Luteolin reduces obesity-associated insulin resistance in mice by activating AMPKα1 signalling in adipose tissue macrophages

Abstract

Aims/hypothesis Inflammatory polarisation of adipose tissue macrophages (ATMs) plays a critical role in the development of obesity-associated metabolic diseases such as insulin resistance and diabetes. Our previous study indicated that dietary luteolin (LU) could prevent the establishment of insulin resistance in mice fed a high-fat diet (HFD). Here, we further investigated the effects of LU, which is a natural flavonoid, on pre-established insulin resistance and obesityassociated ATM polarisation in mice. Methods Five-week-old C57/BL6 mice were fed on a low-fat diet or HFD for 20 weeks, with some mice receiving supplementation with 0.01% LU from weeks 1 or 10 of the HFD to assess the actions of LU on insulin resistance and ATM polarisation. Furthermore, the role of LU in metabolicdysfunction-associated macrophage phenotypes was investigated in vitro. Results Dietary LU supplementation, either for 20 weeks or from weeks 10 to 20 of an HFD, significantly improved insulin resistance in HFD-fed mice. In addition, inflammatory macrophage infiltration and polarisation were suppressed in mouse epididymal adipose tissues. Furthermore, LU treatment directly reversed lipopolysaccharide-stimulated and metabolism-regulated molecules, and induced inflammatory polarisation in mouse RAW264.7 cells and peritoneal cavity resident macrophages. Finally, using the selective AMPactivated protein kinase (AMPK) inhibitor compound C and Ampkα1 (also known as Prkaa1) silencing with siRNA, we found that LU activated AMPKα1 in macrophages to inhibit their inflammatory polarisation and enhanced insulin signals in adipocytes that were stimulated with macrophageconditioned media. Conclusions/interpretation Dietary LU ameliorated insulin resistance in diet-induced obese mice by promoting AMPKα1 signalling in ATMs.

Luteolin attenuates sepsis‑induced myocardial�injury by enhancing autophagy in mice

“…AMPK directly activates ULK1 through the phosphorylation of Ser 317 and Ser 777 to facilitate autophagy (22). In addition, luteolin regulates AMPK signaling in numerous other circumstances, including enhancing the survival of human umbilical vein endothelial cells against oxidative stress by modulating AMPK/protein kinase c pathway (52), improving atherosclerosis in mice via regulating AMPK/sirtuin1 signaling in macrophages (53) and reducing obesity-associated insulin resistance in mice by activating AMPK signaling in adipose tissue macrophages (54). In the present study, notably, the protective effect of luteolin was also abolished by the AMPK inhibitor compound c, as demonstrated by the decreased Lc3 II and Beclin1 expression, enhanced p62 expression, destabilized mitochondrial membrane potential, and increased cardiomyocyte apoptosis.…”

Broussonetia papyrifera Root Bark Extract Exhibits Anti-inflammatory Effects on Adipose Tissue and Improves Insulin Sensitivity Potentially Via AMPK Activation

“…In addition, AMPK ameliorates insulin resistance in obesity [10,11,25,26]. It has been reported that AMPK activators specifically suppressed the expression of pro-inflammatory genes and the activation of NF-κB-mediated signaling [27,28]. The molecular mechanism for NF-κB activation is: (1) the degradation of IκB in a ubiquitin-dependent manner is triggered through its phosphorylation by IKK; (2) IκB degradation results in nuclear translocation of NF-κB [29].…”

Tinospora cordifolia preserves pancreatic beta cells and enhances glucose uptake in adipocytes to regulate glucose metabolism in diabetic rats

“…T. cordifolia contains diverse type of chemical compounds, such as flavonoids, alkaloids, and some tannins (Singh & Chaudhuri, ). Quercetin (Arias, Macarulla, Aguirre, Martinez‐Castano, & Portillo, ), kaempferol (Alkhalidy et al, ), luteolin (Zhang et al, ), and epicatechin (Cremonini, Bettaieb, Haj, Fraga, & Oteiza, ) showed their antidiabetic effects via enhancing insulin secretion and insulin sensitization. The synergistic action of those components could regulate blood glucose in diabetic animals.…”