Knockout of TSC2 in Nav1.8+ neurons predisposes to the onset of normal weight obesity
Objective: Obesity and nutrient oversupply increase mammalian target of rapamycin (mTOR) signaling in multiple cell types and organs, contributing to the onset of insulin resistance and complications of metabolic disease. However, it remains unclear when and where mTOR activation mediates these effe...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-02-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877822002332 |
| _version_ | 1811173428977205248 |
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| author | Jennifer M. Brazill David Shin Kristann Magee Anurag Majumdar Ivana R. Shen Valeria Cavalli Erica L. Scheller |
| author_facet | Jennifer M. Brazill David Shin Kristann Magee Anurag Majumdar Ivana R. Shen Valeria Cavalli Erica L. Scheller |
| author_sort | Jennifer M. Brazill |
| collection | DOAJ |
| description | Objective: Obesity and nutrient oversupply increase mammalian target of rapamycin (mTOR) signaling in multiple cell types and organs, contributing to the onset of insulin resistance and complications of metabolic disease. However, it remains unclear when and where mTOR activation mediates these effects, limiting options for therapeutic intervention. The objective of this study was to isolate the role of constitutive mTOR activation in Nav1.8-expressing peripheral neurons in the onset of diet-induced obesity, bone loss, and metabolic disease. Methods: In humans, loss of function mutations in tuberous sclerosis complex 2 (TSC2) lead to maximal constitutive activation of mTOR. To mirror this in mice, we bred Nav1.8-Cre with TSC2fl/fl animals to conditionally delete TSC2 in Nav1.8-expressing neurons. Male and female mice were studied from 4- to 34-weeks of age and a subset of animals were fed a high-fat diet (HFD) for 24-weeks. Assays of metabolism, body composition, bone morphology, and behavior were performed. Results: By lineage tracing, Nav1.8-Cre targeted peripheral sensory neurons, a subpopulation of postganglionic sympathetics, and several regions of the brain. Conditional knockout of TSC2 in Nav1.8-expressing neurons (Nav1.8-TSC2KO) selectively upregulated neuronal mTORC1 signaling. Male, but not female, Nav1.8-TSC2KO mice had a 4–10% decrease in body size at baseline. When challenged with HFD, both male and female Nav1.8-TSC2KO mice resisted diet-induced gains in body mass. However, this did not protect against HFD-induced metabolic dysfunction and bone loss. In addition, despite not gaining weight, Nav1.8-TSC2KO mice fed HFD still developed high body fat, a unique phenotype previously referred to as ‘normal weight obesity’. Nav1.8-TSC2KO mice also had signs of chronic itch, mild increases in anxiety-like behavior, and sex-specific alterations in HFD-induced fat distribution that led to enhanced visceral obesity in males and preferential deposition of subcutaneous fat in females. Conclusions: Knockout of TSC2 in Nav1.8+ neurons increases itch- and anxiety-like behaviors and substantially modifies fat storage and metabolic responses to HFD. Though this prevents HFD-induced weight gain, it masks depot-specific fat expansion and persistent detrimental effects on metabolic health and peripheral organs such as bone, mimicking the ‘normal weight obesity’ phenotype that is of growing concern. This supports a mechanism by which increased neuronal mTOR signaling can predispose to altered adipose tissue distribution, adipose tissue expansion, impaired peripheral metabolism, and detrimental changes to skeletal health with HFD – despite resistance to weight gain. |
| first_indexed | 2024-04-10T17:46:42Z |
| format | Article |
| id | doaj.art-a36ce77cbd184d64b7d05943a7a4ecf6 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-10T17:46:42Z |
| publishDate | 2023-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-a36ce77cbd184d64b7d05943a7a4ecf62023-02-03T04:57:52ZengElsevierMolecular Metabolism2212-87782023-02-0168101664Knockout of TSC2 in Nav1.8+ neurons predisposes to the onset of normal weight obesityJennifer M. Brazill0David Shin1Kristann Magee2Anurag Majumdar3Ivana R. Shen4Valeria Cavalli5Erica L. Scheller6Department of Medicine, Division of Bone and Mineral Diseases, Washington University, Saint Louis, MO, USADepartment of Medicine, Division of Bone and Mineral Diseases, Washington University, Saint Louis, MO, USADepartment of Medicine, Division of Bone and Mineral Diseases, Washington University, Saint Louis, MO, USADepartment of Medicine, Division of Bone and Mineral Diseases, Washington University, Saint Louis, MO, USADepartment of Medicine, Division of Bone and Mineral Diseases, Washington University, Saint Louis, MO, USADepartment of Neuroscience, Washington University, Saint Louis, MO, USA; Center of Regenerative Medicine, Washington University School of Medicine, Saint Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, USADepartment of Medicine, Division of Bone and Mineral Diseases, Washington University, Saint Louis, MO, USA; Center of Regenerative Medicine, Washington University School of Medicine, Saint Louis, MO, USA; Department of Cell Biology and Physiology, Washington University, Saint Louis, MO, USA; Department of Biomedical Engineering, Washington University, Saint Louis, MO, USA; Corresponding author. 660 S. Euclid Ave St. Louis, MO 63110, USA.Objective: Obesity and nutrient oversupply increase mammalian target of rapamycin (mTOR) signaling in multiple cell types and organs, contributing to the onset of insulin resistance and complications of metabolic disease. However, it remains unclear when and where mTOR activation mediates these effects, limiting options for therapeutic intervention. The objective of this study was to isolate the role of constitutive mTOR activation in Nav1.8-expressing peripheral neurons in the onset of diet-induced obesity, bone loss, and metabolic disease. Methods: In humans, loss of function mutations in tuberous sclerosis complex 2 (TSC2) lead to maximal constitutive activation of mTOR. To mirror this in mice, we bred Nav1.8-Cre with TSC2fl/fl animals to conditionally delete TSC2 in Nav1.8-expressing neurons. Male and female mice were studied from 4- to 34-weeks of age and a subset of animals were fed a high-fat diet (HFD) for 24-weeks. Assays of metabolism, body composition, bone morphology, and behavior were performed. Results: By lineage tracing, Nav1.8-Cre targeted peripheral sensory neurons, a subpopulation of postganglionic sympathetics, and several regions of the brain. Conditional knockout of TSC2 in Nav1.8-expressing neurons (Nav1.8-TSC2KO) selectively upregulated neuronal mTORC1 signaling. Male, but not female, Nav1.8-TSC2KO mice had a 4–10% decrease in body size at baseline. When challenged with HFD, both male and female Nav1.8-TSC2KO mice resisted diet-induced gains in body mass. However, this did not protect against HFD-induced metabolic dysfunction and bone loss. In addition, despite not gaining weight, Nav1.8-TSC2KO mice fed HFD still developed high body fat, a unique phenotype previously referred to as ‘normal weight obesity’. Nav1.8-TSC2KO mice also had signs of chronic itch, mild increases in anxiety-like behavior, and sex-specific alterations in HFD-induced fat distribution that led to enhanced visceral obesity in males and preferential deposition of subcutaneous fat in females. Conclusions: Knockout of TSC2 in Nav1.8+ neurons increases itch- and anxiety-like behaviors and substantially modifies fat storage and metabolic responses to HFD. Though this prevents HFD-induced weight gain, it masks depot-specific fat expansion and persistent detrimental effects on metabolic health and peripheral organs such as bone, mimicking the ‘normal weight obesity’ phenotype that is of growing concern. This supports a mechanism by which increased neuronal mTOR signaling can predispose to altered adipose tissue distribution, adipose tissue expansion, impaired peripheral metabolism, and detrimental changes to skeletal health with HFD – despite resistance to weight gain.http://www.sciencedirect.com/science/article/pii/S2212877822002332mTORBoneHigh fat dietSkinny fatNormal weight obesitySensory nerve |
| spellingShingle | Jennifer M. Brazill David Shin Kristann Magee Anurag Majumdar Ivana R. Shen Valeria Cavalli Erica L. Scheller Knockout of TSC2 in Nav1.8+ neurons predisposes to the onset of normal weight obesity Molecular Metabolism mTOR Bone High fat diet Skinny fat Normal weight obesity Sensory nerve |
| title | Knockout of TSC2 in Nav1.8+ neurons predisposes to the onset of normal weight obesity |
| title_full | Knockout of TSC2 in Nav1.8+ neurons predisposes to the onset of normal weight obesity |
| title_fullStr | Knockout of TSC2 in Nav1.8+ neurons predisposes to the onset of normal weight obesity |
| title_full_unstemmed | Knockout of TSC2 in Nav1.8+ neurons predisposes to the onset of normal weight obesity |
| title_short | Knockout of TSC2 in Nav1.8+ neurons predisposes to the onset of normal weight obesity |
| title_sort | knockout of tsc2 in nav1 8 neurons predisposes to the onset of normal weight obesity |
| topic | mTOR Bone High fat diet Skinny fat Normal weight obesity Sensory nerve |
| url | http://www.sciencedirect.com/science/article/pii/S2212877822002332 |
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