Abstract
Diet-induced obesity is associated with increased adipose tissue activated macrophages. Yet, how macrophages integrate fatty acid (FA) signals remains unclear. We previously demonstrated that Fyn deficiency (fynKO) protects against high fat diet-induced adipose tissue macrophage accumulation. Herein, we show that inflammatory markers and reactive oxygen species are not induced in fynKO bone marrow-derived macrophages exposed to the saturated FA palmitate, suggesting that Fyn regulates macrophage function in response to FA signals. Palmitate activates Fyn and re-localizes Fyn into the nucleus of RAW264.7, J774 and wild-type bone marrow-derived macrophages. Similarly, Fyn activity is increased in cells of adipose tissue stromal vascular fraction of high fat-fed control mice, with Fyn protein being located in the nucleus of these cells. We demonstrate that Fyn modulates palmitate-dependent oxidative stress in macrophages. Moreover, Fyn catalytic activity is necessary for its nuclear re-localization and downstream effects, as Fyn pharmacological inhibition abolishes palmitate-induced Fyn nuclear redistribution and palmitate-dependent increase of oxidative stress markers. Importantly, mono-or polyunsaturated FAs do not activate Fyn, and fail to re-localize Fyn to the nucleus. Together these data demonstrate that macrophages integrate nutritional FA signals via a differential activation of Fyn that distinguishes, at least partly, the effects of saturated versus unsaturated fats.
Highlights
Obesity, the most potent trigger for the development of type 2 diabetes and insulin resistance, has reached pandemic proportions and will affect more than 475 million individuals worldwide in the 15 years [1]
Obesity is characterized by chronic low-grade inflammation and high fat diets promote invasion of immune cells, macrophages into peripheral tissues
This is supported by the recent observation that M1 cell-surface markers are lacking in adipose tissue macrophages (ATMs) of obese humans and mice [14], which demonstrates that the phenotypic switch from anti-inflammatory (M2) to pro-inflammatory (M1) macrophages, and its role in adipose tissue inflammation is more complex than originally described
Summary
The most potent trigger for the development of type 2 diabetes and insulin resistance, has reached pandemic proportions and will affect more than 475 million individuals worldwide in the 15 years [1]. Obesity is the result of dysregulation of a number of biological processes, including the disturbance of whole body homeostasis including immune functions [2]. In this regard, obesity is associated with systemic low-grade inflammation, called meta-inflammation characterized by accumulation of immune cells in peripheral tissues such as liver, skeletal muscle and adipose tissue [3,4,5,6]. In addition to the increased immune cell number, obesityinduced inflammation is defined by a modification of immune cell populations with increased B [6] and T lymphocytes [7], neutrophils [8] and mast cells [9]; and decreased natural killer cells and eosinophil numbers, www.impactjournals.com/oncotarget promoting insulin resistance, in the adipose tissues of obese individuals [10]. The hallmark of meta-inflammation is that the inflammatory processes are stimulated by the same excessive nutrient supply that dysregulates energy metabolism and insulin sensitivity
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