Hepatic serine and lipid metabolism drive diabetic peripheral neuropathy

Abstract Type 2 diabetes represents a disease spectrum in which chronic metabolic dysfunction damages multiple organ systems including liver, kidneys, and peripheral nerves1,2. While onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidemia3-7, aberrant amino acid metabolism also contributes to pathogenesis of diabetes and potentially its complications8-10. Serine and glycine are closely related non-essential amino acids11,12 that are consistently reduced in patients with metabolic syndrome10,13-16, but the mechanistic drivers of serine deficiency and the downstream metabolic and phenotypic consequences remain unclear. Low systemic serine, a serine-opathy, is also emerging as a hallmark of macular and peripheral nerve disorders. Specifically, serine deficiency correlates positively with impaired visual acuity and peripheral neuropathy (PN)17-19. Here we demonstrate that aberrant serine homeostasis in the liver drives serine and glycine deficiencies in genetically obese and hyperglycaemic mice. This serine-opathy can be diagnosed with a serine tolerance test that quantifies systemic serine disposal. Mimicking these metabolic alterations via dietary serine/glycine restriction together with high fat intake dramatically accelerates thermal hypoalgesia in mice and reduces epidermal sensory nerve density, which are accompanied by extensive sciatic nerve lipid remodeling. These phenotypes were subsequently normalized by myriocin, linking serine-associated PN with sphingolipid biosynthesis. These findings identify systemic serine deficiency and dyslipidemia as novel risk factors for PN that may be exploited therapeutically.