Peripheral Neuropathy and Hindlimb Paralysis in a Mouse Model of Adipocyte-Specific Knockout of Lkb1
Brown adipose tissues (BAT) burn lipids to generate heat through uncoupled respiration, thus representing a powerful target to counteract lipid accumulation and obesity. The tumor suppressor liver kinase b1 (Lkb1) is a key regulator of cellular energy metabolism; and adipocyte-specific knockout of L...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-10-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396417303705 |
| _version_ | 1819225673468739584 |
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| author | Yan Xiong Jessica C. Page Naagarajan Narayanan Chao Wang Zhihao Jia Feng Yue Xine Shi Wen Jin Keping Hu Meng Deng Riyi Shi Tizhong Shan Gongshe Yang Shihuan Kuang |
| author_facet | Yan Xiong Jessica C. Page Naagarajan Narayanan Chao Wang Zhihao Jia Feng Yue Xine Shi Wen Jin Keping Hu Meng Deng Riyi Shi Tizhong Shan Gongshe Yang Shihuan Kuang |
| author_sort | Yan Xiong |
| collection | DOAJ |
| description | Brown adipose tissues (BAT) burn lipids to generate heat through uncoupled respiration, thus representing a powerful target to counteract lipid accumulation and obesity. The tumor suppressor liver kinase b1 (Lkb1) is a key regulator of cellular energy metabolism; and adipocyte-specific knockout of Lkb1 (Ad-Lkb1 KO) leads to the expansion of BAT, improvements in systemic metabolism and resistance to obesity in young mice. Here we report the unexpected finding that the Ad-Lkb1 KO mice develop hindlimb paralysis at mid-age. Gene expression analyses indicate that Lkb1 KO upregulates the expression of inflammatory cytokines in interscapular BAT and epineurial brown adipocytes surrounding the sciatic nerve. This is followed by peripheral neuropathy characterized by infiltration of macrophages into the sciatic nerve, axon degeneration, reduced nerve conductance, and hindlimb paralysis. Mechanistically, Lkb1 KO reduces AMPK phosphorylation and amplifies mammalian target-of-rapamycin (mTOR)-dependent inflammatory signaling specifically in BAT but not WAT. Importantly, pharmacological or genetic inhibition of mTOR ameliorates inflammation and prevents paralysis. These results demonstrate that BAT inflammation is linked to peripheral neuropathy. |
| first_indexed | 2024-12-23T10:13:20Z |
| format | Article |
| id | doaj.art-f2a903d937044669a1747e06a48efa14 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-23T10:13:20Z |
| publishDate | 2017-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-f2a903d937044669a1747e06a48efa142022-12-21T17:50:53ZengElsevierEBioMedicine2352-39642017-10-0124C12713610.1016/j.ebiom.2017.09.017Peripheral Neuropathy and Hindlimb Paralysis in a Mouse Model of Adipocyte-Specific Knockout of Lkb1Yan Xiong0Jessica C. Page1Naagarajan Narayanan2Chao Wang3Zhihao Jia4Feng Yue5Xine Shi6Wen Jin7Keping Hu8Meng Deng9Riyi Shi10Tizhong Shan11Gongshe Yang12Shihuan Kuang13Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, ChinaDepartment of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47906, USADepartment of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47906, USADepartment of Animal Sciences, Purdue University, West Lafayette, IN 47906, USADepartment of Animal Sciences, Purdue University, West Lafayette, IN 47906, USADepartment of Animal Sciences, Purdue University, West Lafayette, IN 47906, USALaboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, ChinaJoint Laboratory of Lipid Metabolism, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Beijing 100193, ChinaJoint Laboratory of Lipid Metabolism, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Beijing 100193, ChinaDepartment of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47906, USADepartment of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47906, USADepartment of Animal Sciences, Purdue University, West Lafayette, IN 47906, USALaboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, ChinaDepartment of Animal Sciences, Purdue University, West Lafayette, IN 47906, USABrown adipose tissues (BAT) burn lipids to generate heat through uncoupled respiration, thus representing a powerful target to counteract lipid accumulation and obesity. The tumor suppressor liver kinase b1 (Lkb1) is a key regulator of cellular energy metabolism; and adipocyte-specific knockout of Lkb1 (Ad-Lkb1 KO) leads to the expansion of BAT, improvements in systemic metabolism and resistance to obesity in young mice. Here we report the unexpected finding that the Ad-Lkb1 KO mice develop hindlimb paralysis at mid-age. Gene expression analyses indicate that Lkb1 KO upregulates the expression of inflammatory cytokines in interscapular BAT and epineurial brown adipocytes surrounding the sciatic nerve. This is followed by peripheral neuropathy characterized by infiltration of macrophages into the sciatic nerve, axon degeneration, reduced nerve conductance, and hindlimb paralysis. Mechanistically, Lkb1 KO reduces AMPK phosphorylation and amplifies mammalian target-of-rapamycin (mTOR)-dependent inflammatory signaling specifically in BAT but not WAT. Importantly, pharmacological or genetic inhibition of mTOR ameliorates inflammation and prevents paralysis. These results demonstrate that BAT inflammation is linked to peripheral neuropathy.http://www.sciencedirect.com/science/article/pii/S2352396417303705Brown adipocyteLiver kinase b1 (serine/threonine kinase 11)InflammationSciatic nervemTORParalysis |
| spellingShingle | Yan Xiong Jessica C. Page Naagarajan Narayanan Chao Wang Zhihao Jia Feng Yue Xine Shi Wen Jin Keping Hu Meng Deng Riyi Shi Tizhong Shan Gongshe Yang Shihuan Kuang Peripheral Neuropathy and Hindlimb Paralysis in a Mouse Model of Adipocyte-Specific Knockout of Lkb1 EBioMedicine Brown adipocyte Liver kinase b1 (serine/threonine kinase 11) Inflammation Sciatic nerve mTOR Paralysis |
| title | Peripheral Neuropathy and Hindlimb Paralysis in a Mouse Model of Adipocyte-Specific Knockout of Lkb1 |
| title_full | Peripheral Neuropathy and Hindlimb Paralysis in a Mouse Model of Adipocyte-Specific Knockout of Lkb1 |
| title_fullStr | Peripheral Neuropathy and Hindlimb Paralysis in a Mouse Model of Adipocyte-Specific Knockout of Lkb1 |
| title_full_unstemmed | Peripheral Neuropathy and Hindlimb Paralysis in a Mouse Model of Adipocyte-Specific Knockout of Lkb1 |
| title_short | Peripheral Neuropathy and Hindlimb Paralysis in a Mouse Model of Adipocyte-Specific Knockout of Lkb1 |
| title_sort | peripheral neuropathy and hindlimb paralysis in a mouse model of adipocyte specific knockout of lkb1 |
| topic | Brown adipocyte Liver kinase b1 (serine/threonine kinase 11) Inflammation Sciatic nerve mTOR Paralysis |
| url | http://www.sciencedirect.com/science/article/pii/S2352396417303705 |
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