TY - UNPB
T1 - Peripheral sgp130-mediated trans-signaling blockade induces obesity and insulin resistance in mice via PPARα suppression
AU - Lanton, Tali
AU - Levkovitch-Siany, Orr
AU - Udi, Shiran
AU - Tam, Joseph
AU - Abramovitch, Rinat
AU - Perles, Sharon
AU - Williams, Evan
AU - Rachmilewitz, Jacob
AU - Mor, Uria
AU - Elinav, Eran
AU - Schmidt-Arras, Dirk
AU - Rehman, Ateequr
AU - Rosenstiel, Philip
AU - Giannou, Anastasios
AU - Huber, Samuel
AU - Rose-John, Stefan
AU - Galun, Eithan
AU - Axelrod, Jonathan H.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - IL-6 signaling via its receptor (IL-6R) and co-receptor (gp130) performs multiple roles in regulating metabolic homeostasis. However, gp130 is also expressed systemically in a soluble form (sgp130), which limits soluble IL-6 receptor (sIL-6R)-mediated signaling – also called trans-signaling. Here we find that transgenic peripheral sgp130-mediated trans-signaling blockade induces mature-onset obesity, while differentially affecting age-dependent behavioral determinants of energy expenditure. In youth, trans-signaling blockade increases feeding associated with reduced leptin sensitivity but increases energy expenditure to maintain metabolic balance. In aging, reduced physical activity predisposes mice to adiposity, adipose tissue macrophage recruitment, hepatosteatosis, hyperglycemia, and insulin resistance. Mechanistically, trans-signaling blockade reduces hepatic Stat3 phosphorylation and suppresses PPARα, associated with miR-21 upregulation, while pharmacological activation of PPARα prevents obesity and hepatosteatosis, and rescues insulin sensitivity. Together these experiments reveal a role for peripheral IL-6 trans-signaling in metabolic homeostasis and provide clinical significance to elevated sgp130 levels found in some obese and diabetic patients.Competing Interest StatementS.R.-J. is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein, and has stock ownership in CONARIS.
AB - IL-6 signaling via its receptor (IL-6R) and co-receptor (gp130) performs multiple roles in regulating metabolic homeostasis. However, gp130 is also expressed systemically in a soluble form (sgp130), which limits soluble IL-6 receptor (sIL-6R)-mediated signaling – also called trans-signaling. Here we find that transgenic peripheral sgp130-mediated trans-signaling blockade induces mature-onset obesity, while differentially affecting age-dependent behavioral determinants of energy expenditure. In youth, trans-signaling blockade increases feeding associated with reduced leptin sensitivity but increases energy expenditure to maintain metabolic balance. In aging, reduced physical activity predisposes mice to adiposity, adipose tissue macrophage recruitment, hepatosteatosis, hyperglycemia, and insulin resistance. Mechanistically, trans-signaling blockade reduces hepatic Stat3 phosphorylation and suppresses PPARα, associated with miR-21 upregulation, while pharmacological activation of PPARα prevents obesity and hepatosteatosis, and rescues insulin sensitivity. Together these experiments reveal a role for peripheral IL-6 trans-signaling in metabolic homeostasis and provide clinical significance to elevated sgp130 levels found in some obese and diabetic patients.Competing Interest StatementS.R.-J. is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein, and has stock ownership in CONARIS.
U2 - https://doi.org/10.1101/2020.09.24.309716
DO - https://doi.org/10.1101/2020.09.24.309716
M3 - Preprint
T3 - bioRxiv
BT - Peripheral sgp130-mediated trans-signaling blockade induces obesity and insulin resistance in mice via PPARα suppression
ER -
