The non-inflammatory role of macrophage migration inhibitory factor in regulating insulin resistance and hypertriglyceridemia
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Date
2024-07-08
Authors
Huang, Yiheng
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Abstract
Insulin resistance (IR) and hypertriglyceridemia are two major symptoms of metabolic dysfunction, which are regulated by endocrine function and lipid storage in white adipose tissue (WAT). Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine regulating metabolic dysfunction. We currently identified how adipose MIF regulated IR and hypertriglyceridemia through the following mechanisms.
(1) MIF is involved in the development of non-inflammatory IR by a cross-talk between preadipocyte factor 1+ (Pref-1+) cells and adipocytes in WAT.
Pref-1 expression is negatively associated with circulating MIF levels in obese human subjects and animal models in the absence of adipose inflammation. Pref-1 is released from Pref-1+ cells including M2 (anti-inflammatory) macrophages, endothelial cells or progenitors in WAT. Its release inhibits MIF derived from both Pref-1+ cells and adipocytes by binding with integrin β1 and inhibiting the mobilization of p115. High palmitic acid (PA) induces protease-activated receptor 2 (PAR2) expression in Pref-1+ cells, thereby downregulating Pref-1 expression and release in an AMP-activated protein kinase (AMPK)-dependent manner. The loss of Pref-1 increases adipose MIF secretion contributing to non-inflammatory IR in obesity. In contrast, treatment with Pref-1 blunts the increase in circulating plasma MIF levels and subsequent IR induced by a high palmitic acid diet (PD).
(2) MIF inhibits lipoprotein lipase (LPL) that catalyzes the degradation of plasma triglyceride (TG) and upregulates adipose lipid storage.
LPL hydrolyzes circulating TG to release free fatty acids (FFAs) and it promotes lipid storage in WAT. Obesity-associated high PAR2 expression is inversely correlated with LPL expression in WAT, leading to hypertriglyceridemia. MIF reduces LPL expression and activity in adipocytes. High circulating MIF levels in mice models with PD feeding or high MIF expression suppress adipose LPL, which is associated with increased plasma TG levels. However, the low adipose LPL expression and activity is reversed in Par2-/- mice. Thus, high PA increased activation of PAR2, facilitating adipose MIF secretion, and then resulted in low LPL-induced hypertriglyceridemia.
We identified the mechanisms of MIF in mediating IR and hypertriglyceridemia in both human subjects and animal models. Our translational research will provide important clinical implications for the development of new therapeutic strategies for metabolic syndrome.
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Keywords
Insulin resistance, Hypertriglyceridemia, White adipose tissue, Macrophage migration inhibitory factor