Profiling Plasma Metabolite Alterations in Diet-Induced Obesity and Diabetes Using NMR Metabolomics

Abstract: Diets rich in saturated fat and sedentary lifestyles markedly contribute to obesity and metabolic syndrome-related diseases, including type 2 diabetes mellitus (T2D). Metabolite profiling plays a pivotal role in understanding these metabolic diseases. This thesis comprises insights from four distinct studies to illuminate metabolic imbalances induced by diet-induced obesity (DIO), covering topics related to the duration of dietary regimens, potential benefits of dietary interventions on the brain and metabolism, and the impact of underlying T2D on post-stroke recovery. Using a combination of proton nuclear magnetic resonance (1H-NMR) spectroscopy and mass spectrometry (MS), study I initially demonstrated the superiority of the combined approach in characterizing the effects of DIO on plasma metabolites. The robustness of this method was further validated in a human cohort, underscoring its translational potential in unravelling metabolic imbalances. In study II, female mice exposed to high-fat diet (HFD) exhibited brain metabolism alterations and memory deficits, which were mitigated by taurine and N-acetylcysteine (NAC) supplementation. These supplements not only ameliorated HFD-induced memory impairment but also elicited distinct effects on metabolic alterations within the hippocampus. Systemically, 1H-NMR metabolomics data in study III revealed that NAC and taurine treatments impacted plasma metabolites. Ultimately, as explored in study IV using 1H-NMR metabolomics, unique metabolite changes in male mice with T2D following transient middle cerebral artery occlusion were reported. Specifically, metabolite changes that link T2D to poor neurological outcomes after stroke were observed. In summary, this thesis underscores the significance of metabolite profiling in elucidating the complexities of metabolic diseases, memory impairment, and post-stroke recovery in DIO mouse models. It also emphasizes the translational character of such findings to human pathophysiology.