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

doi:10.1016/j.isci.2023.106923

A pref-1-controlled non-inflammatory mechanism of insulin resistance

iScience. 2023 May 19;26(6):106923. doi: 10.1016/j.isci.2023.106923. eCollection 2023 Jun 16.

Authors

Yiheng Huang¹, Donghong Cui², Liujun Chen¹, Haibin Tong³, Hong Wu⁴, Grace K Muller⁵, Yadan Qi¹, Shuxia Wang⁶, Jinjie Xu⁷, Xiang Gao⁸, Kathleen E Fifield⁹, Lingyan Wang⁹, Zhengyuan Xia¹⁰, Jacqueline L Vanderluit⁹, Suixin Liu¹¹, Lin Leng¹², Guang Sun⁹, John McGuire¹³, Lawrence H Young^{12

14}, Richard Bucala¹², Dake Qi^{1

9}

Affiliations

¹ College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
² Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ College of Life and Environment Sciences, Wenzhou University, Wenzhou, Zhejiang, China.
⁴ Institute of Cardiovascular Disease, Henan University of Chinese Medicine, Zhengzhou, Henan, China.
⁵ Department of Cell and Molecular Physiology, Loyola University, Chicago, IL, USA.
⁶ Department of Cardiology, The General Hospital of Chinese PLA, Beijing, China.
⁷ Beijing Anding Hospital, Capital Medical University, Beijing, China.
⁸ College of Life Sciences, Qingdao University, Qingdao, Shandong, China.
⁹ Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
¹⁰ Guangdong Medical University, Zhanjiang, China.
¹¹ Division of Cardiac Rehabilitation, Department of Physical Medicine & Rehabilitation, Xiangya Hospital of Central South University, Changsha, Hunan, China.
¹² Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
¹³ Department of Medical Biophysics, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.
¹⁴ Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.

Abstract

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.

Keywords: Cell biology; Immunology; Molecular biology; Transcriptomics.

Grants and funding

UL1 TR001863/TR/NCATS NIH HHS/United States