Aaron Brown

Education

A.A.: Liberal Arts, University of Maine, Orono
B.S.: Biochemistry, University of Maine, Orono
Ph.D.: Molecular/Cellular Biology & Biochemistry, University of Maine / The Jackson Laboratory

Research

Our laboratory is exploring ways to increase energy expenditure to combat obesity and metabolic syndrome by studying stem cells and signaling pathways that give rise to adipose tissue. There are several types of adipose tissue. Chronic periods of overeating result in weight gain due to excess energy being stored as fats in white adipose tissue. Accumulation of white adipose tissue in overweight individuals correlates with metabolic syndrome and disease. Brown adipose tissue plays the opposite role by converting energy stored in fats to heat. Brown adipose tissue plays a role in keeping infants and other mammals warm through a process known as non-shivering thermogenesis, which is activated when the sympathetic nervous system senses cold exposure. Studies have found that the activity of brown adipose tissue in both humans and rodents correlates positively with reduced risk of metabolic syndrome, making it an attractive tissue to develop obesity therapies. To take advantage of the potential therapeutic properties of brown adipose tissue, we are developing both mouse and human models to study brown adipose development and activation. Examples of projects include:

Modulation of TGF-beta and BMP signaling pathways to activate or increase the size of brown adipose tissue

Studies of transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP) signaling in mice have shown that these pathways are important for the development and activation of brown adipose. We are creating mouse models to target specific genes that give rise to key signaling components found in these pathways in an attempt to identify therapeutic targets that can enhance brown adipose function. These genetic studies will lead to the generation of therapeutic compounds that can be used to increase energy expenditure and decrease weight gain.

Generation of human brown adipose tissue from pluripotent stem cells for the treatment of metabolic syndrome

One obstacle in the study of brown adipose tissue development in humans has been the difficulty of procuring adult and early stage embryonic and fetal tissues. To solve this problem, we are developing cell culture methods to generate a renewable source of brown adipocyte specific stem cells from induced pluripotent stem cells (iPS cells). Direct reprogramming of somatic cells into iPS cells resets them to an early embryonic stem cell-like state and also raises the possibility of producing patient-matched cells for the study and treatment of obesity. Using these models, we are attempting to determine how brown adipose develops in humans and how this tissue can be therapeutically activated. This includes the study of both of TGFB and BMP signaling pathways and how they contribute toward the development of human brown adipose. Using immunodeficient mice, we are also exploring ways to determine if human iPS-generated brown adipose can be transplanted directly in animals in an attempt to see if it can serve directly as a therapeutic tissue to increase energy expenditure and combat metabolic syndrome.

Selected Publications

Guo Q, Kim A, Li B, Ransick A, Bugacov H, Chen X, Lindström N, Brown A, Oxburgh L, Ren B, McMahon AP. A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells. Elife. 2021 Feb 15;10:e64444. doi: 10.7554/eLife.64444.

Brown AC. Brown adipocytes from induced pluripotent stem cells-how far have we come? Ann N Y Acad Sci. 2020 Mar;1463(1):9-22. doi: 10.1111/nyas.14257.

Su S, Guntur AR, Nguyen DC, Fakory SS, Doucette CC, Leech C, Lotana H, Kelley M, Kohli J, Martino J, Sims- Lucas S, Liaw L, Vary C, Rosen CJ, Brown AC. A Renewable Source of Human Beige Adipocytes for Development of Therapies to Treat Metabolic Syndrome. Cell Rep. 2018 Dec 11;25(11):3215-3228.e9. doi: 10.1016/j.celrep.2018.11.037.

Blocking FSH induces thermogenic adipose tissue and reduces body fat. Liu P, Ji Y, Yuen, Rendina-Ruedy E, DeMambro VE, Dhawan S, Abu-Amer W, Izadmehr S, Zhou B, Shin AC, Latif R, Thangeswaran P, Gupta A, Li J, Shnayder V, Robinson ST, Yu YE, Zhang X, Yang F, Lu P, Zhou Y, Zhu LL, Oberlin DJ, Davies TF, Reagan MR, Brown AC, Kumar TR, Epstein S, Iqbal J, Avadhani NG, New MI, Molina H, van Klinken JB, Guo EX, Buettner C, Haider S, Bian Z, Sun L, Rosen CJ, Zaidi M. Nature. 2017 Jun 1;546(7656):107-112. Read Abstract

Growth Factor Regulation in the Nephrogenic Zone of the Developing Kidney. Oxburgh L, Muthukrishnan SD, Brown AC. Results Probl Cell Differ. 2017;60:137-164 Read Abstract

Brown AC, Muthukrishnan S, Oxburgh L. A Synthetic Niche for Nephron Progenitor Cells. Developmental Cell. 2015 Jul 27;34(2):229-41.

Yuwen Li, Jiao Liu, Wencheng Li, Aaron Brown, Melody Baddoo, Marilyn Li, Thomas Carroll, Leif Oxburgh, Yumei Feng, and Zubaida Saifudeen. p53 Enables Metabolic Fitness and Self-Renewal of Nephron Progenitor Cells. Development. 2015 Apr 1;142(7):1228-41

Fetting JL, Guay JA, Karolak MJ, Iozzo RV, Adams DC, Maridas DE, Brown AC, Oxburgh L. FOXD1 promotes nephron progenitor differentiation by repressing decorin in the embryonic kidney. Development. 2014 Jan;141(1):17-27.

Leif Oxburgh, Aaron C. Brown, Deepthi Muthukrishnan, Jennifer L. Fetting. Bone morphogenetic protein signaling in nephron progenitor cells. Pediatric nephrology. 2013 Aug 20.

Brown AC, Muthukrishnan S, Guay JA, Adams DC, Schafer DA, Fetting JL, Oxburgh L. Role for compartmentalization in nephron progenitor differentiation. PNAS. 2013. Mar 19;110(12):4640-5.

Brown AC, Adams DC, de Caestecker M, Yang X, Friesel R, Oxburgh L. FGF/EGF signaling regulates self renewal of renal progenitor cells during embryonic development. Development. 2011;138,5099-5112.

Brown AC, Blank U, Adams DC, Karolak MJ, Fetting JL, Hill BL, Oxburgh L. Isolation and culture of cells from the nephrogenic zone of the embryonic mouse kidney. J Vis Exp. 2011 Apr 22;(50).

Oxburgh L, Brown AC, Fetting J, Hill B. BMP signaling in the nephron progenitor niche. Pediatr Nephrol. 2011 Mar 4.

Blank U, Brown AC, Adams DC, Karolak MJ, Oxburgh L. BMP7 promotes proliferation of nephron progenitor cells via a JNK-dependent mechanism. Development. 2009;136(21):3557-66.

Serreze DV, Choisy-Rossi CM, Grier A, T. Holl M, Chapman HD, Gahagan JR, Osborne MA, Zhang W, King BL, Brown AC, Roopenian DC, and Marron MP. Through regulation of TCR expression levels, an Idd7 region gene(s) interactively contributes to the impaired thymic deletion of autoreactive diabetogenic CD8+ T cells in NOD mice1. J Immunol. 2008;180(5):3250-9.

Ostrov DA, Barnes CL, Smith LE, Binns S, Brusko TM, Brown AC, Quint PS, Litherland SA, Roopenian DC, Iczkowski KA.Characterization of HKE2: an ancient antigen encoded in the major histocompatibility complex. Tissue Antigens. 2007;69(2):181-8.

Petkova SB, Akilesh S, Sproule TJ, Christianson GJ, Al Khabbaz H, Brown AC, Presta LG, Meng YG, Roopenian DC. Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int Immunol. 2006;18(12):1759-69.

Brown AC, Lerner CP, Graber JH, Shaffer DJ, Roopenian DC. Pooling and PCR as a method to combat low frequency gene targeting in ES cells. Cytotechnology. 2006;51(2):81-8.

Brown AC, Olver W, Donnelly C, May M, Naggert J, Shaffer DJ, Roopenian DC. Searching QTLs by Gene Expression: Analysis of Diabesity. BMC Genet. 2005;10:12.

Brown AC, Kai K, May ME, Brown DC, Roopenian DC. ExQuest, A novel method for deciphering and displaying quantitative gene expression from ESTs. Genomics. 2004;83(3):528-39.

Hart GT, Shaffer DJ, Akilesh S, Brown AC, Moran L, Roopenian DC, Baker PJ. Quantitative gene expression profiling implicates genes for susceptibility and resistance to alveolar bone loss. Infect Immun. 2004;72:4471-9.

Luedtke B, Pooler LM, Choi EY, Tranchita AM, Reinbold C, Brown AC, Shaffer DJ, Roopenian DC, Malarkannan S. A single nucleotide polymorphism in the Emp3 gene differentially affects the quantity of allelic epitopes that define the H4 minor histocompatibility antigen. Immunogenetics. 2003;55:284-95.

Wang X, Phelan SA, Forsman-Semb K, Taylor EF, Petros C, Brown AC, Learner CP, Paigen B. Mice with targeted mutation of peroxiredoxin 6 develop normally but are susceptible to oxidative stress. J Biol Chem. 2003;278(27):25179-90.

Roopenian DC, Christianson, GJ, Sproule TJ, Brown AC, Akilesh S, Jung N, Petkova S, Avanessyan L, Choi, EY, Shaffer DJ, Eden PA, Anderson CL. The MHC class I-like IgG receptor (FcRn) controls perinatal IgG transport, IgG homostasis and the fate of IgG-Fc coupled drugs. J Immunol. 2003;170:3528-3533.

Roopenian DC, Choi EY, Brown AC. The immunogenomics of minor histocompatibility antigens. Immunol Rev. 2002;190:86-94.

Brown AC, Muthukrishnan S, Oxburgh L. A Synthetic Niche for Nephron Progenitor Cells. Developmental Cell. 2015 July 16. In press.