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  3. Mfat-1 ameliorates cachexia after hypoxic-ischemic brain damage in mice by protecting the hypothalamus-pituitary-adrenal axis

Mfat-1 ameliorates cachexia after hypoxic-ischemic brain damage in mice by protecting the hypothalamus-pituitary-adrenal axis

  • Life Sci. 2023 Oct 11:333:122172. doi: 10.1016/j.lfs.2023.122172.
Yumeng Zhang 1,  Wenhan Lu 1,  Xiaoxue Li 1,  Yu Wang 2,  Lin Li 1,  Yifan Dai 3,  Haiyuan Yang 4,  Ying Wang 5
Affiliations

Affiliations

  • 1 Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, 211166, China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 211166, China.
  • 2 School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
  • 3 Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, 211166, China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China.
  • 4 Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, 211166, China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address: hyyang@njmu.edu.cn.
  • 5 Department of Medical Genetics, School of Basic Medical Science, Nanjing Medical University, Nanjing, 211166, China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address: ywang@njmu.edu.cn.
PMID: 37832632 DOI: 10.1016/j.lfs.2023.122172
Abstract

Aims: Cachexia, a metabolic syndrome, affects 21 % of patients suffering from ischemic encephalopathy. However, the specific mechanism and prevention measures are still unclear. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been proven to reduce inflammatory cytokine levels during ischemic events, but whether they have a protective effect against cachexia after hypoxic-ischemic brain damage (HIBD) remains unclear.

Main methods: C57BL/6J wild-type and mfat-1 transgenic male mice were treated with and without HIBD. One day after HIBD, the epididymal white fat, gastrocnemius muscle and hypothalamus were weighed and analyzed the phenotypic changes. RNA Sequencing was applied to gastrocnemius muscle to identify differential genes and pathways in HIBD groups. The effect of HPA axis on cachexia post-HIBD was examined via adrenalectomy, dexamethasone (0.1 mg/kg), and corticosterone injection (100 mg/kg).

Key findings: The results showed that the incidence of cachexia in mfat-1 mice, which produce high proportion of n-3 PUFAs, was significantly lower than that in wild-type mice post-HIBD. Cachexia-related factors, such as inflammation, muscle atrophy and lipid metabolism were significantly improved in mfat-1 HIBD. RNA Sequencing revealed that catabolic and Proteasome pathways were significantly downregulated. In hypothalamus, inflammatory cytokines, lipid peroxidation levels were reduced. Corticosterone, Glucocorticoid Receptor, and dexamethasone suppression test all showed that mfat-1 improved the dysfunction of the HPA axis post-HIBD. The present study elucidated for the first time that mfat-1 reduced HIBD-induced hyperactivation of the HPA axis in mice by reducing inflammation and oxidative stress and contributed to the reduction of metabolic imbalance in peripheral tissues.

Significance: Our study provides mechanistic information for the development of intervention strategies to prevent cachexia.

Keywords

Cachexia; Catabolic; Hypoxic-ischemic brain damage; Mfat-1.

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