Host Metabolic Changes during Mycobacterium Tuberculosis Infection Cause Insulin Resistance in Adult Mice
Tuberculosis (TB) is a highly infectious bacterial disease that primarily attacks the lungs. TB is manifested either as latent TB infection (LTBI) or active TB disease, the latter posing a greater threat to life. The risk of developing active TB disease from LTBI is three times higher in individuals...
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MDPI AG
2022-03-01
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| Series: | Journal of Clinical Medicine |
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| Online Access: | https://www.mdpi.com/2077-0383/11/6/1646 |
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| author | Neelam Oswal Kezia Lizardo Dhanya Dhanyalayam Janeesh P. Ayyappan Hariprasad Thangavel Scott K. Heysell Jyothi F. Nagajyothi |
| author_facet | Neelam Oswal Kezia Lizardo Dhanya Dhanyalayam Janeesh P. Ayyappan Hariprasad Thangavel Scott K. Heysell Jyothi F. Nagajyothi |
| author_sort | Neelam Oswal |
| collection | DOAJ |
| description | Tuberculosis (TB) is a highly infectious bacterial disease that primarily attacks the lungs. TB is manifested either as latent TB infection (LTBI) or active TB disease, the latter posing a greater threat to life. The risk of developing active TB disease from LTBI is three times higher in individuals with type 2 diabetes mellitus (T2DM). The association between TB and T2DM is becoming more prominent as T2DM is rapidly increasing in settings where TB is endemic. T2DM is a chronic metabolic disorder characterized by elevated blood glucose, insulin resistance, and relative insulin deficiency. Insulin resistance and stress-induced hyperglycemia have been shown to be increased by TB and to return to normal upon treatment. Previously, we demonstrated that adipocytes (or fat tissue) regulate pulmonary pathology, inflammation, and <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) load in a murine model of TB. Metabolic disturbances of adipose tissue and/or adipocyte dysfunction contribute to the pathogenesis of T2DM. Thus, pathological adipocytes not only regulate pulmonary pathology, but also increase the risk for T2DM during TB infection. However, the cellular and molecular mechanisms driving the interaction between hyperglycemia, T2DM and TB remain poorly understood. Here, we report the impact of <i>Mtb</i> infection on the development of insulin resistance in mice fed on a regular diet (RD) versus high-fat diet (HFD) and, conversely, the effect of hyperglycemia on pulmonary pathogenesis in juvenile and adult mouse models. Overall, our study demonstrated that <i>Mtb</i> persists in adipose tissue and that <i>Mtb</i> infection induces irregular adipocyte lipolysis and loss of fat cells via different pathways in RD- and HFD-fed mice. In RD-fed mice, the levels of TNFα and HSL (hormone sensitive lipase) play an important role whereas in HFD-fed mice, ATGL (adipose triglyceride lipase) plays a major role in regulating adipocyte lipolysis and apoptosis during <i>Mtb</i> infection in adult mice. We also showed that <i>Mtb</i> infected adult mice that were fed an RD developed insulin resistance similar to infected adult mice that were overweight due to a HFD diet. Importantly, we found that a consequence of <i>Mtb</i> infection was increased lipid accumulation in the lungs, which altered cellular energy metabolism by inhibiting major energy signaling pathways such as insulin, AMPK and mToR. Thus, an altered balance between lipid metabolism and glucose metabolism in adipose tissue and other organs including the lungs may be an important component of the link between <i>Mtb</i> infection and subsequent metabolic syndrome. |
| first_indexed | 2024-03-09T19:37:17Z |
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| institution | Directory Open Access Journal |
| issn | 2077-0383 |
| language | English |
| last_indexed | 2024-03-09T19:37:17Z |
| publishDate | 2022-03-01 |
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| spelling | doaj.art-281b4126570142c0ab6338a3785247532023-11-24T01:50:01ZengMDPI AGJournal of Clinical Medicine2077-03832022-03-01116164610.3390/jcm11061646Host Metabolic Changes during Mycobacterium Tuberculosis Infection Cause Insulin Resistance in Adult MiceNeelam Oswal0Kezia Lizardo1Dhanya Dhanyalayam2Janeesh P. Ayyappan3Hariprasad Thangavel4Scott K. Heysell5Jyothi F. Nagajyothi6Center for Discovery and Innovation, Hackensack University Medical Center, Hackensack, NJ 07110, USACenter for Discovery and Innovation, Hackensack University Medical Center, Hackensack, NJ 07110, USACenter for Discovery and Innovation, Hackensack University Medical Center, Hackensack, NJ 07110, USADepartment of Biochemisty, University of Kerala, Thiruvananthapuram 695034, Kerala, IndiaCenter for Discovery and Innovation, Hackensack University Medical Center, Hackensack, NJ 07110, USADivision of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA 22908, USACenter for Discovery and Innovation, Hackensack University Medical Center, Hackensack, NJ 07110, USATuberculosis (TB) is a highly infectious bacterial disease that primarily attacks the lungs. TB is manifested either as latent TB infection (LTBI) or active TB disease, the latter posing a greater threat to life. The risk of developing active TB disease from LTBI is three times higher in individuals with type 2 diabetes mellitus (T2DM). The association between TB and T2DM is becoming more prominent as T2DM is rapidly increasing in settings where TB is endemic. T2DM is a chronic metabolic disorder characterized by elevated blood glucose, insulin resistance, and relative insulin deficiency. Insulin resistance and stress-induced hyperglycemia have been shown to be increased by TB and to return to normal upon treatment. Previously, we demonstrated that adipocytes (or fat tissue) regulate pulmonary pathology, inflammation, and <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) load in a murine model of TB. Metabolic disturbances of adipose tissue and/or adipocyte dysfunction contribute to the pathogenesis of T2DM. Thus, pathological adipocytes not only regulate pulmonary pathology, but also increase the risk for T2DM during TB infection. However, the cellular and molecular mechanisms driving the interaction between hyperglycemia, T2DM and TB remain poorly understood. Here, we report the impact of <i>Mtb</i> infection on the development of insulin resistance in mice fed on a regular diet (RD) versus high-fat diet (HFD) and, conversely, the effect of hyperglycemia on pulmonary pathogenesis in juvenile and adult mouse models. Overall, our study demonstrated that <i>Mtb</i> persists in adipose tissue and that <i>Mtb</i> infection induces irregular adipocyte lipolysis and loss of fat cells via different pathways in RD- and HFD-fed mice. In RD-fed mice, the levels of TNFα and HSL (hormone sensitive lipase) play an important role whereas in HFD-fed mice, ATGL (adipose triglyceride lipase) plays a major role in regulating adipocyte lipolysis and apoptosis during <i>Mtb</i> infection in adult mice. We also showed that <i>Mtb</i> infected adult mice that were fed an RD developed insulin resistance similar to infected adult mice that were overweight due to a HFD diet. Importantly, we found that a consequence of <i>Mtb</i> infection was increased lipid accumulation in the lungs, which altered cellular energy metabolism by inhibiting major energy signaling pathways such as insulin, AMPK and mToR. Thus, an altered balance between lipid metabolism and glucose metabolism in adipose tissue and other organs including the lungs may be an important component of the link between <i>Mtb</i> infection and subsequent metabolic syndrome.https://www.mdpi.com/2077-0383/11/6/1646tuberculosistype 2 diabetesdiet and ageinsulin resistanceadipose tissueinflammation |
| spellingShingle | Neelam Oswal Kezia Lizardo Dhanya Dhanyalayam Janeesh P. Ayyappan Hariprasad Thangavel Scott K. Heysell Jyothi F. Nagajyothi Host Metabolic Changes during Mycobacterium Tuberculosis Infection Cause Insulin Resistance in Adult Mice Journal of Clinical Medicine tuberculosis type 2 diabetes diet and age insulin resistance adipose tissue inflammation |
| title | Host Metabolic Changes during Mycobacterium Tuberculosis Infection Cause Insulin Resistance in Adult Mice |
| title_full | Host Metabolic Changes during Mycobacterium Tuberculosis Infection Cause Insulin Resistance in Adult Mice |
| title_fullStr | Host Metabolic Changes during Mycobacterium Tuberculosis Infection Cause Insulin Resistance in Adult Mice |
| title_full_unstemmed | Host Metabolic Changes during Mycobacterium Tuberculosis Infection Cause Insulin Resistance in Adult Mice |
| title_short | Host Metabolic Changes during Mycobacterium Tuberculosis Infection Cause Insulin Resistance in Adult Mice |
| title_sort | host metabolic changes during mycobacterium tuberculosis infection cause insulin resistance in adult mice |
| topic | tuberculosis type 2 diabetes diet and age insulin resistance adipose tissue inflammation |
| url | https://www.mdpi.com/2077-0383/11/6/1646 |
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