Mechanisms by which swimming exercise and diet control improve hypothalamic lesions in APOE-/- mice with high-fat diet

doi:10.12307/2023.471

Abstract

Abstract: BACKGROUND: Swimming exercise and diet control are currently recognized as important interventions to improve metabolic abnormalities. Hypothalamic sirtuin 3 (SIRT3) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) are important factors regulating energy metabolism, but the correlation between the effects of swimming exercise and diet control on hypothalamic lesions in apolipoprotein E knockout (APOE-/-) mice with high-fat diet and the PGC-1α-SIRT3 pathway is still unclear.
OBJECTIVE: To investigate the possible mechanism of swimming exercise and diet control in regulating hypothalamic lesions of APOE-/- mice with high-fat diet.
METHODS: Fifty 20-week-old APOE-/- mice were randomly divided into normal diet group, high-fat diet group, diet control group, swimming exercise group and diet control+swimming exercise group, with 10 mice in each group. Except for the control group (normal diet), the other groups were fed with high-fat diet (21% fat, 0.15% cholesterol) for 8 weeks. After 8 weeks of feeding, the diet control group and the diet control+swimming exercise group were normally fed, and there were no changes in the other groups. The swimming exercise group and the diet control+swimming exercise group were given no weight-bearing swimming for 8 weeks in total. Mice were weighed at the same time each week, and changes in hypothalamic metabolites, including N-acetyl aspartate (NAA), choline complex (Cho), creatine (Cr), and myo inositol (MI) were detected by magnetic resonance spectrum of the hypothalamus. Morphological changes of mitochondria and myelin sheath in the hypothalamus were detected by electron microscopy. SIRT3 and PGC-1α protein expression was detected by western blot.
RESULTS AND CONCLUSION: The body mass of the control group was significantly lower than that of the other four groups after high-fat diet feeding. After 8 weeks of intervention, the body mass of swimming exercise group, diet control group, diet control+swimming exercise group was significantly lower than that of high-fat diet group (P < 0.05), and the decreasing trend of diet control+swimming exercise group was the most obvious. Compared with the control group, the NAA/Cr and Cho/Cr of the high-fat diet group decreased significantly, and the MI/Cr increased significantly (P < 0.05). Compared with the high-fat diet group, the NAA/Cr and Cho/Cr of the diet control group, the swimming exercise group and the diet control+swimming exercise group increased significantly, while the MI/Cr decreased significantly (P < 0.05). The improvement effect on NAA/Cr and Cho/Cr of diet control+swimming exercise group was better than that of diet control group and swimming exercise group. The protein levels of SIRT3 and PGC-1α in the hypothalamus of diet control group, swimming exercise group and diet control+swimming exercise group were significantly higher than those of high-fat diet group (P < 0.05). The results of electron microscopy showed that in the high-fat diet group the mitochondria of mice were swollen, the crists were broken, disappeared or vacuolated, the myelin mechanism was blurred, most of the myelin was separated from the middle and edge, and the vacuolated degeneration was observed. The morphology and structure of mitochondria and myelin were improved after diet control and swimming exercise intervention. These findings indicate that both swimming exercise and diet control can effectively improve high-fat-induced hypothalamic lesions, and the combination of the two achieves better outcomes. The underlying mechanism is related to up-regulating the expression of mitochondria-related proteins PGC-1α and SIRT3, improving hypothalamic neurometabolism, and alleviating mitochondrial dysfunction.

Key words: swimming exercise, diet control, high-fat diet, hypothalamus, magnetic resonance spectrum

CLC Number:

Ding Linlin, Lu Taotao, Wei Wei, Li Yongxu, Lin Libin, Lin Zhicheng, Xue Xiehua. Mechanisms by which swimming exercise and diet control improve hypothalamic lesions in APOE-/- mice with high-fat diet[J]. Chinese Journal of Tissue Engineering Research, 2023, 27(20): 3136-3142.

Figures/Tables 6

References

[1] NEUFER PD, BAMMAN MM, MUOIO DM, et al. Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits. Cell Metab. 2015;22(1):4-11.
[2] JAKICIC JM, ROGERS RJ, DAVIS KK, et al. Role of Physical Activity and Exercise in Treating Patients with Overweight and Obesity. Clin Chem. 2018;64(1):99-107.
[3] HEADLAND M, CLIFTON PM, CARTER S, et al. Weight-Loss Outcomes: A Systematic Review and Meta-Analysis of Intermittent Energy Restriction Trials Lasting a Minimum of 6 Months. Nutrients. 2016;8(6):354.
[4] DOUGLASS JD, DORFMAN MD, THALER JP. Glia: silent partners in energy homeostasis and obesity pathogenesis. Diabetologia. 2017;60(2):226-236.
[5] KENNEDY GC, MITRA J. The effect of d-amphetamine on energy balance in hypothalamic obese rats. Br J Nutr. 1963;17:569-573.
[6] KENNEDY GC, MITRA J. Hypothalamic control of energy balance and the reproductive cycle in the rat. J Physiol. 1963;166:395-407.
[7] LIZARBE B, CHERIX A, DUARTE J, et al. High-fat diet consumption alters energy metabolism in the mouse hypothalamus. Int J Obes (Lond). 2019;43(6):1295-1304.
[8] NYAMUGENDA E, TRENTZSCH M, RUSSELL S, et al. Injury to hypothalamic Sim1 neurons is a common feature of obesity by exposure to high-fat diet in male and female mice. J Neurochem. 2019;149(1):73-97.
[9] ZHANG N, BI S. Effects of physical exercise on food intake and body weight: Role of dorsomedial hypothalamic signaling. Physiol Behav. 2018;192:59-63.
[10] SHIUCHI T, MIYATAKE Y, OTSUKA A, et al. Role of orexin in exercise-induced leptin sensitivity in the mediobasal hypothalamus of mice. Biochem Biophys Res Commun. 2019;514(1):166-172.
[11] CHANG GR, HOU PH, CHEN WK, et al. Exercise Affects Blood Glucose Levels and Tissue Chromium Distribution in High-Fat Diet-Fed C57BL6 Mice. Molecules. 2020;25(7):1658.
[12] HAN B, JIANG W, LIU H, et al. Upregulation of neuronal PGC-1alpha ameliorates cognitive impairment induced by chronic cerebral hypoperfusion. Theranostics. 2020;10(6):2832-2848.
[13] KUMAR S, LOMBARD DB. Mitochondrial sirtuins and their relationships with metabolic disease and cancer. Antioxid Redox Signal. 2015;22(12): 1060-1077.
[14] YIN J, NIELSEN M, CARCIONE T, et al. Apolipoprotein E regulates mitochondrial function through the PGC-1alpha-sirtuin 3 pathway. Aging (Albany NY). 2019;11(23):11148-11156.
[15] BRANDON JA, FARMER BC, WILLIAMS HC, et al. APOE and Alzheimer’s Disease: Neuroimaging of Metabolic and Cerebrovascular Dysfunction. Front Aging Neurosci. 2018;10:180.
[16] CHIRICO EN, Di CATALDO V, CHAUVEAU F, et al. Magnetic resonance imaging biomarkers of exercise-induced improvement of oxidative stress and inflammation in the brain of old high-fat-fed ApoE(-/-) mice. J Physiol. 2016;594(23):6969-6985.
[17] WANROOY BJ, KUMAR KP, WEN SW, et al. Distinct contributions of hyperglycemia and high-fat feeding in metabolic syndrome-induced neuroinflammation. J Neuroinflammation. 2018;15(1):293.
[18] COURTIES A, SELLAM J, BERENBAUM F. Metabolic syndrome-associated osteoarthritis. Curr Opin Rheumatol. 2017;29(2):214-222.
[19] 谭吉凤, 肖轶卉, 王果, 等. 高脂饮食联合光照周期改变对不同性别小鼠体重的影响[J]. 现代生物医学进展,2022,22(10):1817-1820.
[20] 欧海龙, 张礼林, 何晓兰, 等. ApoE~(-/-)小鼠动脉粥样硬化模型的建立[J]. 生命科学研究,2015,19(2):141-144.
[21] 吕昕儒, 魏伟, 王夏蕾, 等. 基于胆固醇逆转运探讨泽泻白术配伍改善ApoE~(-/-)小鼠动脉粥样硬化的作用[J]. 中国动脉硬化杂志, 2021,29(4):286-294.
[22] CHAKRABORTY G, MEKALA P, YAHYA D, et al. Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase. J Neurochem. 2001; 78(4):736-745.
[23] LOPEZ-VALDES HE, MARTINEZ-CORIA H. The Role of Neuroinflammation in Age-Related Dementias. Rev Invest Clin. 2016;68(1):40-48.
[24] CHANG L, MUNSAKA SM, KRAFT-TERRY S, et al. Magnetic resonance spectroscopy to assess neuroinflammation and neuropathic pain. J Neuroimmune Pharmacol. 2013;8(3):576-593.
[25] LIZARBE B, SOARES AF, LARSSON S, et al. Neurochemical Modifications in the Hippocampus, Cortex and Hypothalamus of Mice Exposed to Long-Term High-Fat Diet. Front Neurosci. 2018;12:985.
[26] CHERIX A, SONTI R, LANZ B, et al. In Vivo Metabolism of [1,6-(13)C2]Glucose Reveals Distinct Neuroenergetic Functionality between Mouse Hippocampus and Hypothalamus. Metabolites. 2021;11(1):50.
[27] JOSHI AU, MOCHLY-ROSEN D. Mortal engines: Mitochondrial bioenergetics and dysfunction in neurodegenerative diseases. Pharmacol Res. 2018;138:2-15.
[28] JIN S, DIANO S. Mitochondrial Dynamics and Hypothalamic Regulation of Metabolism. Endocrinology. 2018;159(10):3596-3604.
[29] CARRARO RS, SOUZA GF, SOLON C, et al. Hypothalamic mitochondrial abnormalities occur downstream of inflammation in diet-induced obesity. Mol Cell Endocrinol. 2018;460:238-245.
[30] WARDELMANN K, BLUMEL S, RATH M, et al. Insulin action in the brain regulates mitochondrial stress responses and reduces diet-induced weight gain. Mol Metab. 2019;21:68-81.
[31] RAEFSKY SM, MATTSON MP. Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance. Free Radic Biol Med. 2017;102:203-216.
[32] REAL-HOHN A, NAVEGANTES C, RAMOS K, et al. The synergism of high-intensity intermittent exercise and every-other-day intermittent fasting regimen on energy metabolism adaptations includes hexokinase activity and mitochondrial efficiency. PLoS One. 2018;13(12):e202784.
[33] WANG SY, ZHU S, WU J, et al. Exercise enhances cardiac function by improving mitochondrial dysfunction and maintaining energy homoeostasis in the development of diabetic cardiomyopathy. J Mol Med (Berl). 2020;98(2):245-261.
[34] PEERAPANYASUT W, KOBROOB A, PALEE S, et al. Activation of Sirtuin 3 and Maintenance of Mitochondrial Integrity by N-Acetylcysteine Protects Against Bisphenol A-Induced Kidney and Liver Toxicity in Rats. Int J Mol Sci. 2019;20(2):267.
[35] ZHANG J, XIANG H, LIU J, et al. Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target. Theranostics. 2020;10(18): 8315-8342.
[36] RIUS-PEREZ S, TORRES-CUEVAS I, MILLAN I, et al. PGC-1alpha, Inflammation, and Oxidative Stress: An Integrative View in Metabolism. Oxid Med Cell Longev. 2020;2020:1452696.
[37] JOHNSON ML, IRVING BA, LANZA IR, et al. Differential Effect of Endurance Training on Mitochondrial Protein Damage, Degradation, and Acetylation in the Context of Aging. J Gerontol A Biol Sci Med Sci. 2015;70(11):1386-1393.
[38] PEREZ S, RIUS-PEREZ S, FINAMOR I, et al. Obesity causes PGC-1alpha deficiency in the pancreas leading to marked IL-6 upregulation via NF-kappaB in acute pancreatitis. J Patho. 2019;247(1):48-59.
[39] BAE JY, WOO J, KANG S, et al. Effects of detraining and retraining on muscle energy-sensing network and meteorin-like levels in obese mice. Lipids Health Dis. 2018;17(1):97.
[40] CHENG A, WANG J, GHENA N, et al. SIRT3 Haploinsufficiency Aggravates Loss of GABAergic Interneurons and Neuronal Network Hyperexcitability in an Alzheimer’s Disease Model. J Neurosci. 2020; 40(3):694-709.