title: Dietary reversal of neuropathy in a murine model of prediabetes and metabolic syndrome.
abstract: Patients with metabolic syndrome, which is defined as obesity, dyslipidemia, hypertension and impaired glucose tolerance (IGT), can develop the same macro- and microvascular complications as patients with type 2 diabetes, including peripheral neuropathy. In type 2 diabetes, glycemic control has little effect on the development and progression of peripheral neuropathy, suggesting that other metabolic syndrome components may contribute to the presence of neuropathy. A parallel phenomenon is observed in patients with prediabetes and metabolic syndrome, where improvement in weight and dyslipidemia more closely correlates with restoration of nerve function than improvement in glycemic status. The goal of the current study was to develop a murine model that resembles the human condition. We examined longitudinal parameters of metabolic syndrome and neuropathy development in six mouse strains/genotypes (BKS-wt, BKS-Leprdb/+, B6-wt, B6-Leprdb/+, BTBR-wt, and BTBR-Lepob/+) fed a 54% high-fat diet (HFD; from lard). All mice fed a HFD developed large-fiber neuropathy and IGT. Changes appeared early and consistently in B6-wtmice, and paralleled the onset of neuropathy. At 36 weeks, B6-wtmice displayed all components of the metabolic syndrome, including obesity, IGT, hyperinsulinemia, dyslipidemia and oxidized low density lipoproteins (oxLDLs). Dietary reversal, whereby B6-wtmice fed a HFD from 4-20 weeks of age were switched to standard chow for 4 weeks, completely normalized neuropathy, promoted weight loss, improved insulin sensitivity, and restored LDL cholesterol and oxLDL by 50% compared with levels in HFD control mice. This dietary reversal model provides the basis for mechanistic studies investigating peripheral nerve damage in the setting of metabolic syndrome, and ultimately the development of mechanism-based therapies for neuropathy.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Lucy M
authors.identifier: 0000-0002-5206-8010
authors.initials: LM
authors.lastname: Hinder
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Phillipe D
authors.identifier: 0000-0002-6365-3477
authors.initials: PD
authors.lastname: O'Brien
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Hayes
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Carey
authors.initials: C
authors.lastname: Backus
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Solway
authors.affiliation: Department of Neurology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Catrina
authors.initials: C
authors.lastname: Sims-Robinson
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA efeldman@umich.edu.
authors.forename: Eva L
authors.identifier: 0000-0002-9162-2694
authors.initials: EL
authors.lastname: Feldman
mesh_terms: D017667:Adipocytes / Q000473:pathology; D052436:Adipose Tissue, White / Q000473:pathology; D000818:Animals; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D003929:Diabetic Neuropathies / Q000097:blood / Q000178:diet therapy*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004822:Epididymis / Q000473:pathology; D005247:Feeding Behavior; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000178:diet therapy*; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000473:pathology; D010641:Phenotype; D011236:Prediabetic State / Q000097:blood / Q000178:diet therapy*
chemical_list: D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D002784:Cholesterol
keywords: Diabetic complications; Dietary intervention; High-fat diet; Impaired glucose tolerance; Obesity; Strain comparison