Increased uremic toxins in cerebrospinal fluid of obese mice cause insulin resistance

Brain insulin resistance represents a major health threat but its mechanisms remain still to be deciphered. We aim in this study to identify novel molecular metabolites in the cerebrospinal fluid (CSF) which associate with brain insulin resistance and test their effect on central insulin signaling.

We performed an unbiased metabolomics analysis of the CSF from different mouse models of obesity and diabetes such as the db/db mouse and diet-induced obesity models. Hypothalamic neuronal cells (CLU183) as well as coronal brain slices and primary cortical neurons were stimulated with identified uremic toxins (p-cresol sulfate, PCS at 200 – 600µM and indoxyl sulfate, IndS at 236 mg/L) followed by 10 – 100nM insulin treatment and assessment of insulin signaling using western blotting techniques.

We identified uremic toxins, PCS and IndS, which were increased 2 to 5 fold in the brain of obese compared to lean animals. In order to delineate the role of these compounds towards insulin sensitivity we incubated in vitro hypothalamic and cortical neurons as well as ex-vivo brain slices with acute or chronic doses of PCS and IndS and studied insulin-induced insulin receptor signaling pathway activation. PCS increased insulin receptor activation and downstream kinases by 28% and 20%, respectively, while IndS decreased the expression of Insulin receptor and IRS1 by 66% and 52%, respectively.

Our findings indicate that the accumulation of uremic toxins in the brain and in the CSF of obese mice could induce brain insulin resistance, thus contributing to the metabolic dysfunctions observed in insulin-resistant brain state.