Our lab focuses on the biology of adipose (fat) cells and tissue. Adipose tissue is a highly dynamic and plastic organ, regulating many aspects of whole-body physiology. In addition to its crucial role in maintaining energy levels, adipose tissue regulates body weight, body temperature, blood pressure, insulin sensitivity and serves as a hub for immune responses. Depots of adipose tissue are distributed throughout the body, including underneath the skin, around internal organs, within bones and surrounding large blood vessels, serving specialized functions in each of these locations.
Adipose tissues are defined by the presence of specialized lipid-handling cells called adipocytes. Mammals have two main subtypes of adipocytes, white and brown. White adipocytes are specialized for energy storage and release in response to systemic demand. By contrast, brown adipocytes expend chemical energy (lipid, sugars) in the form of heat to protect animals against hypothermia during cold exposure. Brown fat-like cells, called beige adipocytes, can also be induced to develop within WAT depots in response to various stimuli, thereby augmenting thermogenic capacity.
Adipose tissues are also central players in the development and health consequences of obesity, which has reached epidemic proportions in the US and many parts of the world. Obesity is a leading cause or contributor to an expanding array of diseases such as type 2 diabetes, heart disease, stroke, arthritis, and many types of cancer. In some people, persistent weight gain overburdens the capacity of adipose tissue to safely sequester the excess nutritional energy. In these cases, the adipose tissue becomes inflamed and fibrotic, leading to ectopic deposition of lipid in liver and other tissues. This obesity-induced impairment of adipose tissue function is a primary driver of insulin resistance (pre-diabetes), fatty liver and other metabolic complications, which can eventually progress to type 2 diabetes.
Our lab is investigating mechanisms that control the development and remodeling of adipose tissue in response to external stimuli, such as cold exposure, obesity, and certain diets. In the setting of obesity, promoting adipocyte hyperplasia via the differentiation of resident progenitor cells into new fat cells is associated with improved metabolic health. Furthermore, promoting brown and beige fat cell development and function can protect against obesity and metabolic diseases.
Our projects are divided into two main areas:
(1) Brown fat biology and therapeutic potential.
Brown and beige fat can counteract obesity by expending excess nutritional energy. Increased brown adipose tissue function also promotes a healthy metabolic phenotype by burning toxic metabolites such as fatty acids, glucose, and branched chain amino acids, thereby preventing their accumulation in many organs. In humans, the amount of brown fat tissue is inversely correlated with body mass index, suggesting a potential role for brown fat in regulating body weight. Furthermore, there is great hope that brown fat-targeted therapies can be developed for obesity, fatty liver and diabetes.
Our lab is focused on identifying and understanding the mechanisms that regulate brown fat cell development and function. We are also interested in determining non-canonical functions for brown and beige fat cells in metabolic regulation.
(2) Adipose tissue remodeling responses
Adipose tissue undergoes dynamic metabolic and structural remodeling in response to various stimuli. For example, during cycles of fasting and feeding, adipocytes dramatically alter their metabolic program to accommodate the energetic needs of the organism. Upon chronic cold exposure, white adipose tissue undergoes dramatic remodeling, involving the development of thermogenic beige fat cells, recruitment of blood vessels and increased arborization of nerve fibers. During weight gain, adipose tissue can expand through metabolically beneficial adipocyte hyperplasia and/or via maladaptive adipocyte hypertrophy. In aging, adipose tissue undergoes pronounced fibrotic changes and brown fat activity is reduced.
Our lab is focused on determining the pathways that control these adipose tissue responses. We are focusing on the role of several recently identified mesenchymal cell populations, including how these cell types contribute to adipocyte renewal, fibrosis and inflammatory responses.
The long term goal is to develop novel approaches to promote metabolically-beneficial adipose tissue remodeling responses for reducing the risk of type 2 diabetes and related disease.
Stem Cells, Embryonic development, Adipocyte progenitors, Brown adipose tissue, White adipose tissue, Mesenchymal stem cells, PRDM16, PPARgamma
1. Brown Adipocyte Development
A priority is to determine the brown fat cell lineage hierarchy in mice and human. This will involve defining the cell types, including stem cells, progenitor cells and preadipocyte cells (and transition states) along the brown adipocyte developmental trajectory. We are also investigating the mechanisms governing cell fate transitions involved in brown adipocyte commitment and differentiation. These studies involve the application of human stem cell models and various mouse developmental systems.
2. Transcriptional mechanisms in adipocyte differentiation.
We have previously defined several transcriptional components of brown fat cells, including EBF2, PRDM16 and DPF3. Our ongoing studies focus on determining the mechanism-of-action of these factors and their associated proteins. We are also applying genome-wide methods to evaluate chromatin regulation and transcriptional mechanisms in human adipocyte differentiation. Our initial screening studies have identified several novel factors for further investigation.
3. Adipose Tissue Remodeling
Determine the mechanisms that control adipose tissue remodeling in response to various stimuli, including cold exposure and obesity. Projects are focused on understanding the pathways that regulate white and beige adipocyte differentiation, fibrosis responses and immune cell infiltration. A major unresolved question in the field relate to the nature of the pathways that regulate the proliferation, self-renewal, and differentiation of adipocyte progenitor cells in vivo. We are particularly interested in mechanisms of inter-cellular communication, for example mesenchymal cell-immune cell interactions, and adipocyte-precursor interactions.
4. Identify genes and pathways that confer susceptibility to type 2 diabetes
As part of an NIH Consortium effort, we will investigate the role of candidate human genes and pathways in the development and progression of insulin resistance, fatty liver, type 2 diabetes and related metabolic disorders. Studies are being conducted in human fat cell models and through use of mouse in vivo genetic disease models.
5. Mesenchymal cell heterogeneity and fibrosis responses
Single cell transcriptomic analyses have revealed substantial heterogeneity within the connective tissue (ie. fibroblast) compartment of many organs, including fat tissue. We are interested in examining the role of various cell populations in organ development, renewal, and disease.
Please contact me if you are interested in discussing a rotation project in the lab.
Rachel Stine, PhD
Karima Drareni, PhD
Injae Hwang, PhD
Yang Chen, PhD
Corey Holman, BSc (CAMB)
Seoyoung Jun, BSc (Biology)
Samay Sampat, BSc
Michelangella Arbocco, BSc
Matthew Harms (Scientist, Astra-Zeneca)
Zeynep Firtina (Associate Professor, Genetics and Bioengineering, Izmir University)
Sona Rajakumari (Assistant Professor, Indian Institute of Science)
Megan Coyle (Patent agent, Philadelphia)
Suzi Shapira (Postdoctoral fellow, UCLA)
Brian Kwon (Dental School, UPenn)
Jeff Ishibashi (Scientist, Gene Therapy Program, UPenn)
Anthony Angueira (MD/PhD student, UPenn)
Alex Sakers (MD/PhD student, UPenn)
Chihiro Okada (Medical School, NYU)
David Merrick (Assistant Professor, Dept. of Medicine, UPenn)
Angueira AR, Shapira SN, Ishibashi J, Sampat S, Sostre-Colón J, Emmett MJ, Titchenell PM, Lazar MA, Lim HW, Seale P.: Early B Cell Factor Activity Controls Developmental and Adaptive Thermogenic Gene Programming in Adipocytes. Cell Reports 30(9): 2869-2878, March 2020.
Merrick D, Sakers A, Irgebay Z, Okada C, Calvert C, Morley MP, Percec I, Seale P: Identification of a mesenchymal progenitor cell hierarchy in adipose tissue. Science 364(6438): eaav2501, April 2019.
Wang W, Ishibashi J, Trefely S, Shao M, Cowan AJ, Sakers A, Lim HW, O'Connor S, Doan MT, Cohen P, Baur JA, King MT, Veech RL, Won KJ, Rabinowitz JD, Snyder NW, Gupta RK, Seale P: A PRDM16-Driven Metabolic Signal from Adipocytes Regulates Precursor Cell Fate. Cell Metab. 30(1): 174-189, July 2019.
Stine RR, Sakers AP, TeSlaa T, Kissig M, Stine ZE, Kwon CW, Cheng L, Lim HW, Kaestner KH, Rabinowitz JD, Seale P.: PRDM16 Maintains Homeostasis of the Intestinal Epithelium by Controlling Region-Specific Metabolism. Cell Stem Cell 25(6): 830-845, Dec 2019.
Shapira Suzanne N, Lim Hee-Woong, Rajakumari Sona, Sakers Alexander P, Ishibashi Jeff, Harms Matthew J, Won Kyoung-Jae, Seale Patrick: EBF2 transcriptionally regulates brown adipogenesis via the histone reader DPF3 and the BAF chromatin remodeling complex. Genes Dev. 31(7): 660-673, Apr 2017.
Kissig Megan, Ishibashi Jeff, Harms Matthew J, Lim Hee-Woong, Stine Rachel R, Won Kyoung-Jae, Seale Patrick: PRDM16 represses the type I interferon response in adipocytes to promote mitochondrial and thermogenic programing. EMBO J. 36(11): 1528-1542, Jun 2017.
Rajakumari S, Wu J, Ishibashi J, Lim H-W, Won KJ, Reed RR, Seale P: Ebf2 determines and maintains brown adipocyte identity. Cell Metab 17: 562-74, Apr 2013.
Wang Wenshan, Seale Patrick: Control of brown and beige fat development. Nature reviews. Molecular cell biology 17(11): 691-702, 11 2016.
Ishibashi J, Seale P: Beige can be slimming. Science 328: 1113-4, 2010.
Harms MJ, Lim HW, Ho Y, Shapira SN, Ishibashi J, Rajakumari S, Steger DJ, Lazar MA, Won KJ, Seale P: PRDM16 binds MED1 and controls chromatin architecture to determine a brown fat transcriptional program. Genes Dev 29(3): 298-307, Feb 2015.
Wang W, Kissig M, Rajakumari S, Huang L, Lim HW, Won KJ, Seale P: Ebf2 is a selective marker of brown and beige adipogenic precursor cells. Proc Natl Acad Sci U S A 111(40): 14466-71, Oct 2014.
Harms M, Seale P: Brown and beige fat: development, function and therapeutic potential. Nat Med 19: 1252-63, 2013.
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Last updated: 02/01/2022
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