Oswal Neelam, Lizardo Kezia, Dhanyalayam Dhanya, Ayyappan Janeesh P, Thangavel Hariprasad, Heysell Scott K, Nagajyothi Jyothi F
Center for Discovery and Innovation, Hackensack University Medical Center, Hackensack, NJ 07110, USA.
Department of Biochemisty, University of Kerala, Thiruvananthapuram 695034, Kerala, India.
J Clin Med. 2022 Mar 16;11(6):1646. doi: 10.3390/jcm11061646.
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 () 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 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 persists in adipose tissue and that 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 infection in adult mice. We also showed that 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 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 infection and subsequent metabolic syndrome.
结核病（TB）是一种极具传染性的细菌性疾病，主要侵袭肺部。结核病表现为潜伏性结核感染（LTBI）或活动性结核病，后者对生命构成更大威胁。2型糖尿病（T2DM）患者从LTBI发展为活动性结核病的风险高出三倍。随着T2DM在结核病流行地区迅速增加，结核病与T2DM之间的关联日益显著。T2DM是一种慢性代谢紊乱疾病，其特征为血糖升高、胰岛素抵抗和相对胰岛素缺乏。结核病已被证明会增加胰岛素抵抗和应激诱导的高血糖，并在治疗后恢复正常。此前，我们在结核病小鼠模型中证明，脂肪细胞（或脂肪组织）调节肺部病理、炎症和（）负荷。脂肪组织的代谢紊乱和/或脂肪细胞功能障碍促成了T2DM的发病机制。因此，病理性脂肪细胞不仅调节肺部病理，还会增加结核病感染期间患T2DM的风险。然而，驱动高血糖、T2DM和结核病之间相互作用的细胞和分子机制仍知之甚少。在此，我们报告了感染对正常饮食（RD）喂养与高脂饮食（HFD）喂养小鼠胰岛素抵抗发展的影响，反之，高血糖对幼年和成年小鼠模型肺部发病机制的影响。总体而言，我们的研究表明，在脂肪组织中持续存在，并且感染通过不同途径在RD和HFD喂养的小鼠中诱导不规则脂肪细胞脂解和脂肪细胞丢失。在RD喂养的小鼠中，TNFα和激素敏感脂肪酶（HSL）水平起重要作用，而在HFD喂养的小鼠中，成人小鼠感染期间，脂肪甘油三酯脂肪酶（ATGL）在调节脂肪细胞脂解和凋亡中起主要作用。我们还表明，感染的RD喂养成年小鼠发展出的胰岛素抵抗与因HFD饮食而超重的感染成年小鼠相似。重要的是，我们发现感染的一个后果是肺部脂质积累增加，这通过抑制胰岛素、AMPK和mToR等主要能量信号通路改变了细胞能量代谢。因此，脂肪组织和包括肺部在内的其他器官中脂质代谢与葡萄糖代谢之间的平衡改变可能是感染与随后代谢综合征之间联系的重要组成部分。
