Dietary monounsaturated fatty acids reduce nerve inflammation and improve nerve function in murine models of obesity

Introduction: Peripheral neuropathy (PN) is a morbid and disabling condition that frequently develops during diabetes and prediabetes. In patients with type 2 diabetes and prediabetes, obesity is a major risk factor for PN indicating that dietary fatty acids may contribute to the molecular pathogenesis of PN. Recent evidence shows that overconsumption of dietary saturated fatty acids (SFAs) contributes to PN progression in prediabetic murine models of PN whereas monounsaturated fatty acids (MUFAs) improve nerve function without improving metabolic function, but the molecular basis for this differential impact on nerve function is incompletely understood. Fatty acids are known regulators of systemic inflammation, but the impact of SFAs and MUFAs on inflammation of the peripheral nervous system is not fully characterized. Methods: Herein, we used a mouse model of diet-induced obesity and prediabetic PN to determine if dietary SFAs and MUFAs alter nerve chemokines and cytokines, and to identify specific chemokines and cytokines that correlate with PN progression. Results: Mice fed an HFD enriched in SFAs (HFD-SFA) developed metabolic dysfunction and PN, as indicated by impaired hind paw withdrawal, decreased nerve conduction velocity (NCV), and loss of intraepidermal nerve fiber density (IENFD). Conversely, mice fed an HFD enriched in MUFAs (HFD-MUFA) for the duration of the study retained normal nerve function despite the development of metabolic dysfunction, and mice switched from HFD-SFA to HFD-MUFA regained nerve function. We next assessed the effect of dietary SFAs and MUFAs on peripheral nerve chemokines and cytokines using a multiplexing analysis to determine inflammatory factors underlying PN progression. Interestingly, a correlation analysis between PN phenotypes and chemokines and cytokines revealed a unique inflammatory profile associated with each PN phenotyping test. Impaired NCV in HFD-SFA mice correlated with elevated levels of sciatic nerve cytokines TNF-α and M-CSF, which was prevented or normalized by HFD-MUFA feeding. Impaired hind paw withdrawal in HFD-SFA mice correlated with changes in GM-CSF, IL-6, IL-9, IL-15, KC, MIP-1α, and VEGF. Discussion: These results indicate that dietary SFAs and MUFAs differentially impact chemokine and cytokine levels in the peripheral nerves of murine models of prediabetic PN, which may contribute to PN pathogenesis.