Hypothalamic POMC expression is required for peripheral
insulin action on hepatic gluconeogenesis through regulating
STAT3 in sepsis rats
* , Nannan Zhang
, Kaipeng Duan
, Bimin Shi
Department of Endocrinology and Metabolism, The First Afﬁliated Hospital of Soochow University, Suzhou, Jiangsu, China
Department of Cardiology, The First Afﬁliated Hospital of Soochow University, Suzhou, Jiangsu, China
Department of General Surgery, The First Afﬁliated Hospital of Soochow University, Suzhou, Jiangsu, China
Received: August 5, 2017; Accepted: October 6, 2017
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 investi-
gated whether liver inﬂammatory pathway and central neuropeptides were involved in the process. In sepsis rats, hepatic IKK/NF-jB 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 neu-
ropeptide proopiomelanocortin (POMC) expression, hepatic NF-jB pathway and STAT3 phosphorylation. Furthermore, knockdown of hypothala-
mic POMC signiﬁcantly diminished protective effect of insulin on hepatic GNG and insulin-induced STAT3 inactivation, but not inﬂammation or
IKK/NF-jB pathway. These results suggest that hepatic IKK/NF-jB 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.
Sepsis commonly happens in critical illness and usually causes severe
complications, such as metabolic disorders, in which reduced feeding,
increased energy expenditure and dysregulated glucose homoeostasis
are recognized as hallmarks . Additionally, because of multiple func-
tions of the liver, high levels of pro-inﬂammatory cytokines and oxida-
tive insults-induced liver injury have critical effects on the outcome of
sepsis patients . Depend on the severity and stage of sepsis,
changes in glucose metabolism are complex . Notably, albeit sepsis
is usually associated with hyperglycaemia, hypoglycaemia is observed
in models of sepsis and thought to be associated with mortality of sep-
tic patients [4–6]. Earlier studies reported that insulin treatment pro-
tects against multiple organ damages caused by sepsis and reduces
mortality among critical patients . Although animal experiments
have demonstrated NF-jB pathway and glycogen synthase kinase
(GSK)-3b inhibition were involved [8–10], the precise molecular mech-
anisms underlying beneﬁcial effects of insulin remain undeﬁned.
Signal transducer and activator of transcription 3 (STAT3) has
been demonstrated a putative role in regulating expression of hepatic
gluconeogenic genes . Phosphorylated STAT3 is recruited to the
promoter regions of G6Pase and PEPCK, leading to reduced gene
expression. This is supported by the fact that liver-speciﬁc STAT3
knockout resulted in increased expression of these genes, on the con-
trary, overexpression of active STAT3 in the liver caused reduced
gene expression of PEPCK and G6Pase, as well as blood glucose
[12–14]. In addition, intraperitoneal administration of lipopolysaccha-
ride (LPS) increased the phosphorylation of STAT3 in the liver .
Hypothalamus plays critical roles in the regulation of energy meta-
bolism balance as well as the maintenance of glucose homoeostasis
. Pro-opiomelanocortin (POMC) is principally expressed in the
arcuate nucleus (ARC) of the hypothalamus and the nucleus of the
tractus solitarius (NTS) of the brainstem . The peptide precursor
POMC can be further cleaved into a-melanocyte-stimulating hormone
These authors contributed equally to this work.
*Correspondence to: Bin FENG
ª 2017 The Authors.
Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
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J. Cell. Mol. Med. Vol 22, No 3, 2018 pp. 1696-1707