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 #
5R01DK097441-03
Application #
8690055
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2012-09-10
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
$343,650
Indirect Cost
$126,150
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
Altshuler-Keylin, Svetlana; Shinoda, Kosaku; Hasegawa, Yutaka et al. (2016) Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance. Cell Metab 24:402-19
Ohyama, Kana; Nogusa, Yoshihito; Shinoda, Kosaku et al. (2016) A Synergistic Antiobesity Effect by a Combination of Capsinoids and Cold Temperature Through Promoting Beige Adipocyte Biogenesis. Diabetes 65:1410-23
Inagaki, Takeshi; Sakai, Juro; Kajimura, Shingo (2016) Transcriptional and epigenetic control of brown and beige adipose cell fate and function. Nat Rev Mol Cell Biol 17:480-95
Koh, Eun Hee; Chen, Yong; Bader, David A et al. (2016) Mitochondrial Activity in Human White Adipocytes Is Regulated by the Ubiquitin Carrier Protein 9/microRNA-30a Axis. J Biol Chem 291:24747-24755
(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Chondronikola, Maria; Volpi, Elena; Børsheim, Elisabet et al. (2016) Brown Adipose Tissue Activation Is Linked to Distinct Systemic Effects on Lipid Metabolism in Humans. Cell Metab 23:1200-6
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
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
Kazak, Lawrence; Chouchani, Edward T; Jedrychowski, Mark P et al. (2015) A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 163:643-55
Kajimura, Shingo; Spiegelman, Bruce M; Seale, Patrick (2015) Brown and Beige Fat: Physiological Roles beyond Heat Generation. Cell Metab 22:546-59

Showing the most recent 10 out of 22 publications