Edible Pueraria lobata-Derived Exosomes Promote M2 Macrophage Polarization.

Pueraria lobata (known as Gegen) is an edible and medicinal herb that is a nutritious medicine food homology plant in China. Previous studies indicated that P. lobata plays an essential role in controlling cytokines. However, the exact mechanism of the inflammation response is still unknown. In this study, we observed the uptake of P. lobata-derived exosomes (Exos) in isolated mouse macrophages. Our results show that P. lobata-derived Exos shift M1 macrophages toward the M2. These data present that P. lobata and puerarin might exert and enhance anti-inflammatory effects through the activation of exosomes and shifts in macrophage polarization, providing strong evidence for the application of P. lobata as novel an anti-inflammatory therapeutic biomaterial.

RAGE displays sex-specific differences in obesity-induced adipose tissue insulin resistance.

BACKGROUND: The receptor for advanced glycation end products (RAGE) plays an important role in obesity-associated insulin sensitivity. We have also previously reported that RAGE deficiency improved insulin resistance in obesity-induced adipose tissue. The current study was aimed to elucidate the sex-specific mechanism of RAGE deficiency in adipose tissue metabolic regulation and systemic glucose homeostasis. METHODS: RAGE-deficient (RAGE-/-) mice were fed a high-fat diet (HFD) and subjected to glucose and insulin tolerance tests. Subcutaneous adipose tissue (sAT) was collected, and macrophage polarization was assessed by quantitative real-time PCR. Immunoblotting was performed to evaluate the insulin signaling in adipose tissues. RESULTS: Under HFD feeding conditions, body weight and adipocyte size of female RAGE deficient (RAGE-/-) were markedly lower than that of male mice. Female RAGE-/- mice showed significantly improved glucose and insulin tolerance compared to male RAGE-/- mice, accompanied with increased M2 macrophages polarization. Expressions of genes involved in anti-oxidant and browning were up-regulated in adipose tissues of female RAGE-/- mice. Moreover, insulin-induced AKT phosphorylation was significantly elevated in adipose tissue in female RAGE-/- mice compared to male RAGE-/- mice. CONCLUSIONS: Our findings suggest that RAGE-mediated adipose tissue insulin resistance is sex-specific, which is associated with different expression of genes involved in anti-oxidant and browning and insulin-induced AKT phosphorylation.

Statin-Induced Geranylgeranyl Pyrophosphate Depletion Promotes Ferroptosis-Related Senescence in Adipose Tissue.

Statin treatment is accepted to prevent adverse cardiovascular events. However, atorvastatin, an HMG-CoA reductase inhibitor, has been reported to exhibit distinct effects on senescent phenotypes. Whether atorvastatin can induce adipose tissue senescence and the mechanisms involved are unknown. The effects of atorvastatin-induced senescence were examined in mouse adipose tissue explants. Here, we showed that statin initiated higher levels of mRNA related to cellular senescence markers and senescence-associated secretory phenotype (SASP), as well as increased accumulation of the senescence-associated ß-galactosidase (SA-ß-gal) stain in adipose tissues. Furthermore, we found that the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+ were elevated in adipose tissues treated with atorvastatin, accompanied by a decrease in the expression of glutathione (GSH), and glutathione peroxidase 4 (GPX4), indicating an iron-dependent ferroptosis. Atorvastatin-induced was prevented by a selective ferroptosis inhibitor (Fer-1). Moreover, supplementation with geranylgeranyl pyrophosphate (GGPP), a metabolic intermediate, reversed atorvastatin-induced senescence, SASP, and lipid peroxidation in adipose tissue explants. Atorvastatin depleted GGPP production, but not Fer-1. Atorvastatin was able to induce ferroptosis in adipose tissue, which was due to increased ROS and an increase in cellular senescence. Moreover, this effect could be reversed by the supplement of GGPP. Taken together, our results suggest that the induction of ferroptosis contributed to statin-induced cell senescence in adipose tissue.

In situ transplantation of adipose-derived stem cells via photoactivation improves glucose metabolism in obese mice.

BACKGROUND: Accumulating evidence suggests that enhanced adipose tissue macrophages (ATMs) are associated with metabolic disorders in obesity and type 2 diabetes. However, therapeutic persistence and reduced homing stem cell function following cell delivery remains a critical hurdle for the clinical translation of stem cells in current approaches. METHODS: We demonstrate that the effect of a combined application of photoactivation and adipose-derived stem cells (ASCs) using transplantation into visceral epididymal adipose tissue (EAT) in obesity. Cultured ASCs were derived from subcutaneous white adipose tissue isolated from mice fed a normal diet (ND). RESULTS: In diet-induced obesity, implantation of light-treated ASCs improved glucose tolerance and ameliorated systemic insulin resistance. Intriguingly, compared with non-light-treated ASCs, light-treated ASCs reduced monocyte infiltration and the levels of ATMs in EAT. Moreover, implantation of light-treated ASCs exerts more anti-inflammatory effects by suppressing M1 polarization and enhancing macrophage M2 polarization in EAT. Mass spectrometry revealed that light-treated human obese ASCs conditioned medium retained a more complete secretome with significant downregulation of pro-inflammatory cytokines and chemokines. CONCLUSIONS: These data suggest that the combined application of photoactivation and ASCs using transplantation into dysfunctional adipose tissue contribute to selective suppression of inflammatory responses and protection from insulin resistance in obesity and type 2 diabetes.