Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2

Abstract

Adipose tissue macrophage (ATM) inflammation is involved with meta-inflammation and pathology of metabolic complications. Here we report that in adipocytes, elevated lactate production, previously regarded as the waste product of glycolysis, serves as a danger signal to promote ATM polarization to an inflammatory state in the context of obesity. Adipocyte-selective deletion of lactate dehydrogenase A (Ldha), the enzyme converting pyruvate to lactate, protects mice from obesity-associated glucose intolerance and insulin resistance, accompanied by a lower percentage of inflammatory ATM and reduced production of pro-inflammatory cytokines such as interleukin 1β (IL-1β). Mechanistically, lactate, at its physiological concentration, fosters the activation of inflammatory macrophages by directly binding to the catalytic domain of prolyl hydroxylase domain-containing 2 (PHD2) in a competitive manner with α-ketoglutarate and stabilizes hypoxia inducible factor (HIF-1α). Lactate-induced IL-1β was abolished in PHD2-deficient macrophages. Human adipose lactate level is positively linked with local inflammatory features and insulin resistance index independent of the body mass index (BMI). Our study shows a critical function of adipocyte-derived lactate in promoting the pro-inflammatory microenvironment in adipose and identifies PHD2 as a direct sensor of lactate, which functions to connect chronic inflammation and energy metabolism.

Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a mouse model of Friedreich’s ataxia

“…Augmented lactate levels in adipose tissue and plasma are widely reported in obese/diabetic subjects (Krycer et al, 2020;Feng et al, 2022). Metabolically, we found that FXN-deficient adipocytes have increased glycolytic activity and consequent hyperproduction of lactate.…”

“…Lactate was previously regarded as the waste product of glycolysis. Recently, it has emerged that lactate serves as a danger signal that promotes polarization of resident macrophages towards a pro-inflammatory M1-like state in the context of obesity (Feng et al, 2022;Lin et al, 2022). Based on this evidence and our RNAseq results, we determined the leukocyte abundance in SVCs isolated from vWAT.…”

“…Hypovascularization and vWAT expansion can lead to lowering of oxygen availability, decrease of mitochondrial respiration and metabolic reprogramming towards glycolysis and lactate production. Notably, increased levels of lactate in WAT are typical of T2D conditions (Feng et al, 2022;Lin et al, 2022). In order to pinpoint possible metabolic alterations of WAT, we isolated SVCs, and pre-adipocytes were induced to differentiate.…”

Targeting PI3K/AKT signaling pathway in obesity

“…Adipose tissue is a structurally heterogeneous endocrine organ that consists of fat cells (adipocytes) and their precursors (preadipocytes) [38], as well as fibroblasts, endothelial cells, vascular cells [10], resident immune cells (predominantly macrophages) [39], and neuronal cells [40]. These different cell types are essential for the physiological role of the adipose tissue, but they often interact in the pathophysiological complications of obesity.…”

Lactate: a pearl dropped in the ocean—an overlooked signal molecule in physiology and pathology

“…Additionally, lactate interacts with NDRG Family Member 3 (NDRG 3) to protect it from ubiquitination degradation and response to hypoxia. In adipose macrophages, the adipocyte‐derived lactate binds to prolyl hydroxylase domain containing 2 (PHD2) to promote adipose inflammation and insulin resistance (T. Feng et al, 2022). Collectively, these findings indicate that these receptors/sensors can not necessarily explain every physiological phenomenon mediated by lactate, and there should be yet‐undiscovered receptors/sensors linked with lactate signaling.…”