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NIH grant 1R01DK149012-01: The impact of dietary fatty acids and TNF-alpha on neuropathy associated with metabolic syndrome
Institute: {'code': 'DK', 'abbreviation': 'NIDDK', 'name': 'National Institute of Diabetes and Digestive and Kidney Diseases', 'admin_org_id': '12500020', 'admin_funding_url': ''}. PI: Amy E Rumora. Award: $798942.
Start: 2026-08-28T00:00:00.
Abstract
Peripheral neuropathy (PN) is a common complication of diabetes, prediabetes, and the metabolic syndrome.
PN causes a progressive decrease in sensory function resulting in severe morbidity characterized by loss of
sensation, poor balance, and can eventually lead to amputation of the effected limb. Despite the prevalence
and debilitating nature of this neurological complication, there is currently no disease-modifying treatment, and
the molecular mechanisms that underlie PN in the metabolic syndrome are incompletely understood. Mice fed
a high-fat diet rich in saturated fatty acids develop both the metabolic syndrome and PN similar to their human
counterparts. We recently discovered that switching these mice from a high-fat diet enriched with saturated
fatty acids to a high-fat diet enriched with monounsaturated fatty acids significantly improved nerve function
without affecting metabolic impairments. These results indicate that dietary saturated and monounsaturated
fatty acids differentially regulate nerve function in the context of the metabolic syndrome. To identify novel
therapeutic targets for metabolic syndrome PN, it is important to understand the cell type-specific changes that
underlie PN pathogenesis. The metabolic syndrome is often linked to chronic inflammation that impacts a
multitude of tissues and alters lipid metabolism and energy homeostasis. Saturated fatty acids have generally
been associated with pro-inflammatory pathways, whereas monounsaturated fatty acids reduce inflammation.
However, specific inflammatory factors and downstream alterations in lipid metabolism and energy
homeostasis by these fatty acids in the peripheral nerves is not known. Herein, we hypothesize that saturated
fatty acids induce neuroinflammation and toxic lipid metabolism pathways, while dietary monounsaturated fatty
acids reverse the aberrant pathways thereby restoring nerve function. We will test these hypotheses by 1)
identifying cell-specific changes in lipid metabolism that underlie PN 2) determine the resident or infiltrating
inflammatory cells that contribute to PN progression during the metabolic syndrome, and 3) assess the role of
tumor necrosis factor (TNF) and neutral sphingomyelinase, an enzyme that hydrolyzes sphingomyelin, as a
central lipid metabolism mediator that connects inflammation with lipid metabolism to regulate nerve function in
mice with metabolic syndrome PN. Altogether, these studies will determine the specific lipid metabolism and
inflammatory pathways that underlie PN as well as the molecular changes that drive the beneficial effect of
monounsaturated fatty acids. Successful completion of these studies will greatly enhance our understanding of
the molecular pathways that impact nerve function in metabolic syndrome and provide specific therapeutic
targets for PN.document fetched 2026-09-06 02:47