Coagulation factors promote brown adipose tissue dysfunction and abnormal systemic metabolism in obesity

Yuka Hayashi, Ippei Shimizu, Yohko Yoshida, Ryutaro Ikegami, Masayoshi Suda, Goro Katsuumi, Shinya Fujiki, Kazuyuki Ozaki, Manabu Abe, Kenji Sakimura, Shujiro Okuda, Toshiya Hayano, Kazuhiro Nakamura, Kenneth Walsh, Naja Zenius Jespersen, Søren Nielsen, Camilla Scheele, Tohru Minamino

Abstract

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.

OriginalsprogEngelsk
Artikelnummer104547
TidsskriftiScience
Vol/bind25
Udgave nummer7
ISSN2589-0042
DOI
StatusUdgivet - 15 jul. 2022

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