RATIONALE: Insulin resistance is a major contributor to the development of type 2 diabetes, a multi-organ disease affecting >3x10⁸ individuals. Over the last decade, the correlation between immune cell activation and insulin resistance ‒ or metabolic inflammation ‒ has revolutionized how obesity-linked diabetes is understood. High-fat diets (HFD), obesity, and saturated fats trigger pro-inflammatory pathways in adipose tissue and muscle macrophages, contributing to peripheral insulin resistance. In contrast, unsaturated fat consumption has beneficial effects on whole-body insulin sensitivity, but it is unknown if these effects are mediated through skewing anti-inflammatory macrophage polarization.

METHODS: Bone marrow-derived macrophages (BMDMs) from C57BL/6 mice were grown in culture and treated with BSA-conjugated saturated fatty acid palmitate (PA), unsaturated fatty acid palmitoleate (PO), or BSA. To evaluate dietary effects in vivo, BMDMs were isolated from C57BL/6 mice fed HFD (60% kcal) or low-fat diet (LFD) for 18 weeks.

RESULTS: Macrophages treated with PA displayed increased pro-inflammatory gene expression (Nos2, Ciita, Cxcl1) and cytokine secretion (KC, IL6, TNFα) relative to those given BSA, while PO up-regulated anti-inflammatory genes (Arg1, Chi3l3, Tgfb1). Interestingly, co-incubation with PO prevented PA-induced pro-inflammatory gene expression, cytokine secretion, and NFκB activation. To assess the in vivo effect of diet on macrophage polarization, we isolated bone marrow from high or low fat-fed mice and derived BMDMs over 7 days. Macrophages from HFD-fed mice showed elevated pro-inflammatory gene expression and cytokine secretion, revealing ex vivo memory of the in vivo environment. Moreover, a 6 h treatment with PO reversed this pro-inflammatory phenotype to resemble macrophages from LFD-fed mice. These results reveal the plasticity of macrophages in response to distinct fats.

DISCUSSION: Saturated and unsaturated fats differentially affect macrophage polarization, conferring a pro- or anti-inflammatory phenotype, respectively. Polarization appears to be reversible, as palmitoleate abolished inflammation resulting from palmitate treatment or high-fat diet. Our findings demonstrate a novel mechanism by which an unsaturated fat attenuates the metabolic inflammation of macrophages that in vivo precedes insulin resistance.