Targeted activation of PPARG or AKT1 alleviates liver injury in mice with type 2 diabetes and sepsis by modulating inflammatory and metabolic pathways

BACKGROUND: The simultaneous presence of sepsis and type 2 diabetic mellitus (T2DM) has a synergistic effect on hepatic damage. Although the activation of peroxisome proliferator-activate receptor gamma (PPARG) and AKT serine/threonine kinase 1 (AKT1) have been shown to confer protection alone in isolated models of sepsis or T2DM. The present study was designed to systematically assess the effects of PPARG or AKT1 activation on inflammatory responses and glucose and lipid metabolism as well as intestinal barrier function in a murine model of T2DM and sepsis (T2DM/sepsis), and understand the molecular pathways involved. METHODS: Mice were treated with either the PPARG agonist pioglitazone or the AKT1 activator SC79 and we then evaluated survival, inflammatory indicators, metabolic changes, tissue pathology, intestinal barrier integrity, and gut microbiota composition. Mechanistic studies focused on the PPARG/AMPK and PI3K/AKT1/mTOR signaling pathways. RESULTS: Activation of either PPARG or AKT1 was associated with significantly increased survival rates, reduced systemic and hepatic levels of pro-inflammatory cytokines, increased the expression of anti-inflammatory mediators, ameliorated the abnormalities of the glucose and lipid metabolism, and partially improved hepatic, pulmonary, and intestinal injury. Mechanistically, PPARG activation mainly activated the PPARG/AMPK pathway and AKT1 activation enhanced the PI3K/AKT1/mTOR pathway. Furthermore, the intestinal barrier integrity and gut microbiota composition was partially improved. CONCLUSION: These results suggest that targeting PPARG or AKT1 is associated with protection against sepsis-associated liver injury in mice with T2DM by modulating the PPARG/AMPK axis or the PI3K/AKT1/mTOR pathway, respectively, which may collectively contribute to anti-inflammatogenic, metabolic, and gut-barrier protective mechanisms.