Aaron Brown, PhD

Faculty Scientist I

Education

AA: Liberal Arts, University of Maine, Orono
BS:  Biochemistry, University of Maine, Orono
PhD: Molecular/Cellular Biology & Biochemistry, University of Maine / The Jackson Laboratory

Attempts to address the public health risk of obesity are focusing on brown and beige adipose tissue, which are promising therapeutic targets for combating human obesity and related metabolic disorders. Brown and beige adipocytes become metabolically activated in response to cold-stimulated release of norepinephrine by the sympathetic nervous system, where they expend energy stored in glucose and lipids to generate heat. This process, known as non-shivering thermogenesis, likely evolved in mammals to increase neonatal survival and provide warmth in cold temperatures. Studies in mice show that activated brown adipose tissue can prevent obesity through increased energy expenditure and protect against diet-induced insulin resistance and hepatic steatosis (fatty liver) through paracrine/endocrine signaling. Modifying obesity and diabetes in humans by stimulating energy expenditure in adipose tissue with drugs has largely been unsuccessful. One potential alternative to drugs is to generate cell-based therapies to supplement obese patients with additional brown or beige adipose tissue, their adipogenic precursors, or secreted factors derived from these cells. However, in humans, brown and beige adipocyte progenitor cells require invasive methods to procure, and have restricted expansion and differentiation potential and become more limited or absent with increasing age and weight gain. To overcome these problems, our laboratory has developed human models of brown and beige adipocytes by reprogramming somatic cells from diabetic patients using induced pluripotent stem cell (iPSC) technology. These iPSC-derived adipocytes are renewable, show high metabolic activity and secrete anti-diabetic factors, making them a good model for generation of anti-obesity/diabetic therapies. We are currently generating 3-dimensional adipose tissue models for engraftment testing in obese/diabetic mice to determine their overall regenerative potential. In addition, we are studying factors secreted by thermogenic adipocytes that may have the potential reverse metabolic dysfunction.

Ed Jachimowicz

Scientific Manager
jachie@mmc.org

Michele Karolak

Technology Manager
karolm@mmc.org

Su Su, PhD

Staff Scientist I
sus@mmc.org

Chad Doucette

Research Assistant I
CDoucette@mmc.org

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 Reports. Featured article. 2018 Dec 11;25(11):3215-3228.

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.

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.

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.