Neurodegeneration Alters Metabolic Profile and Sirt 1 Signaling in High-Fat-Induced Obese Mice

Abstract

Different factors may contribute to the development of neurodegenerative diseases. Among them, metabolic syndrome (MS), which has reached epidemic proportions, has emerged as a potential element that may be involved in neurodegeneration. Furthermore, studies have shown the importance of the sirtuin family in neuronal survival and MS, which opens the possibility of new pharmacological targets. This study investigates the influence of sirtuin metabolic pathways by examining the functional capacities of glucose-induced obesity in an excitotoxic state induced by a quinolinic acid (QA) animal model. Mice were divided into two groups that received different diets for 8 weeks: one group received a regular diet, and the other group received a high-fat diet (HF) to induce MS. The animals were submitted to a stereotaxic surgery and subdivided into four groups: Standard (ST), Standard-QA (ST-QA), HF and HF-QA. The QA groups were given a 250 nL quinolinic acid injection in the right striatum and PBS was injected in the other groups. Obese mice presented with a weight gain of 40 % more than the ST group beyond acquiring an insulin resistance. QA induced motor impairment and neurodegeneration in both ST-QA and HF-QA, although no difference was observed between these groups. The HF-QA group showed a reduction in adiposity when compared with the groups that received PBS. Therefore, the HF-QA group demonstrated a commitment-dependent metabolic pathway. The results suggest that an obesogenic diet does not aggravate the neurodegeneration induced by QA. However, the excitotoxicity induced by QA promotes a sirtuin pathway impairment that contributes to metabolic changes.

Upregulation of Foreign Body Response in Obese Mice

“…In animals fed with the HF diet, the body weight, BMI, and Lee index were 19.42%, 43.1%, and 12.8% higher than those of nonobese mice (fed with standard mice chow). Our findings are consistent with several publications that have shown the effects of an HF diet on body weight and adiposity .…”

“…Obesity was induced in male C57/BL6 mice ( n = 15) by feeding them a HF diet for 12 weeks. The diet was prepared according to the standards of the Association of Official Analytical Chemists, as described previously . The HF diet was composed of 35.94% carbohydrate, 21.98% protein, and 42.07% fat, equaling 4.38 kcal/g.…”

TLR4 mutation protects neurovascular function and cognitive decline in high-fat diet-fed mice

“…Studies of human and animal models provide strong evidence that alterations in glucose metabolism, such as hyperglycemia or MS, could have a negative effect on brain function [29,37,38]. In this study, we explored the specific contributions of a HFD to neuroinflammation in an experimental mouse model of MS. We demonstrate that long-term ingestion of a HFD induces region-specific effects on the brain, elevating microglial numbers, and decreasing the coverage of astrocytes in the cerebral vessels of the hippocampus.…”

The modern view on the role of glyprolines by metabolic syndrome

“…It has been demonstrated that a high-fat diet used for the development of MS does not exacerbate the neurodegeneration caused by quinolinic acid, but it does worsen the sirtuin pathway that promotes fat metabolism. 49 Other researchers indicate that many neurodegenerative diseases are associated with metabolic dysfunction, which is manifested by changes in lipid metabolism, since neurons have a heterogeneous lipid composition necessary for the development and functioning of the nervous system. The relationship between neurodegeneration and changes in the metabolism of phospholipids and sphingolipids, mitochondrial morphology, and membrane remodeling was established.…”

“…In the survival of neurons in MS, the importance of the sirtuin family is shown, which opens up opportunities for new pharmacological targets. It has been demonstrated that a high‐fat diet used for the development of MS does not exacerbate the neurodegeneration caused by quinolinic acid, but it does worsen the sirtuin pathway that promotes fat metabolism 49 …”