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

doi:10.1016/j.isci.2022.104547

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

iScience. 2022 Jun 7;25(7):104547. doi: 10.1016/j.isci.2022.104547. eCollection 2022 Jul 15.

Authors

Yuka Hayashi¹, Ippei Shimizu², Yohko Yoshida^{2

3}, Ryutaro Ikegami¹, Masayoshi Suda², Goro Katsuumi², Shinya Fujiki¹, Kazuyuki Ozaki¹, Manabu Abe^{4

5}, Kenji Sakimura^{4

5}, Shujiro Okuda⁶, Toshiya Hayano⁷, Kazuhiro Nakamura⁸, Kenneth Walsh⁹, Naja Zenius Jespersen¹⁰, Søren Nielsen¹⁰, Camilla Scheele^{10

11}, Tohru Minamino^{2

12}

Affiliations

¹ Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
² Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8431, Japan.
³ Department of Advanced Senotherapeutics, Juntendo University Graduate School of Medicine, Tokyo 113-8431, Japan.
⁴ Department of Cellular Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuo-ku, Niigata 951-8585, Japan.
⁵ Department of Animal Model Development, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuo-ku, Niigata 951-8585, Japan.
⁶ Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
⁷ Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Shiga 525-8577 Japan.
⁸ Department of Integrative Physiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
⁹ Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
¹⁰ The Centre of Inflammation and Metabolism and Centre for Physical Activity Research Rigshospitalet, Copenhagen, Denmark.
¹¹ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
¹² Japan Agency for Medical Research and Development-Core Research for Evolutionary Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.

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.

Keywords: Biological sciences; Cell biology; Human Physiology; Human metabolism.