Persistent, unresolved inflammation in adipose tissue is a major contributor to obesity-associated metabolic complications. However, the molecular links between lipid-overloaded adipocytes and inflammatory immune cells in obese adipose tissues remain elusive. Here we identified adipocyte-secreted microRNA-34a (miR-34a) as a key mediator through its paracrine actions on adipose-resident macrophages. The expression of miR-34a in adipose tissues was progressively increased with the development of dietary obesity. Adipose-selective or adipocyte-specific miR-34a-KO mice were resistant to obesity-induced glucose intolerance, insulin resistance, and systemic inflammation, and this was accompanied by a significant shift in polarization of adipose-resident macrophages from proinflammatory M1 to antiinflammatory M2 phenotype. Mechanistically, mature adipocyte-secreted exosomes transported miR-34a into macrophages, thereby suppressing M2 polarization by repressing the expression of Krüppel-like factor 4 (Klf4). The suppressive effects of miR-34a on M2 polarization and its stimulation of inflammatory responses were reversed by ectopic expression of Klf4 in both bone marrow-derived macrophages and adipose depots of obese mice. Furthermore, increased miR-34a expression in visceral fat of overweight/obese subjects correlated negatively with reduced Klf4 expression, but positively with the parameters of insulin resistance and metabolic inflammation. In summary, miR-34a was a key component of adipocyte-secreted exosomal vesicles that transmitted the signal of nutrient overload to the adipose-resident macrophages for exacerbation of obesity-induced systemic inflammation and metabolic dysregulation.

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.

Diabetes mellitus (type 1 and type 2) and its various complications continue to place a huge burden on global medical resources, despite the availability of numerous drugs that successfully lower blood glucose levels. The major challenging issue in diabetes management is the prevention of various complications that remain the leading cause of diabetes-related mortality. Moreover, the limited long-term durability of monotherapy and undesirable side effects of currently used anti-diabetic drugs underlie the urgent need for novel therapeutic approaches. Phytochemicals represent a rich source of plant-derived molecules that are of pivotal importance to the identification of compounds with therapeutic potential. In this review, we aim to discuss recent advances in the identification of a large array of phytochemicals with immense potential in the management of diabetes and its complications. Given that metabolic inflammation has been established as a key pathophysiological event that drives the progression of diabetes, we focus on the protective effects of representative phytochemicals in metabolic inflammation. This paper also discusses the potential of phytochemicals in the development of new drugs that target the inflammation in the management of diabetes and its complications.

Gestational diabetes mellitus (GDM) is characterized by the development of hyperglycemia and insulin resistance during the second or third trimester of pregnancy, associated with considerable risks to both the mother and developing fetus. Although emerging evidence suggests an association between the altered gut microbiota and GDM, remarkably little is known about the microbial and metabolic mechanisms that link the dysbiosis of the gut microbiota to the development of GDM. In this study, a metagenome-wide association study and serum metabolomics profiling were performed in a cohort of pregnant women with GDM and pregnant women with normal glucose tolerance (NGT). We identified gut microbial alterations associated with GDM and linked to the changes in circulating metabolites. Blood metabolite profiles revealed that GDM patients exhibited a marked increase in 2-hydroxybutyric acid and L-alpha-aminobutyric acid, but a decrease in methionine sulfoxide, allantoin, and dopamine and dopaminergic synapse, when compared with those in NGT controls. Short-chain fatty acid-producing genera, including Faecalibacterium, Prevotella, and Streptococcus, and species Bacteroides coprophilus, Eubacterium siraeum, Faecalibacterium prausnitzii, Prevotella copri, and Prevotella stercorea, were significantly reduced in GDM patients relative to those in NGT controls. Bacterial co-occurrence network analysis revealed that pro-inflammatory bacteria were over-represented as the core species in GDM patients. These microbial and metabolic signatures are closely associated with clinical parameters of glucose metabolism in GDM patients and NGT controls. In conclusion, we identified circulating dopamine insufficiency, imbalanced production of SCFAs, and excessive metabolic inflammation as gut microbiota-driven multiple parallel hits linked to GDM development. This work might explain in part the mechanistic link between altered gut microbiota and GDM pathogenesis, and suggest that gut microbiota may serve as a promising target to intervene in GDM.

Marked enhancement of neutrophil infiltration in the liver is a hallmark of acute liver failure (ALF), a severe life-threatening disease with varying etiologies. However, the mechanisms and pathophysiological role corresponding to hepatic neutrophil infiltration during ALF development remain poorly characterized. Experimental ALF was induced in 10-week-old male microRNA-223 (miR-223) knockout (KO) mice, neutrophil elastase (NE) KO mice, and wild-type controls by intraperitoneal injection of galactosamine hydrochloride and lipopolysaccharide. Age-matched mice were injected with phosphate-buffered saline and served as vehicle controls. Mouse liver with ALF showed evident formation of neutrophil extracellular traps (NETs), which were enhanced markedly in miR-223 KO mice. The blockade of NETs by pharmacologic inhibitor GSK484 significantly attenuated neutrophil infiltration and massive necrosis in mouse liver with ALF. ALF-related hepatocellular damage and mortality in miR-223 KO mice were aggravated significantly and accompanied by potentiated neutrophil infiltration in the liver when compared with wild-type controls. Transcriptomic analyses showed that miR-223 deficiency in bone marrow predominantly caused the enrichment of pathways involved in neutrophil degranulation. Likewise, ALF-induced hepatic NE enrichment was potentiated in miR-223 KO mice. Genetic ablation of NE blunted the formation of NETs in parallel with significant attenuation of ALF in mice. Pharmaceutically, pretreatment with the NE inhibitor sivelestat protected mice against ALF. The present study showed the miR-223/NE axis as a key modulator of NETs, thereby exacerbating oxidative stress and neutrophilic inflammation to potentiate hepatocellular damage and liver necrosis in ALF development, and offering potential targets against ALF.