Our research is focused on extracellular matrix (ECM) remodeling in obesity, diabetes, and cardiovascular diseases. In the body, metabolically active mesenchymal cells are surrounded by a fibrous network of ECM proteins, for example, collagens, elastin, and fibronectin. Embedded within the dense network of ECM proteins, fat cells (adipocytes) and their precursor cells constantly change their shape and function in response to nutritional and hormonal cues.

• Matrix metalloproteinase (MMP) and adipose tissue/vascular biology: A membrane-type matrix metalloproteinase called MT1-MMP (MMP14) promotes adipose tissue expansion in obesity (Chun et al., Diabetes 2010). Mechanistically, MMP14-dependent collagen degradation is necessary for adipogenic histone modifications (Sato-Kusubata et al., Mol. Endocrinol. 2011). We have identified that Sca1-positive adipose tissue stromal cells play a leading role in adipose tissue ECM remodeling (Tokunaga et al., Matrix Biology 2014). This study led to the identification of TCF21 transcription factor, which drives interleukin 6 (IL6) expression and MMP-dependent ECM remodeling in white adipose tissues (Akama and Chun, J Biol Chem 2018). Our recent efforts newly identified the beneficial role played by MT1-MMP expressed by vascular smooth muscle cells (VSMC) in preventing atherosclerosis and aneurysm formation in mice (Barnes et al, J Am Heart Assoc. 2017).

• Matricellular protein in obesity complications : Thrombospondin 1 (TSP1 or THBS1) is a matricellular protein, which is produced by visceral adipose tissues and skeletal muscles in obesity. TSP1 causes skeletal muscle fibrosis and insulin resistance in mice and humans (Inoue et al., Endocrinology 2013, Matsuo et al, Metabolism 2015, Lin et al, Biochem Pharmacol 2016). TSP1 may cause fibro-adipogenic remodeling of diaphragm muscles, which may underlie the impaired respiratory function in obesity (Buras et al., Diabetes 2019).

• Organ on chip and three-dimensional (3D) organoid culture: In collaboration with researchers at Biointerfaces Institute of NCRC, we have developed a prototypical on-chip adipose tissue model for better understanding of metabolic tissue crosstalk on-chip (Moraes et al., Integr Biol 2013, Akama et al, Methods Mol Biol. 2017 ). Our recent study using human orbital fibroblast 3D organoids demonstrate that hypoxia inducible factor 2A (HIF2A) plays a central role in fibrotic tissue remodeling in Graves' eye disease (Hikage et al, Endocrinology 2019).

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Recent findings from our lab

HIF2A-LOX pathway promotes fibrotic tissue remodeling in thyroid-associated orbitopathy

Fumihito Hikage Stephen Atkins Alon Kahana Terry J Smith Tae-Hwa Chun

https://academic.oup.com/endo/advance-article/doi/10.1210/en.2018-00272/5150427

Free access.

Fibro-Adipogenic Remodeling of the Diaphragm in Obesity-Associated Respiratory Dysfunction

Eric D. Buras, Kimber Converso-Baran, Carol S. Davis, Takeshi Akama, Fumihito Hikage, Daniel E. Michele, Susan V. Brooks and Tae-Hwa Chun

Diabetes 2018 Oct; db180209.

https://doiorg/10.2337/db18-0209

Transcription factor 21 (Tcf21) promotes proinflammatory interleukin 6 expression and extracellular matrix
remodeling in visceral adipose stem cells

http://www.jbc.org/content/early/2018/03/14/jbc.RA117.000456.short?rss=1