The global epidemic of obesity has put fat tissue at the center of attention. My laboratory is dedicated to understanding the molecular and developmental mechanisms controlling the formation of different adipose tissue depots. We are using a variety of molecular, cellular, and genetic approaches to ask the following questions:
1) How do fat cells form in vivo during normal tissue development?
2) How do new fat cells form in adults when the demand for energy storage is high?
3) What are the adipose progenitor cells? Where are they localized and where do they come from?
4) What factors determine which kind of fat cell will be formed during development?
The ultimate goal of our research is to use our understanding of adipocyte development to generate novel therapeutic strategies for the treatment of obesity and metabolic disease.
1. Transcriptional Control of Preadipocyte Competency
We recently identified the C2H2 zinc finger protein Zfp423 as a transcriptional regulator of preadipocyte determination. We are using molecular, cellular, and biochemical techniques to identify upstream regulators of Zfp423 as well as downstream effectors of Zfp423 function in adipogenesis. In addition, we are using genetic mouse models to elucidate the requirement of Zfp423 in adipose biology in vivo. Identifying additional critical transcriptional components controlling preadipocyte commitment is a major focus of our lab.
Immunohistochemistry staining of interscapular brown fat of wild-type and Zfp423-deficient animals reveals diminished brown fat size, abnormal tissue architecture, and poor expression of brown fat markers (UCP1) in Zfp423 knockout mice.
2. Localization and Developmental Origin of Preadipocytes
We have developed transgenic mice expressing Green Fluorescent Protein (GFP) under the control of the Zfp423 locus. Isolation of GFP expressing cells from adipose-derived stromal cultures selects for primary preadipose fibroblasts; this allows us to study primary preadipocytes derived from various fat depots in the mouse. Histological localization of GFP expression in Zfp423GFP mice, combined with other genetic approaches, allows us to track preadipocyte during development and in obesity.
Isolation of GFP+ fibroblasts from adipose-derived stromal cultures selects for committed preadipocytes.
Where these progenitors come from and how/when they are stimulated to become adipocytes is the focus of study in my laboratory. (Image designed by Eric Smith, Boston, MA)