Obesity develops when energy intake chronically exceeds total energy expenditure. Currently, most anti- obesity medications act to repress energy intake, either by suppressing appetite or by inhibiting intestinal fat absorption. However, due to side effects including depression, oily bowel movements and steatorrhea, there is an urgent need for alternative approaches. Because brown adipose tissue (BAT) dissipates energy to produce heat as a defense against cold and obesity, altering the molecular pathway to increase the amount or thermogenic activity of BAT may lead to an alternative and effective therapeutic intervention to counteract human obesity and metabolic disorders. Our long-term goals are to understand the molecular circuits that regulate the fate specification of brown adipose cells and to investigate their physiological roles in energy homeostasis. We have previously shown that brown adipocytes arise from a subset of dermomytomal precursors through the action of a transcription factor, PRDM16;however, it remains unclear how the PRDM16 action in the myoblast-to-brown fat switch is regulated. We identified a lysine methyltransferase, EHMT1 as a critical component of the PRDM16 transcriptional complex. EHMT1 is expressed at its highest in BAT and is highly induced by PRDM16. Notably, EHMT1 appears to act as a developmental switch of brown adipocytes versus myocytes. Importantly, loss of the EHMT1 gene is associated with obesity in mice and in humans;however, its underlying mechanism remains completely unknown. Our current objective is thus to investigate the physiological function and mechanism of EHMT1 that controls brown adipose cell fate in vivo. Based on our preliminary data, we will test the hypothesis that EHMT1 plays a pivotal role in energy homeostasis as a developmental switch that controls brown adipose cell fate through modulating the function of the PRDM16 complex. To test this hypothesis, we will pursue the following specific aims:
In Aim1, we will determine the genetic requirement of EHMT1 in the fate specification and maintenance of brown adipose cells in vitro and in vivo.
In Aim2, we will analyze the metabolic phenotypes of adipose-specific EHMT1 knockout mice and EHMT1 heterozygous null mice and critically characterize EHMT1's physiological role in controlling energy expenditure and glucose homeostasis in vivo.
In Aim3, we will conduct biochemical analyses and use cultured cells to elucidate the mechanism by which EHMT1 acts as a developmental switch of brown fat lineage. The expected outcome of these studies is to characterize a completely novel upstream regulatory pathway of brown adipose cell fate specification. Our findings will have a significant impact, because, to our knowledge, this study will characterize the first enzyme that controls the cell fate switch between brown adipose versus skeletal muscle. The identified mechanism will allow us to manipulate this developmental pathway by pharmacological approaches, which may provide a possible therapeutic target.

Public Health Relevance

Obesity and its metabolic consequences continue to be among the most important biomedical challenges in the USA today. Because brown fat dissipates energy to produce heat as a defense against cold and obesity, understanding the molecular control of brown fat development and function will provide new and promising therapeutic strategies for human obesity. Hence, the proposed research is closely aligned with the part of NIH's mission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK097441-01
Application #
8418644
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2012-09-10
Project End
2017-06-30
Budget Start
2012-09-10
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$340,388
Indirect Cost
$122,888
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Dentistry
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Sponton, Carlos Henrique; Kajimura, Shingo (2017) Burning Fat and Building Bone by FSH Blockade. Cell Metab 26:285-287
Fukunaka, Ayako; Fukada, Toshiyuki; Bhin, Jinhyuk et al. (2017) Zinc transporter ZIP13 suppresses beige adipocyte biogenesis and energy expenditure by regulating C/EBP-? expression. PLoS Genet 13:e1006950
Kajimura, Shingo (2017) Adipose tissue in 2016: Advances in the understanding of adipose tissue biology. Nat Rev Endocrinol 13:69-70
Ikeda, Kenji; Kang, Qianqian; Yoneshiro, Takeshi et al. (2017) UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat Med 23:1454-1465
Giordano, Antonio; Perugini, Jessica; Kristensen, David M et al. (2017) Mammary alveolar epithelial cells convert to brown adipocytes in post-lactating mice. J Cell Physiol 232:2923-2928
Bertholet, Ambre M; Kazak, Lawrence; Chouchani, Edward T et al. (2017) Mitochondrial Patch Clamp of Beige Adipocytes Reveals UCP1-Positive and UCP1-Negative Cells Both Exhibiting Futile Creatine Cycling. Cell Metab 25:811-822.e4
Altshuler-Keylin, Svetlana; Kajimura, Shingo (2017) Mitochondrial homeostasis in adipose tissue remodeling. Sci Signal 10:
Sonne, Si Brask; Yadav, Rachita; Yin, Guangliang et al. (2017) Obesity is associated with depot-specific alterations in adipocyte DNA methylation and gene expression. Adipocyte 6:124-133
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Altshuler-Keylin, Svetlana; Shinoda, Kosaku; Hasegawa, Yutaka et al. (2016) Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance. Cell Metab 24:402-419

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