The PPE2 protein of Mycobacterium tuberculosis is responsible for the development of hyperglycemia and insulin resistance during tuberculosis

Diabetes is a known risk factor for tuberculosis (TB), but clinical evidences suggest that TB itself can induce hyperglycaemia and insulin resistance, though the underlying mycobacterial factors are not known. Herein, we implicate PPE2, a secretory PE/PPE family protein of Mycobacterium tuberculosis (Mtb), as a key modulator of adipose tissue physiology that contributes to the development of insulin resistance. In mice, PPE2 caused fat loss, adipocyte hypertrophy, immune cell infiltration, impaired glucose tolerance, reduced expression of PPAR-γ, C/EBP-α, adiponectin and higher insulin resistance. Transcriptomic analysis revealed PPE2 altered expression of genes associated with chemokine/cytokine, ribosomal biogenesis and lipase signaling. PPE2 induced lipolysis by activating cAMP–PKA–HSL axis, increased circulating free fatty acids, a feature also observed in TB patient sera. Interestingly, PPE2-immunization mitigated these effects, suggesting its potential as a subunit vaccine. Overall, this study identifies PPE2 as a key link between Mtb-infection, adipose tissue dysfunction and insulin resistance.