Coagulation factors promote brown adipose tissue dysfunction and abnormal systemic metabolism in obesity
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Brown adipose tissue (BAT) has a role in maintaining systemic metabolic health in rodents and humans. Here, we show that metabolic stress induces BAT to produce coagulation factors, which then—together with molecules derived from the circulation—promote BAT dysfunction and systemic glucose intolerance. When mice were fed a high-fat diet (HFD), the levels of tissue factor, coagulation Factor VII (FVII), activated coagulation Factor X (FXa), and protease-activated receptor 1 (PAR1) expression increased significantly in BAT. Genetic or pharmacological suppression of coagulation factor-PAR1 signaling in BAT ameliorated its whitening and improved thermogenic response and systemic glucose intolerance in mice with dietary obesity. Conversely, the activation of coagulation factor-PAR1 signaling in BAT caused mitochondrial dysfunction in brown adipocytes and systemic glucose intolerance in mice fed normal chow. These results indicate that BAT produces endogenous coagulation factors that mediate pleiotropic effects via PAR1 signaling under metabolic stress.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 104547 |
| Tidsskrift | iScience |
| Vol/bind | 25 |
| Udgave nummer | 7 |
| Antal sider | 23 |
| ISSN | 2589-0042 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
This work was supported by a Grant-in-Aid for Scientific Research (A) ( 20H00533 ) from MEXT , AMED - CREST under Grant Number JP20gm1110012 , Moonshot Research and Development Program ( 21zf0127003s0201 ), MEXT Supported Program for the Scleroderma Research Foundation at Private Universities Japan, Private University Research Branding Project, and Leading Initiative for Excellent Young Researchers, and grants from the Science Research Promotion Fund, the Takeda Medical Research Foundation , the Vehicle Racing Commemorative Foundation , Ono Medical Research Foundation , and the Suzuken Memorial Foundation (to T.M.). This research was also supported by grants from the Uehara Memorial Foundation , Kowa Life Science Foundation , SENSHIN Medical Research Foundation , Ono Medical Research Foundation , The Nakajima Foundation , Suzuken Memorial Foundation , as well as a Grant for Basic Science Research Projects from The Sumitomo Foundation , a Grant-in-Aid for Encouragement of Young Scientists (A) ( JSPS KAKENHI Grant Number 16H06244 ), grants from the Japan Cardiovascular Research Foundation , a Grant-in-Aid for Scientific Research (B) ( 19H03650 ), AMED Project for Elucidating and Controlling Mechanisms of Aging and Longevity under Grant Number JP21gm5010002 , and The Japan Geriatrics Society (to I.S.). Furthermore, support was provided by a Grant-in-Aid for Scientific Research (C) ( 19K08974 ), Yujin Memorial Grant, Sakakibara Memorial Research Grant from The Japan Research Promotion Society for Cardiovascular Diseases , TERUMO Life Science Foundation , Kanae Foundation (to Y.Y.), and by a grant from Bourbon (to T.M., I.S., and Y.Y.) and the joint research funds from Bayer (to T.M.). NZ.J. is supported by a research grant from the Danish Diabetes Academy , which is funded by the Novo Nordisk Foundation , grant number; NNF17SA0031406 .
Publisher Copyright:
© 2022 The Author(s)
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