Seale Lab

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. PPARg and members of the c/EBP family of transcription factors have been shown to orchestrate the terminal adipocyte differentiation process. However, these factors are expressed in both brown and white adipose cells and are thus presumed not to control white vs. brown adipose cell fate.

Several factors have been shown to influence the white versus brown adipose cell phenotype including: PGC-1a; FoxC2; pRb; p107 and RIP140. In a global expression screen of all known mouse transcriptional components, we 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 near-complete program of brown adipogenesis including induction of most brown adipose-selective genes, suppression of white adipose-selective genes and increased mitochondrial biogenesis. Reduction of PRDM16 in brown adipocytes causes a complete loss of the brown adipose phenotype. Most strikingly, loss of PRDM16 from brown adipogenic cells promotes the induction of skeletal muscle genes and differentiation. These data are consistent with a function for PRDM16 in the control of brown adipocyte versus skeletal muscle cell fate.

More recently, we identified EBF2 (Early B-Cell Factor 2) as a potential upstream regulator of Prdm16. EBF2 is a master regulator of brown adipose development that directs Peroxisome proliferator-activated receptor G (PPARG), to its brown-fat specific sites. However, it isn't known if EBF2 or other EBF factors have roles in adaptive cold responses. We are using in vivo and in vitro models of thermogenic activation to understand the roles EBF proteins play in regulating developmental and environmental thermogenic gene programs.

Close

Ageing is associated with a loss of capacity to induce beigeing of fat tissue.  Mice that are one-year old show a dramatically impaired response to cold-induced thermogenesis in subcutaneous adipose compared to young animals.  Concurrently, there is an increase in fibrosis in the aged fat tissue that can reduce the function of the existing cells.

We have discovered that the transcription factor PRDM16 manages the differentiation of adipose progenitors, encouraging them to mature into functional (beige) adipocytes and inhibiting fibrosis.  It does this by regulating the production of a metabolic signal by existing adipocytes, that is perceived by the adipose progenitors as they differentiate.  We are exploring the molecular pathways that regulate the production and transduction of this signal, in order to gain insights into how they become dysregulated during ageing.

Close

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 using single-cell sequencing technology to characterize the non-haematopoietic cellular populations that comprise developing and adult fat tissue.  These studies have allowed us to identify genetic signatures of adipose precursors at various states of determination and differentiation, giving us the ability to isolate early adipose stem cell populations for further study.  Using these progenitors, we are learning about the molecular events that control the development and function of fat cells.  Our ongoing work continues to develop new approaches to characterize these precursors in normal development and in obesity, as we seek to identify key regulatory components that control the activation, expansion and differentiation of these cells in response to developmental or metabolic cues.

Close

Perivascular adipose tissue (PVAT) surrounds large blood vessels throughout the body and is uniquely positioned to regulate vascular physiology. PVAT shares transcriptional similarities to classical brown adipose tissue, suggesting that factors important in thermogenic adipose (such as EBF2) may also regulate perivascular adipose tissue biology. Our lab has used the distinct developmental lineage of PVAT combined with lineage-restricted expression of EBF2 to generate an in vivo model of PVAT-specific loss of the thermogenic program. We are using this model to explore roles for thermogenic PVAT in regulating adaptive cold responses and atherogenesis.

Close

The epithelial lining of the small intestine is regenerated every 4-5 days.  Populations of stem cells within the intestinal crypts are responsible for generating the massive number of cells required to replace the shed cells and maintain intestine integrity and function.  Stem cells and their derivatives utilize different metabolic programs to fulfill their energetic requirements, yet how the transition between metabolic programs is regulated has not been described.

We have discovered that the transcription factor PRDM16 is a critical regulator of intestinal stem cell metabolism and differentiation in the proximal small intestine.  When PRDM16 is deleted in adult mice, the small intestine rapidly becomes disorganized, dysfunctional, and porous, leading to infection and wasting.  This research project is exploring PRDM16's role in stimulating the expression of fatty acid oxidation genes during small intestine stem cell differentiation.  Furthermore, PRDM16 exhibits differential expression along the length of the intestine, suggesting that stem cells may have regional differences in their biology, which we are also characterizing.

Close