A pref-1-controlled non-inflammatory mechanism of insulin resistance
Yiheng Huang,
Donghong Cui,
Liujun Chen,
Haibin Tong,
Hong Wu,
Grace K. Muller,
Yadan Qi,
Shuxia Wang,
Jinjie Xu,
Xiang Gao,
Kathleen E. Fifield,
Lingyan Wang,
Zhengyuan Xia,
Jacqueline L. Vanderluit,
Suixin Liu,
Lin Leng,
Guang Sun,
John McGuire,
Lawrence H. Young,
Richard Bucala,
Dake Qi
Affiliations
Yiheng Huang
College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
Donghong Cui
Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Liujun Chen
College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
Haibin Tong
College of Life and Environment Sciences, Wenzhou University, Wenzhou, Zhejiang, China
Hong Wu
Institute of Cardiovascular Disease, Henan University of Chinese Medicine, Zhengzhou, Henan, China
Grace K. Muller
Department of Cell and Molecular Physiology, Loyola University, Chicago, IL, USA
Yadan Qi
College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
Shuxia Wang
Department of Cardiology, The General Hospital of Chinese PLA, Beijing, China
Jinjie Xu
Beijing Anding Hospital, Capital Medical University, Beijing, China
Xiang Gao
College of Life Sciences, Qingdao University, Qingdao, Shandong, China
Kathleen E. Fifield
Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
Lingyan Wang
Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
Zhengyuan Xia
Guangdong Medical University, Zhanjiang, China
Jacqueline L. Vanderluit
Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
Suixin Liu
Division of Cardiac Rehabilitation, Department of Physical Medicine & Rehabilitation, Xiangya Hospital of Central South University, Changsha, Hunan, China
Lin Leng
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
Guang Sun
Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
John McGuire
Department of Medical Biophysics, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
Lawrence H. Young
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
Richard Bucala
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
Dake Qi
College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada; Corresponding author
Summary: While insulin resistance (IR) is associated with inflammation in white adipose tissue, we report a non-inflammatory adipose mechanism of high fat-induced IR mediated by loss of Pref-1. Pref-1, released from adipose Pref-1+ cells with characteristics of M2 macrophages, endothelial cells or progenitors, inhibits MIF release from both Pref-1+ cells and adipocytes by binding with integrin β1 and inhibiting the mobilization of p115. High palmitic acid induces PAR2 expression in Pref-1+ cells, downregulating Pref-1 expression and release in an AMPK-dependent manner. The loss of Pref-1 increases adipose MIF secretion contributing to non-inflammatory IR in obesity. Treatment with Pref-1 blunts the increase in circulating plasma MIF levels and subsequent IR induced by a high palmitic acid diet. Thus, high levels of fatty acids suppress Pref-1 expression and secretion, through increased activation of PAR2, resulting in an increase in MIF secretion and a non-inflammatory adipose mechanism of IR.
