Medical Management of Obesity
The Merrick laboratory is located within the Institute for Diabetes, Obesity and Metabolism (IDOM) at the University of Pennsylvania / Perelman School of Medicine and is affiliated with the Department of Medicine Division of Endocrinology as well as the Cell Biology, Physiology and Metabolism Program.
Obesity and the metabolic syndrome represent a profound public health challenge for which there are few effective therapeutics. Fundamentally, obesity arises in the setting of nutrient excess, which stimulates adipose tissue expansion. The healthy growth of adipose tissue depends on the capacity of progenitor cells to undergo de novo adipogenesis. However, the cellular hierarchy and mechanisms governing adipocyte progenitor lineage allocation are poorly understood.
Our research program is focused on understanding the cells types, niche locations and intracellular signaling pathways that regulate mesenchymal progenitor cell activity. Using cutting-edge approaches including single-cell RNA transcriptomics, CRISPR-based rapid mouse model generation and in-vivo lineage tracing, we have discovered several novel progenitor cell populations including Interstitial Progenitor Cells (IPCs) and connective-tissue resident macrophages. IPCs are multipotent progenitors, which can give rise to committed preadipocytes and mature adipocytes. Importantly, we found that IPCs and connective tissue macrophages cohabit the Reticular Interstitium (RI), a fibrous tissue that envelops many organs including adipose depots and represents a novel anatomical niche for mesenchymal progenitors.
Mesenchymal progenitors represent a promising therapeutic target for the treatment of obesity and diabetes. Directing the differentiation of progenitor cells away from a deleterious pro-fibrotic phenotype and towards a metabolically beneficial fate could significantly improve outcomes for patients suffering from the consequences of obesity.
Stefkovich M, Traynor S, Cheng L, Merrick D, Seale P.: Dpp4+ interstitial progenitor cells contribute to basal and high fat diet-induced adipogenesis. Mol Metab Oct 2021.
Merrick D, Seale P.: Skinny Fat Cells Stimulate Wound Healing. Cell Stem Cell 26: 801-803, Jun 2020.
Merrick David, Sakers Alexander, Irgebay Zhazira, Okada Chihiro, Calvert Catherine, Morley Michael P, Percec Ivona, Seale Patrick: Identification of a mesenchymal progenitor cell hierarchy in adipose tissue. Science (New York, N.Y.) 364(6438), April 2019.
Merrick David, Mistry Kavita, Wu Jingshing, Gresko Nikolay, Baggs Julie E, Hogenesch John B, Sun Zhaoxia, Caplan Michael J: Polycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ. Human molecular genetics 28(1): 16-30, January 2019.
Merrick D, Sakers A, Kim J, Irgebay Z, Seale P.: “Population Dynamics of Adipocyte Progenitors.” Kroc Lecture, (2018 and 2019)University of Pennsylvania, Perelman School of Medicine and Department of Medicine Research Day, University of Pennsylvania, June 2018 March 2018 Notes: Poster Presentation.
Merrick David, Bertuccio Claudia A, Chapin Hannah C, Lal Mark, Chauvet Veronique, Caplan Michael J: Polycystin-1 cleavage and the regulation of transcriptional pathways. Pediatric nephrology (Berlin, Germany) 29(4): 505-11, Apr 2014.
Merrick David, Chapin Hannah, Baggs Julie E, Yu Zhiheng, Somlo Stefan, Sun Zhaoxia, Hogenesch John B, Caplan Michael J: The γ-secretase cleavage product of polycystin-1 regulates TCF and CHOP-mediated transcriptional activation through a p300-dependent mechanism. Developmental cell 22(1): 197-210, Jan 2012.
Karihaloo Anil, Koraishy Farrukh, Huen Sarah C, Lee Yashang, Merrick David, Caplan Michael J, Somlo Stefan, Cantley Lloyd G: Macrophages promote cyst growth in polycystic kidney disease. Journal of the American Society of Nephrology : JASN 22(10): 1809-14, Oct 2011.
Lal Mark, Song Xuewen, Pluznick Jennifer L, Di Giovanni Valeria, Merrick David M, Rosenblum Norman D, Chauvet Veronique, Gottardi Cara J, Pei York, Caplan Michael J: Polycystin-1 C-terminal tail associates with beta-catenin and inhibits canonical Wnt signaling. Human molecular genetics 17(20): 3105-17, Oct 2008.
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Last updated: 05/18/2022
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