Hypothalamic POMC expression is required for peripheral insulin action on hepatic gluconeogenesis through regulating...

Liver injury and dysregulated glucose homoeostasis are common manifestations during sepsis. Although plenty of studies reported insulin could protect against multiple organ injuries caused by critical infections among patients, little was known about the precise mechanism. We investigated whether liver inflammatory pathway and central neuropeptides were involved in the process. In sepsis rats, hepatic IKK/NF-κB pathway and STAT3 were strongly activated, along with reduced body weight, blood glucose and suppressed hepatic gluconeogenesis (GNG). Peripheral insulin administration efficiently attenuated liver dysfunction and glucose metabolic disorders by suppressing hypothalamic anorexigenic neuropeptide proopiomelanocortin (POMC) expression, hepatic NF-κB pathway and STAT3 phosphorylation. Furthermore, knockdown of hypothalamic POMC significantly diminished protective effect of insulin on hepatic GNG and insulin-induced STAT3 inactivation, but not inflammation or IKK/NF-κB pathway. These results suggest that hepatic IKK/NF-κB pathway mediates the anti-inflammatory effect of insulin in septic rats, and peripheral insulin treatment may improve hepatic GNG by inhibiting STAT3 phosphorylation dependent on hypothalamic POMC expression.