biostudies-literatureHuang YNatural Sciences and Engineering Research Council of CanadaResearch and Development Corporation of Newfoundland and LabradorChina Scholarship CouncilNCATS NIH HHSNational Institutes of HealthNIAMS NIH HHSCanadian Institutes of Health ResearchNewfoundland and Labrador106923https://www.ebi.ac.uk/biostudies/studies/S-EPMC10239698biostudies-literatureUnknown26(6)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. ThuiScienceA pref-1-controlled non-inflammatory mechanism of insulin resistance.PMC10239698RDC 5404.1980.102RGPIN-2017-04542R01 AR078334UL1 TR001863AR-078334PJT-156116Muller GKXia ZYoung LHFifield KEChen LBucala RMcGuire JLiu SLeng LXu JWu HWang LVanderluit JLHuang YWang SQi YTong HQi DGao XSun GCui DfalseA pref-1-controlled non-inflammatory mechanism of insulin resistance.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. Thu2023-01-01T00:00:00Z2023 Jun2026-05-05T02:53:14.147Z2025-04-04T07:59:28.744ZS-EPMC102396983728381010.1016/j.isci.2023.106923