Obesity is a major risk factor for metabolic disorders such as type-2 diabetes and cardiovascular disease.Obesity results from disturbed energy balance, where energy intake (i.e. feeding) chronically exceeds totalenergy expenditure. Due to its remarkable oxidative capacity to dissipate excess chemical energy, brown fatactivity is tightly linked to the development of obesity and metabolic disorders. Since recent studies clearlydemonstrated the existence of significant deposits of active brown adipose tissue (BAT) in adult humans,altering the amount and activity of BAT could provide a novel therapeutic intervention to counteract obesity andmetabolic syndrome. We have recently identified a zinc finger protein, PRDM16, as a dominant molecular switch in the fate ofbrown fat cells via induction of a 'brown fat program' in white pre-adipocytes and myf5-positive myoblasticprecursors. Most recently, we found that PRDM16 forms a transcriptional complex with the active form ofC/EBP- (LAP), serving as the critical molecular unit that controls the cell fate switch from myoblasticprecursors to brown fat cells. Significantly, ectopic expression of these two factors; PRDM16 and C/EBP- issufficient to reconstitute a fully functional brown fat program in na ve fibroblastic cells, including skin fibroblastsin vitro and in vivo. This proposal aims to investigate the function and molecular basis of engineered brown fat cells induced byPRDM16 and C/EBP- . As a main focus of the first phase (K99), we will utilize transplantation of engineeredbrown fat cells to critically assess their impact on whole body energy expenditure and their anti-obesitypotential (Aim1). In the second phase (R00), we will examine the molecular basis by which the PRDM16-C/EBP- transcriptional complex reprograms a cell fate into brown fat (Aim2). We will also dissect the cAMPsignaling pathways to further improve the function of engineered brown fat (Aim3). Together, these studies willuncover the therapeutic potential of engineered brown fat cells for the treatment of obesity and metabolicdisorders, and also will open my future research avenue as an independent investigator.

Public Health Relevance

A worldwide epidemic of obesity is now a formidable public health issue, since obesity is a major risk factor for many diseases, including type 2 diabetes, cardiovascular disease, stroke, hypertension, and many cancers. Because adult humans indeed have substantial amounts of functioning brown adipose tissue (BAT) that can counteract obesity by raising energy expenditure, understanding and modulating this pathway may provide new opportunities for the development of novel classes of therapeutics for metabolic diseases like obesity and type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Transition Award (R00)
Project #
4R00DK087853-03
Application #
8235443
Study Section
Special Emphasis Panel (NSS)
Program Officer
Haft, Carol R
Project Start
2011-05-01
Project End
2014-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
3
Fiscal Year
2011
Total Cost
$249,000
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Kajimura, S (2015) Promoting brown and beige adipocyte biogenesis through the PRDM16 pathway. Int J Obes Suppl 5:S11-4
Sidossis, Labros; Kajimura, Shingo (2015) Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest 125:478-86
Kajimura, Shingo; Spiegelman, Bruce M; Seale, Patrick (2015) Brown and Beige Fat: Physiological Roles beyond Heat Generation. Cell Metab 22:546-59
Shinoda, Kosaku; Ohyama, Kana; Hasegawa, Yutaka et al. (2015) Phosphoproteomics Identifies CK2 as a Negative Regulator of Beige Adipocyte Thermogenesis and Energy Expenditure. Cell Metab 22:997-1008
Shinoda, Kosaku; Luijten, Ineke H N; Hasegawa, Yutaka et al. (2015) Genetic and functional characterization of clonally derived adult human brown adipocytes. Nat Med 21:389-94
Kajimura, Shingo; Saito, Masayuki (2014) A new era in brown adipose tissue biology: molecular control of brown fat development and energy homeostasis. Annu Rev Physiol 76:225-49
Galmozzi, Andrea; Sonne, Si B; Altshuler-Keylin, Svetlana et al. (2014) ThermoMouse: an in vivo model to identify modulators of UCP1 expression in brown adipose tissue. Cell Rep 9:1584-93
Ohno, Haruya; Shinoda, Kosaku; Ohyama, Kana et al. (2013) EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature 504:163-7
Aune, Ulrike Liisberg; Ruiz, Lauren; Kajimura, Shingo (2013) Isolation and differentiation of stromal vascular cells to beige/brite cells. J Vis Exp :

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