Download Adipocyte-Browning

Browning of Adipocyte
I.
SUMMARY OF BROWNING
Gene expression based classification of white adipocyte Browing Agent
* 기초 Study
- 2000년대 후반 성인에서 근육전구세포 유래 Active Brown Adipose Tissue 발견
- 2010년대 초반 White Adipose Tissue Depot에서 Brown Adipocyte like behavior를 하는
세포 발견 후 Beige Adipocyte로 명명
- Beige Adipocyte는 지방세포 lineage에서 분화하며 WAT와 Beige AT 사이의 Transdifferentiation도 있는 것으로 보고되고 있어 BAT의 분화 촉진 또는 WAT의 Browning이 당뇨
및 비만 치료 기전으로 대두되고 있음.
- 현재 Browning Agent들이 다수 보고되고 있으나 해당 Agent들이 어떻게 작용하고
이것이 global gene expression을 어떤 방식으로 Alter하는지에 대해서는 산발적인 Study를
제외하고 Systematic한 Study가 없는 상태임.
- 연구실에서 Model 세포로 사용중인 3T3 L1 역시 Beige Adipocyte로 분화가 가능하며
이를 이용한 Beiging 현상에 대한 연구가 근래 들어 속속 보고되고 있음
- 이러한 Browning Agent들에는 Dietary Chemical들도 다수 있는 것으로 보고되고 있어
천연물에서 Browning Agent를 찾을 가능성이 높다고 판단됨.
- 따라서 Systematic한 Chemical perturbagen의 global gene expression profiling을 통해
이들 Browning Agent들을 Classify 한다면 이러한 Class에 기반하여 신규 Browning Agent를
Screening 할 수 있을 것으로 판단됨.
White, Brown, and Beige Fat
1. General Information about Adipocytes
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Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose
adipose tissue, specialized in storing energy as fat.
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There are two types of adipose tissue, white adipose tissue (WAT) and brown adipose tissue
(BAT), which are also known as white fat and brown fat, respectively, and comprise two types
of fat cells.
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Although the lineage of adipocytes is still unclear, pre-adipocytes are undifferentiated
fibroblasts that can be stimulated to form adipocytes.
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Mesenchymal stem cells can differentiated into adipocytes, connective tissue, muscle or
bone.
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BAT and WAT are histologically distinct types of tissues.
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In humans, brown fat is abundant at birth but is rapidly replaced by white adipose tissue
(WAT) and is relatively scarce in the adult as an identifiable tissue. Brown fat cells are
interspersed within WAT of rodents and humans. Activation of BAT requires 3-adrenergic
receptor agonism.
2. WAT Browning - Z:\3-Disease\1-Diabetes-기민난영\TPH(Serotonin)\ 160309 김하일
overview.pptx
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Pgc-1, a cold inducible coactivator of PPARγ
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PGC-1α is essential for brown fat thermogenesis
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But, Pgc-1a is not essential for brown fat differentiation
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PRDM16 is selectively expressed in BAT
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PRDM16 induces brown adipogenesis
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Formation of BAT in WAT depot by PRDM16 expression
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KD of PRDM16 in BAT induces skeletal myogenesis
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Brown fat and skeletal muscle arise from Myf5-expressing precursors
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PRDM16 stimulates adipocyte differentiation in myoblasts
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Generation of functional BAT in vivo by expression of PRDM16 and C/EBPβ
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Prdm16 is highly expressed in inguinal WAT (iWAT, SC WAT)
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Prdm16 stimulates BAT development in iWAT
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Mutilocular Ucp1+ cells are prominent in iWAT
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Two distinct adipose cell types from iWAT
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Beige cells have characteristics of both white and brown cell
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Brown fat in adult human are similar to murine beige cells
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Sympathetic control of BAT activity in human
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Metabolically active BAT in healthy adult human
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BAT activity as assessed by PET-CT with 18F-FDG
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Different BAT activity in same human under different conditions
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Discovery of functional BAT in adult human
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Inverse correlation of BAT activity with BMI and body fat
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Supercharging Brown Fat to Battle Obesity - Why turning down the thermostat could help
win the battle of the bulge?
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Factors inducing brown and/or beige adipocytes
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Serotonin (5-HT, 5-hydroxytryptamin)
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5-HT receptor
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Increased 5-HT production in WAT
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Loss of visceral fat by PCPA
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PCPA improves insulin sensitivity
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PCPA increases energy expenditure
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PCPA decreases lipogenesis in eWAT
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PCPA induces beige fat formation in iWAT
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Increased adaptive thermogenesis in brown fat
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Increased size and number of mitochondria in BAT
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Increased glucose uptake into brown fat
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Tph1 FKO are resistant to HFD
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Tph1 FKO increases Ucp1 expression in iWAT
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Tph1 AFKO are resistant to HFD
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5-HT plays different roles in adipose tissues
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Inhibition of peripheral 5-HT as an anti-obesity treatment strategy
<Brown Adipocyte Development>
<Beige Fat Biogenesis>
3. Key References
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Historical perspectives in fat cell biology: the fat cell as a model for the investigation of
hormonal and metabolic pathways, Am J Physiol Cell Physiol, 2012
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Transcriptional control of brown fat determination by PRDM16. Cell Metab. 6, 38–54
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PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008).
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Initiation of myoblast to brown fat switch by a PRDM16–C/EBP-β transcriptional complex.
Nature 460, 1154–1158 (2009).
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Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice.
J. Clin. Invest. 121, 96–105 (2011).
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PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16
protein. Cell Metab. 15, 395–404 (2012).
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Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150,
366–376 (2012).
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Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ. Cell
150, 620–632 (2012).
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Tracking
adipogenesis
during white
adipose tissue development,
expansion and
regeneration. Nature Med. 19, 1338-1344 (2013)
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Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white
fat. Nature 495, 379–383 (2013).
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EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex.
Nature. 504, 163 (2013)
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Ablation of PRDM16 and Beige Adipose Causes Metabolic Dysfunction and a Subcutaneous
to Visceral Fat Switch. Cell. 156, 304-316 (2014)
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Prdm16 is required for the maintenance of brown adipocyte identity and function in adult
mice. Cell Metabolism, 19(4), 593–604.
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Cold-Inducible Zfp516 Activates UCP1 Transcription to Promote Browning of White Fat and
Development of Brown Fat. Molecular Cell.
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The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through
attenuation of hepatic lipogenesis. Nature Medicine, 20(12), 1436–1443.
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Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by
promoting brown adipose tissue thermogenesis. Nature Medicine.
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Brown and Beige Fat: Physiological Roles beyond Heat Generation. Cell Metabolism, 2015
II. DISCOVERY MODEL FOR BROWNING AGENT
1.
PPARg agonists Induce a White-to-Brown Fat Conversion through Stabilization of PRDM16
Protein
- Rosiglitazone induces Browning by inhibiting ubiquitination of PRDM16 in adipocyte, Cell
Metabol., 2012
2.
Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin
resistance, Nat. Med. 2015
3.
White-to-brown metabolic conversion of human adipocytes by JAK inhibition, Nat. Cell.
Biol., 2015
Study Outline
- Beige adipocyte differentiation/transdifferentiation 관련 문헌 Update
- White/beige adipose Tissue gene expression data 수집
- 3T3 L1 기반 White/beige adipocyte gene expression data 수집, 분석
- 3T3 L1 약물처리 expression data 수집, 분석
- 해당 약물처리 data 중에서 browning agent로 알려진 약물 처리 데이터 사이 유사성
분석
- 해당 Agent 처리 후 phenotype 유사성 분석
- 약물 처리 후 expression 유사성 + phenotype 유사성 통합 Scoring
- 유사성 Threshold Study
- 최종 Threshold를 이용하여 Browning Agent Classfy
- 해당 Class들 사이의 약물 유사성 비교 및 신규 Agent 발굴