High Dietary Fat Consumption Impairs Axonal Mitochondrial FunctionIn Vivo

Abstract

Peripheral neuropathy (PN) is the most common complication of prediabetes and diabetes. PN causes severe morbidity for Type 2 diabetes (T2D) and prediabetes patients, including limb pain followed by numbness resulting from peripheral nerve damage. PN in T2D and prediabetes is associated with dyslipidemia and elevated circulating lipids; however, the molecular mechanisms underlying PN development in prediabetes and T2D are unknown. Peripheral nerve sensory neurons rely on axonal mitochondria to provide energy for nerve impulse conduction under homeostatic conditions. Models of dyslipidemia in vitro demonstrate mitochondrial dysfunction in sensory neurons exposed to elevated levels of exogenous fatty acids. Herein, we evaluated the effect of dyslipidemia on mitochondrial function and dynamics in sensory axons of the saphenous nerve of a male high-fat diet (HFD)-fed murine model of prediabetes to identify mitochondrial alterations that correlate with PN pathogenesis in vivo. We found that the HFD decreased mitochondrial membrane potential (MMP) in axonal mitochondria and reduced the ability of sensory neurons to conduct at physiological frequencies. Unlike mitochondria in control axons, which dissipated their MMP in response to increased impulse frequency (from 1 to 50 Hz), HFD mitochondria dissipated less MMP in response to axonal energy demand, suggesting a lack of reserve capacity. The HFD also decreased sensory axonal Ca 21 levels and increased mitochondrial lengthening and expression of PGC1a, a master regulator of mitochondrial biogenesis. Together, these results suggest that mitochondrial dysfunction underlies an imbalance of axonal energy and Ca 21 levels and impairs impulse conduction within the saphenous nerve in prediabetic PN.

Serum lipidomic determinants of human diabetic neuropathy in type 2 diabetes

“…Herein, the lipidomic signatures associated with neuropathy in Pima participants with type 2 diabetes centered on lipids related to mitochondrial function. Indeed, dysfunctional mitochondrial dynamics underpin diabetic neuropathy, 36 including dyslipidemia, which impairs mitochondrial trafficking 20 , 21 , 37 and bioenergetics, leading to energy failure and resulting nerve injury. 37 In the current study, serum linked to neuropathy was characterized by elevated free fatty acids and diminished medium‐chain acylcarnitines.…”

“…Indeed, dysfunctional mitochondrial dynamics underpin diabetic neuropathy, 36 including dyslipidemia, which impairs mitochondrial trafficking 20 , 21 , 37 and bioenergetics, leading to energy failure and resulting nerve injury. 37 In the current study, serum linked to neuropathy was characterized by elevated free fatty acids and diminished medium‐chain acylcarnitines. Free fatty acids are an important energy source through mitochondrial β‐oxidation.…”

A High-Fat Diet Disrupts Nerve Lipids and Mitochondrial Function in Murine Models of Neuropathy

“…Multiple clinical studies identify components of the metabolic syndrome, including dyslipidemia and elevated TGs, as important PN risk factors ( Wiggin et al, 2009 ; Andersen et al, 2018 ). Preclinical research shows these same risk factors adversely impact axonal mitochondrial trafficking and bioenergetics ( Rumora et al, 2018 ; Rumora et al, 2019a ; Sajic et al, 2021 ) resulting in bioenergetic failure in distal peripheral nerve axons and PN ( Feldman et al, 2017 ). Despite the relevance of lipids, both as PN risk factors and in PN pathogenesis, the precise circulating and nerve lipid species most important to PN remain unknown.…”

Single‐cell RNA‐seq uncovers novel metabolic functions of Schwann cells beyond myelination

“…Imaris 3D Analysis Software (Oxford Instruments) isolated fluorescence intensity from high‐resolution Z‐series scans. Integrated fluorescence intensity quantified protein expression along myelin relative to control, per our published protocol (Sajic et al, 2021), and others (Babetto et al, 2020).…”