Skeletal muscle H3K18 lactylation inhibits hepatic gluconeogenesis through IL-6 mediated interorgan communication

Abstract

The mechanisms underlying the dynamic interplay between skeletal muscle and systemic glucose homeostasis in type 2 diabetes remain elusive. Increased lactate level has long been noticed in diabetes, however, whether the elevated lactate is a cause or consequence of impaired glucose metabolism is unclear. Here, we found that elevated circulating lactate levels originated from skeletal muscle with high expression of lactate dehydrogenase A (Ldha), and both metrics correlated strongly with hyperglycemia in both hyperglycemic mouse models and human subjects. Paradoxically, ablation of Ldha in skeletal muscle (LDHA mKO) disrupted whole-body glucose homeostasis, primarily via augmented hepatic gluconeogenesis. Mechanistically, lactate deficiency in muscle epigenetically activated NF-κB signaling through H3K18 lactylation (H3K18la)-mediated transcriptional control of IκBα, which then promoted the transcription of IL-6, thereby reshaping hepatic gluconeogenesis. Lastly, we showed that loss of Ldha in skeletal muscle enhanced hepatic gluconeogenesis and aggravated hyperglycemia in high-fat high-sucrose diet-fed mice. Collectively, our study provides evidence that in glucose intoxication contexts, skeletal muscle-derived lactate acts as the signal to provide negative feedback for hepatic gluconeogenesis, which induces skeletal muscle H3K18la acting as a negative regulator of IL-6 to sustain suppression of hepatic gluconeogenesis, while dysregulation of this network contributes to unrestrained gluconeogenesis in diabetes.