Omega-3 Fatty Acids Prevent Hindpaw Hypersensitivity And Proinflammatory Adipose Tissue Macrophage Phenotype In High-fat-fed Mice

Abstract

Peripheral neuropathy (PN) is a debilitating complication of diabetes, characterized by damage to peripheral nerves and loss of sensation and/or pain in the extremities. Evidence indicates that omega-3 (n-3) fatty acids prevent the development of PN and attenuate adipose inflammation, but the interaction of PN and adipose tissue macrophage (ATMφ) phenotype have not been investigated. PURPOSE: Assess the effects of n-3 fatty acids on PN and ATMφ phenotype in high fat fed mice. METHODS: Male C57Bl/6 mice were randomized to (n = 12-14/group): 10% low fat fish oil (10% FO); 54% high fat fish oil (54% FO); 10% low fat lard (10% L); or 54% high fat lard (54% L). The von Frey test for hindpaw sensitivity was used to characterize PN at baseline then biweekly through week 14. After 14 weeks, the relative percentage of total macrophage cells (F4/80+CD11b+) and M1 (CD206-CD11c+) and M2 (CD206+CD11c-) cell populations were identified using flow cytometry. Group differences were identified by 2 x 2 factorial ANOVA. Pearson correlations were used to assess the relationship between hindpaw withdrawal threshold and ATMφ. RESULTS: Body weight, fasting insulin and glucose, and HOMA-IR were greater in 54% L compared to all other groups. 54% L had greater hindpaw sensitivity compared to 54% FO. M1 macrophage percentage was greater in 54% L compared to all other groups, but there were no significant differences in M2 percentage in 54% L vs. 54% FO. Paw withdrawal threshold was correlated with M2 ATMφ (r = 0.34, p = 0.049). CONCLUSION: n-3 fatty acids prevented excess body weight, insulin resistance, hindpaw hypersensitivity and increased proinflammatory macrophages in high fat fed mice. Less hindpaw sensitivity was positively associated with M2 anti-inflammatory ATMφ. Adipose inflammation may play a role in the development of PN and n-3 fatty acids may inhibit development of PN in part by increasing anti-inflammatory ATMφ cell populations. Supported by SIUE Vaughnie Lindsay New Investigator Award