1. Transcriptional networks controlling the establishment and maintenance of white (energy-storing) and brown/beige (energy-burning) adipose tissue.
We have identified an important role for the C2H2 zinc-finger transcription factor, Zfp423, in adipose tissue. Zfp423 regulates commitment of adipose precursor cells, or “preadipocytes” to the adipose lineage through activation of Pparg, the “master regulator” of adipocyte differentiation. Furthermore, we have revealed a critical role for Zfp423 in maintaining the cellular identity of white adipocytes through suppression of the thermogenic brown/beige adipocyte gene program. Remarkably, loss of genetic inactivation of Zfp423 in adult mice triggers a widespread conversion of white to beige-like adipocytes, leading to resistance or even reversal of diet-induced obesity. Ongoing efforts are focused on identifying pathways that regulate Zfp423 geneexpression in the adipose lineage, as well as critical interacting partners and downstream effectors that mediate its function. Understanding the mechanisms that control Zfp423 expression and function in white adipocytes may lead to novel therapeutic strategies to combat obesity and metabolic disease.
2. Contribution of perivascular (mural) cells to adipose tissue remodeling.
The manner by which adipose tissue expands, or “remodels”, is a critical determinant of metabolic health in obesity. Pathological adipose tissue expansion is characterized enlarged adipocytes, a failure to recruit new adipocytes (adipogenesis), hypoxia, fibrosis, and pro-inflammatory macrophage infiltration. Healthy adipose tissue expansion (observed in the “Metabolically-Healthy” obese) involves recruitment of new adipocytes from resident precursors and lower levels of inflammation. This limits the burden on individual fat cells and prevents the acquisition of insulin resistance.
We have recently determined that adipose Pdgfrb+ perivascular (mural) cells are activated to differentiate into white adipocytes in the setting of obesity. The adipogenic fraction of these adipose mural cells can be identified on the basis of Zfp423 expression. Mural cells with a low level of Zfp423 expression exhibit a pro-inflammatory-like phenotype. Ongoing efforts in the lab are focused on identifying the signals that activate these mural cell precursors in obesity and elucidating the array of functions that mural cells have on energy balance and nutrient homeostasis. Understanding the biology of adipose precursors will shed tremendous insight into the developmental origin of fat tissue and physiological regulation of adipose tissue distribution. 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.