05-19-2021, R21 obesity metabolomics - SI.pdf

Peripheral neuropathy (PN) is a frequent prediabetes and type 2 diabetes (T2D) complication. Multiple clinical studies reveal that obesity and dyslipidemia can also drive PN progression, independent of glycemia. These clinical observations suggest a complex interplay of specific metabolite and/or lipid species may underlie PN. To address this, we completed plasma metabolomic and lipidomic profiling of a population with mean class 3 obesity with (n=44) and without PN (n=44), matched for glycemic status, versus lean non-neuropathic controls (n=43). Lean versus obese comparisons, regardless of PN status, identified the most significant changes in gamma-glutamyl and branched-chain amino acid metabolism from global metabolomics analysis and triacylglycerols from lipidomics. Stratification by PN status within obese individuals identified changes in polyamine, purine biosynthesis, and benzoate metabolism. Lipidomics found diacylglycerols as the most significant sub-pathway distinguishing obese individuals by PN status, with additional contributions from phosphatidylcholines, sphingomyelins, ceramides, and dihydroceramides. Stratifying the obese cohort by glycemic status did not affect separation by PN status. These results suggest obesity may be as strong a PN driver as prediabetes or T2D in individuals with class 3 obesity, at least by plasma metabolomics and lipidomics profile. In summary, both metabolic and complex lipid pathways can differentiate obese individuals with and without PN, independent of glycemic status.