ABSTRACT
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 Mycobacterium tuberculosis (Mtb) 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 Mtb 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 Mtb persists in adipose tissue and that Mtb 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 Mtb infection in adult mice. We also showed that Mtb 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 Mtb 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 Mtb infection and subsequent metabolic syndrome.
ABSTRACT
Chronic Chagas cardiomyopathy (CCC) caused by a parasite Trypanosoma cruzi is a life-threatening disease in Latin America, for which there is no effective drug or vaccine. The pathogenesis of CCC is complex and multifactorial. Previously, we demonstrated T. cruzi infected mice lose a significant amount of fat tissue which correlates with progression of CCC. Based on this an investigation was undertaken during both acute and chronic T. cruzi infection utilizing the FAT-ATTAC murine model (that allows modulation of fat mass) to understand the consequences of the loss of adipocytes in the regulation of cardiac parasite load, parasite persistence, inflammation, mitochondrial stress, ER stress, survival, CCC progression and CCC severity. Mice were infected intraperitoneally with 5x104 and 103 trypomastigotes to generate acute and chronic Chagas models, respectively. Ablation of adipocytes was carried out in uninfected and infected mice by treatment with AP21087 for 10 days starting at 15DPI (acute infection) and at 65DPI (indeterminate infection). During acute infection, cardiac ultrasound imaging, histological, and biochemical analyses demonstrated that fat ablation increased cardiac parasite load, cardiac pathology and right ventricular dilation and decreased survival. During chronic indeterminate infection ablation of fat cells increased cardiac pathology and caused bi-ventricular dilation. These data demonstrate that dysfunctional adipose tissue not only affects cardiac metabolism but also the inflammatory status, morphology and physiology of the myocardium and increases the risk of progression and severity of CCC in murine Chagas disease.
