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Whether TB induced-inflammation impacts metabolic organs and leads to metabolic disorder is ill defined. The liver is the master regulator of metabolism and to determine the impact of pulmonary TB on this organ we undertook an unbiased mRNA and protein analyses of the liver in mice with TB and reanalysed published data on human disease. Pulmonary TB led to upregulation of genes in the liver related to immune signalling and downregulation of genes encoding metabolic processes. In liver, IFN signalling pathway genes were upregulated and this was reflected in increased biochemical evidence of IFN signalling, including nuclear location of phosphorylated Stat-1 in hepatocytes. The liver also exhibited reduced expression of genes encoding the gluconeogenesis rate-limiting enzymes Pck1 and G6pc. Phosphorylation of CREB, a transcription factor controlling gluconeogenesis was drastically reduced in the livers of mice with pulmonary TB as was phosphorylation of other glucose metabolism-related kinases, including GSK3a, AMPK, and p42. In support of the upregulated IFN signalling being linked to the downregulated metabolic functions in the liver, we found suppression of gluconeogenic gene expression and reduced CREB phosphorylation in hepatocyte cell lines treated with interferons. The impact of reduced gluconeogenic gene expression in the liver was seen when infected mice were less able to convert pyruvate, a gluconeogenesis substrate, to the same extent as uninfected mice. Infected mice also showed evidence of reduced systemic and hepatic insulin sensitivity. Similarly, in humans with TB, we found that changes in a metabolite-based signature of insulin resistance correlates temporally with successful treatment of active TB and with progression to active TB following exposure. These data support the hypothesis that TB drives interferon-mediated alteration of hepatic metabolism resulting in reduced gluconeogenesis and drives systemic reduction of insulin sensitivity.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012565","type":"journal-article","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T17:40:28Z","timestamp":1727458828000},"page":"e1012565","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Altered hepatic metabolic landscape and insulin sensitivity in response to pulmonary tuberculosis"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8057-241X","authenticated-orcid":true,"given":"Mrinal 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