Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation

TY - JOUR

T1 - Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation

AU - Wong, Chi Kin

AU - McLean, Brent A.

AU - Baggio, Laurie L.

AU - Koehler, Jacqueline A.

AU - Hammoud, Rola

AU - Rittig, Nikolaj

AU - Yabut, Julian M.

AU - Seeley, Randy J.

AU - Brown, Theodore J.

AU - Drucker, Daniel J.

PY - 2024/1/2

Y1 - 2024/1/2

N2 - Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert anti-inflammatory effects relevant to the chronic complications of type 2 diabetes. Although GLP-1RAs attenuate T cell-mediated gut and systemic inflammation directly through the gut intraepithelial lymphocyte GLP-1R, how GLP-1RAs inhibit systemic inflammation in the absence of widespread immune expression of the GLP-1R remains uncertain. Here, we show that GLP-1R activation attenuates the induction of plasma tumor necrosis factor alpha (TNF-α) by multiple Toll-like receptor agonists. These actions are not mediated by hematopoietic or endothelial GLP-1Rs but require central neuronal GLP-1Rs. In a cecal slurry model of polymicrobial sepsis, GLP-1RAs similarly require neuronal GLP-1Rs to attenuate detrimental responses associated with sepsis, including sickness, hypothermia, systemic inflammation, and lung injury. Mechanistically, GLP-1R activation leads to reduced TNF-α via α1-adrenergic, δ-opioid, and κ-opioid receptor signaling. These data extend emerging concepts of brain-immune networks and posit a new gut-brain GLP-1R axis for suppression of peripheral inflammation.

AB - Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert anti-inflammatory effects relevant to the chronic complications of type 2 diabetes. Although GLP-1RAs attenuate T cell-mediated gut and systemic inflammation directly through the gut intraepithelial lymphocyte GLP-1R, how GLP-1RAs inhibit systemic inflammation in the absence of widespread immune expression of the GLP-1R remains uncertain. Here, we show that GLP-1R activation attenuates the induction of plasma tumor necrosis factor alpha (TNF-α) by multiple Toll-like receptor agonists. These actions are not mediated by hematopoietic or endothelial GLP-1Rs but require central neuronal GLP-1Rs. In a cecal slurry model of polymicrobial sepsis, GLP-1RAs similarly require neuronal GLP-1Rs to attenuate detrimental responses associated with sepsis, including sickness, hypothermia, systemic inflammation, and lung injury. Mechanistically, GLP-1R activation leads to reduced TNF-α via α1-adrenergic, δ-opioid, and κ-opioid receptor signaling. These data extend emerging concepts of brain-immune networks and posit a new gut-brain GLP-1R axis for suppression of peripheral inflammation.

KW - autonomic nervous system

KW - diabetes

KW - G protein-coupled receptor

KW - glucagon-like peptides

KW - gut-brain axis

KW - immune

KW - inflammation

KW - obesity

UR - http://www.scopus.com/inward/record.url?scp=85181775661&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2023.11.009

DO - 10.1016/j.cmet.2023.11.009

M3 - Journal article

C2 - 38113888

AN - SCOPUS:85181775661

SN - 1550-4131

VL - 36

SP - 130

EP - 143

JO - Cell Metabolism

JF - Cell Metabolism

IS - 1

ER -