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

My laboratory explores research focused on harnessing the potential of brown and beige adipose tissues as therapeutic targets for combating human obesity and associated metabolic disorders. In response to cold exposure, brown and beige adipocytes undergo metabolic activation, expending stored energy in glucose and lipids to generate heat—a process known as non-shivering thermogenesis. Activated brown/beige adipose tissue has the potential to prevent obesity through increased energy expenditure and offers protection against diet-induced insulin resistance and hepatic steatosis.

iPSC-Based Therapeutic Strategies to Increase Energy Expenditure

Traditional drug-based methods to increase energy expenditure in human adipose tissue for obesity and diabetes have faced significant challenges and cardiovascular risks. As an alternative, we are exploring cell-based therapies that could supplement obese patients with additional brown or beige adipose tissue, their precursor cells, or the secreted factors derived from these cells. However, obtaining these progenitor cells from humans involves invasive procedures, and their potential for expansion and differentiation diminishes with age and weight gain. To overcome these hurdles, our laboratory has leveraged induced pluripotent stem cell (iPSC) technology, successfully reprogramming somatic cells from both normal and diabetic patients into renewable, metabolically active human beige adipocytes. These cells show promise, secreting anti-diabetic factors and serving as a potential model for developing anti-obesity and anti-diabetic therapies. Additionally, we are actively developing 3-D adipose tissue models for testing in obese/diabetic mice to assess their effectiveness in promoting weight loss and combating obesity-related diabetes.

Optogenetic control of energy expenditure

A significant hurdle in implementing adipocyte cell-based therapies is the need to maintain cell activation post-transplantation. To address this challenge, we utilize optogenetic techniques to engineer adipocytes expressing a blue light-inducible bacterial adenylyl cyclase, capable of increasing intracellular cAMP and activating thermogenesis. This cutting-edge optogenetic tool enables precise temporal, spatial, dosage, and bidirectional control of thermogenesis. Our ongoing objective involves integrating 3-D iPSC-derived beige adipocytes with miniaturized, remote-controlled, blue light wireless transmitters for transplantation testing and the development of metabolic syndrome therapies.

MicroRNA Regulation in Thermogenesis

Recent models propose that exosomes released from brown/beige fat carry diverse signaling molecules, including microRNAs, RNAs, proteins, and lipids, with potential therapeutic impacts on metabolic disorders. An intriguing and underexplored concept is that exosome secretion might offer a swift mechanism for gene expression control within the secreting cell, particularly in microRNA disposal. Supporting this idea, our research highlights a rapid release of exosomes enriched in miR-27—known for its anti-thermogenic properties—during beige adipocyte activation. To delve deeper into miR-27 and its role in thermogenesis, we have developed miR-27 null and conditional mice. Ongoing research aims to identify miR-27 target genes and assess the impact of miR-27 deletion on beige and brown adipose tissue responses to temperature shifts and high-fat diets. This exploration holds the potential for uncovering novel therapies for metabolic diseases associated with miR-27 and its target genes.

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.