(P15-038-24) Sex-Dependent Brain Metabolic Dysregulation in Obesity and Diabetes

Objectives: Obesity and diabetes predispose individuals to cognitive decline and affect brain metabolism. The ob/ob (leptin deficient) and db/db (lacking functional leptin receptor) mouse models are widely used in obesity and diabetes research. Both models on the C57Bl/6J background exhibit obesity, hypercholesterolemia, hyperinsulinemia, glucose intolerance, and insulin resistance compared to controls, however the db/db model exhibits more severe glucose intolerance and insulin resistance. We aimed to compare the effects of the obese and diabetic phenotypes of these models on the brain metabolome to better understand the relationship between obesity, diabetes, and the brain metabolome. Additionally, we aimed to determine the influence of sex on the brain metabolic response to obesity and diabetes.

Methods: Untargeted metabolomics by liquid chromatography-mass spectrometry was conducted on whole brain tissue from 18-week-old male and female ob/ob, db/db, and wild-type (WT) C57Bl/6J mice. Fasting blood glucose, insulin, and cholesterol were assessed, as well as glucose tolerance.

Results: The db/db model exhibited the most distinct global brain metabolome and the greatest sex differences. Both the db/db and ob/ob models exhibited altered (adjusted p < 0.05) metabolites as compared to WT mice, with more metabolites altered in db/db mice. These metabolic differences were sex-dependent in both models, with males exhibiting more altered metabolites than females. Altered choline-containing glycerophospholipids were a key feature which set db/db males apart from the other groups. Some metabolites altered by the ob/ob and db/db phenotypes in females are known to have neuro-modulatory properties.

Conclusions: Both obesity and diabetes can alter the brain metabolome, but diabetes may have a greater effect on the brain metabolome than obesity alone. The effects of obesity and diabetes on the brain metabolome are sex-specific. Males may be more susceptible to this brain metabolic dysregulation, thus highlighting the importance of studying both sexes.

Funding Sources: Residual class settlement funds in the matter of April Krueger v. Wyeth, Inc., Case No. 03-cv-2496 (US District Court, SD of Calif.), Nora Eccles Treadwell Foundation, Frances Lazda Endowed Chair in Women’s Cardiovascular Medicine