MyD88 Inhibition Ameliorates Diabetes-Induced Hepatic Inflammation and Gluconeogenesis Through Adipose IL-10 Induction

Myeloid differentiation factor 88 (MyD88) signaling plays a central role in inflammatory pathway activation. Adipose-derived interleukin-10 (IL-10), which is induced by insulin and lipopolysaccharides, suppresses hepatic glucose production. This study investigated the role of MyD88/IL-10 signaling in diabetes-induced systemic inflammation and hepatic gluconeogenesis. Stromal vascular fractions (SVFs) were isolated from the adipose tissue of <i>Lepr^db</i>^/<i>db</i> and <i>Lepr^db</i>^/<i>db</i>MyD88^-/- mice and treated with IL-10 followed by analysis of inflammatory cytokine expression. IL-10 (10 or 50 ng) was injected into adipose tissue of type 2 DM (T2DM) (<i>Lepr^db</i>^/<i>db</i>) mice to investigate its effect on blood dipeptidyl peptidase-4 (DPP4) activity, insulin resistance, and hepatic gluconeogenic signaling. Hepatic inflammatory markers, gluconeogenic gene expression, and metabolic parameters were assessed. Compared with wild-type mice, <i>Lepr^db</i>^/<i>db</i> mice exhibited significantly reduced FOXP3 protein expression and IL-10 levels in adipose tissue, accompanied by increased blood DPP4 activity and adiponectin levels, elevated hepatic inflammatory cytokines, and increased <i>G6pc</i> and <i>Pck1</i> mRNA expression. In contrast, <i>Lepr^db</i>^/<i>db</i>MyD88^-/- mice showed increased Foxp3 protein and <i>PDGFα</i> mRNA expression, decreased <i>IL-6</i> and <i>CCL2</i> mRNA expression in SVFs, increased IL-10 levels in adipose tissue, and lower blood adiponectin and ALT levels. MyD88 deletion also attenuated Kupffer cell accumulation, hepatic inflammatory cytokine expression, and gluconeogenic gene expression. In vitro, IL-10 treatment of SVFs from <i>Lepr^db</i>^/<i>db</i> mice significantly reduced <i>IL-6</i> and <i>CCL2</i> expression and increased <i>Foxp3</i> mRNA expression. In vivo, adipose IL-10 injection increased <i>Foxp3</i> and <i>IL-10</i> expression, expanded Treg cells in SVFs, and activated hepatic Akt signaling, while suppressing pJNK and pNF-κB signaling. These changes were accompanied by reduced blood DPP4 activity, ALT and adiponectin levels, decreased Kupffer cell-derived inflammatory cytokines, reduced hepatic <i>G6pc</i> and <i>Pck1</i> expression, and improved glucose tolerance. MyD88 signaling induces adipose <i>IL-6</i> and <i>CCL2</i>, liver inflammation and gluconeogenesis, and blood DPP4 activity by reducing IL-10 and Foxp3 of adipose tissue in T2DM. Enhancing adipose IL-10 induces Treg expansion, inhibits JNK and NF-κB signaling, and alleviates hepatic gluconeogenesis and insulin resistance. MyD88 inhibition or IL-10 elevation in adipose tissue may represent a novel strategy for metabolic syndrome.