Potent anti-inflammatory effects of the adiponectin receptor agonist, ALY688

Abstract

Low circulating levels of adiponectin are associated with increased inflammation in a wide-range of disease states. In particular, this applies to obesity-related diseases such as type 2 diabetes, heart failure and non-alcoholic fatty liver disease. Numerous studies have shown that adiponectin exerts anti-inflammatory and beneficial metabolic effects. Hence there has been tremendous interest in developing adiponectin-based therapeutics. Here we examined the effect of ALY688, a small peptide adiponectin receptor agonist, on lipopolysaccharide (LPS)-driven inflammation in vivo and in vitro. We show that ALY688 administration significantly diminished LPS-driven production of pro-inflammatory cytokines and chemokines (i.e., IL-1β, TNF-α, IL-12, IFN-β, MCP-1, KC, RANTES) in mice. Moreover, mice injected with ALY688 exhibited a rapid increase in the anti-inflammatory cytokine, TGF-β. Apart from an increase in total CD3+ T cells, there were no marked changes in the circulating immune cells following ALY688 injection. No alterations in cytokine profile was seen in normal mice given ALY688, suggesting that the effects of ALY688 are context-dependent. Mechanistically, we employed phospho-flow cytometry to demonstrate that circulating immune cells responded rapidly to ALY688 injection by upregulating p-AMPK and p-P38, two well established adiponectin downstream signaling events. These results were confirmed in human peripheral blood mononuclear cells (PBMCs), where ALY688 treatment led to a robust increase in phospho-AMPK and phospho-P38. Altogether, these results show that the adiponectin agonist, ALY688, has strong anti-inflammatory effects by triggering AMPK and P38 activation in vivo and in vit Canadian institutes of Health Research & Allysta Pharmaceuticals This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.