and differentiation of cells that express platelet-derived growth factor receptor alpha (PDGFRA), CD34 and Sca1 (PDGFRA+ cells). PDGFRA+ cells have a unique morphology in which extended processes contact multiple cells in the tissue microenvironment. Surprisingly, these cells also give rise to white adipocytes (WA) that can comprise up to 25% of total fat cells in abdominal fat pads following 8 weeks of high fat feeding. PDGFRA+ cells isolated by fluorescence-activated cell sorting differentiated into both BA and WA in vitro, and generated WA after transplantation in vivo, confirming dual potential. Studies on the interplay of progenitors with niche components demonstrated that ADRB3 activation recruited M2 macrophage to form crown-like structures in epididymal WAT and M2 macrophages released OPN and PDGFC to induce progenitor migration and proliferation. Progenitor activation was dependent on PDGF signaling and attenuated by pharmacologic inhibition of the receptor tyrosine kinase. Together, we identified a novel population of adipocyte progenitors with in vivo dual adipogenic potential that respond to pharmacologic stimulation and nutritional modification and their interaction with adipose tissue macrophages. These finding provides new information on adipose lineage specification and have clinical implication for diabetes therapy and restorative medicine.

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