Patrick Seale, Ph.D.

Description of Research Expertise

RESEARCH OVERVIEW

Obesity is the predominant risk factor for many diseases including: type 2 diabetes, heart disease, stroke and many cancers. We are investigating the regulatory pathways that control the development, differentiation and function of adipose (fat) cells in normal development and in obesity. We are particularly interested in early determination and commitment steps in which mesenchymal stem cells become committed to the adipose cell fate.

There are at least two very distinct types of adipose cells, white and brown, with opposing metabolic activities. White adipose tissue is highly adapted to store any excess energy from food as triglyceride (fat). Excess accumulation of this tissue in obesity has numerous health consequences.
Brown adipose tissue, on the other hand, functions to dissipate chemical energy in the form of heat. By increasing energy expenditure, this tissue can counteract obesity. Strategies that increase the amount or function of brown adipose in humans could be a safe and effective treatment for obesity and its associated diseases.

Key words: Stem Cells, Embryonic development, Adipocyte progenitors, Brown adipose tissue, White adipose tissue


CURRENT PROJECTS

1. Brown Adipocyte Development and PRDM16

Brown fat cells are packed with mitochondria that express Uncoupling Protein-1 (UCP1) in their inner membrane. Brown fat tissue is also highly vascular, enabling it to efficiently distribute heat via the circulation. The molecular pathways that control the process of adipogenic differentiation from preadipocytes have been extensively studied in animal models and cultured cells. Preadipocytes are specialized fibroblast-like cells contained in white and brown fat tissues that differentiate into mature fat storing adipocytes in response to hormonal cues. PPARgamma and members of the c/EBP family of transcription factors have been shown to orchestrate the terminal adipocyte differentiation process in both white and brown cell types. Several factors have been shown to influence the white versus brown adipose cell phenotype including: PGC-1alpha; FoxC2; pRb; p107 and RIP140.

In a global expression screen of all known mouse transcriptional components, we recently identified PRDM16 as a gene expressed selectively in brown adipose cells. Functional and genetic analyses have shown that PRDM16 is necessary and sufficient for the appropriate differentiation of brown adipocytes. Specifically, expression of PRDM16 in white fat or skeletal muscle progenitors activates a program of brown adipogenesis including induction of most brown adipose-selective genes, suppression of white adipose-selective genes and mitochondrial biogenesis. Strikingly, loss of PRDM16 from brown adipogenic cells promotes the induction of skeletal muscle genes and differentiation (Figure 1).



These data are consistent with a function for PRDM16 in the control of brown adipocyte versus skeletal muscle cell fate. Lineage tracing experiments suggest that skeletal myogenic cells and brown adipose cells may arise from similar progenitors during embryonic development (Figure 2). Elucidating the pathways that control lineage specification may uncover novel therapeutic targets to promote brown adipocyte development and limit obesity.

We are now investigating the mechanistic basis by which PRDM16 influences brown adipogenic cell fate using both cell based and mouse genetic approaches.



2. Identification of regulatory genes and pathways in white adipogenic precursors

A major unresolved and central issue in the field of obesity and metabolism research is the identity of the adipogenic precursor cell(s) and pathways that regulate the proliferation and self-renewal of these cells in vivo. We are interested in developing approaches to characterize these precursors in normal development and in obesity. We seek to identify key regulatory components that control the activation, expansion and differentiation of these cells in response to developmental or metabolic cues.




Rotation Projects

Please contact me if you are interested in discussing a rotation project in the lab.


Lab personnel

Postdoctoral Fellow(s) – Jeff Ishibashi
Research Specialist - Matthew Brown