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

Cell Metab. 2023 Dec 5:S1550-4131(23)00420-5. doi: 10.1016/j.cmet.2023.11.009. Online ahead of print.ABSTRACTGlucagon-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.PMID:38113888 | DOI:10.1016/j.cmet.2023.11.009

Source: Cell Metabolism - December 19, 2023 Category: Cytology Authors: Chi Kin Wong Brent A McLean Laurie L Baggio Jacqueline A Koehler Rola Hammoud Nikolaj Rittig Julian M Yabut Randy J Seeley Theodore J Brown Daniel J Drucker Source Type: research