Insulin resistance-related disorders are associated with endothelial dysfunction. Accumulating evidence has suggested a role for adenosine signaling in the regulation of endothelial function. Here, we identified a crucial role of endothelial adenosine kinase (ADK) in the regulation of insulin resistance. Feeding mice with a high-fat diet (HFD) markedly enhanced the expression of endothelial Adk. Ablation of endothelial Adk in HFD-fed mice improved glucose tolerance and insulin sensitivity and decreased hepatic steatosis, adipose inflammation and adiposity, which were associated with improved arteriole vasodilation, decreased inflammation and increased adipose angiogenesis. Mechanistically, ADK inhibition or knockdown in human umbilical vein endothelial cells (HUVECs) elevated intracellular adenosine level and increased endothelial nitric oxide synthase (NOS3) activity, resulting in an increase in nitric oxide (NO) production. Antagonism of adenosine receptor A2b abolished ADK-knockdown-enhanced NOS3 expression in HUVECs. Additionally, increased phosphorylation of NOS3 in ADK-knockdown HUVECs was regulated by an adenosine receptor-independent mechanism. These data suggest that Adk-deficiency-elevated intracellular adenosine in endothelial cells ameliorates diet-induced insulin resistance and metabolic disorders, and this is associated with an enhancement of NO production caused by increased NOS3 expression and activation. Therefore, ADK is a potential target for the prevention and treatment of metabolic disorders associated with insulin resistance.
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Jiean Xu, Qiuhua Yang, Xiaoyu Zhang, Zhiping Liu, Yapeng Cao, Lina Wang, Yaqi Zhou, Xianqiu Zeng, Qian Ma, Yiming Xu, Yong Wang, Lei Huang, Zhen Han, Tao Wang, David Stepp, Zsolt Bagi, Chaodong Wu, Mei Hong and Yuqing Huo
Yingxin Xian, Zonglan Chen, Hongrong Deng, Mengyin Cai, Hua Liang, Wen Xu, Jianping Weng and Fen Xu
Obesity-associated chronic inflammation in adipose tissue is partly attributed to hypoxia with insufficient microcirculation. Previous studies have shown that exenatide, a glucagon-like peptide 1 (GLP-1) receptor agonist, plays an anti-inflammatory role. Here, we investigate its effects on inflammation, hypoxia and microcirculation in white adipose tissue of diet-induced obese (DIO) mice. DIO mice were injected intraperitoneally with exenatide or normal saline for 4 weeks, while mice on chow diet were used as normal controls. The mRNA and protein levels of pro-inflammatory cytokines, hypoxia-induced genes and angiogenic factors were detected. Capillary density was measured by laser confocal microscopy and immunochemistry staining. After 4-week exenatide administration, the dramatically elevated pro-inflammatory cytokines in serum and adipose tissue and macrophage infiltration in adipose tissue of DIO mice were significantly reduced. Exenatide also ameliorated expressions of hypoxia-related genes in obese fat tissue. Protein levels of endothelial markers and pro-angiogenic factors including vascular endothelial growth factor and its receptor 2 were augmented in accordance with increased capillary density by exenatide in DIO mice. Our results indicate that inflammation and hypoxia in adipose tissue can be mitigated by GLP-1 receptor agonist potentially via improved angiogenesis and microcirculation in obesity.
Isis Gabrielli Barbieri de Oliveira, Marcos Divino Ferreira Junior, Paulo Ricardo Lopes, Dhiogenes Balsanufo Taveira Campos, Marcos Luiz Ferreira-Neto, Eduardo Henrique Rosa Santos, Paulo Cezar de Freitas Mathias, Flávio Andrade Francisco, Bruna Del Vechio Koike, Carlos Henrique de Castro, André Henrique Freiria-Oliveira, Gustavo Rodrigues Pedrino, Rodrigo Mello Gomes and Daniel Alves Rosa
Disruptions in circadian rhythms have been associated with several diseases, including cardiovascular and metabolic disorders. Forced internal desynchronization induced by a period of T-cycles of 22 h (T22 protocol) reaches the lower limit of entrainment and dissociates the circadian rhythmicity of the locomotor activity into two components, driven by different outputs from the suprachiasmatic nucleus (SCN). The main goal of this study was to evaluate the cardiovascular and metabolic response in rats submitted to internal desynchronization by T22 protocol. Male Wistar rats were assigned to either a control group subjected to a usual T-cycles of 24 h (12 h–12 h) or an experimental group subjected to the T22 protocol involving a 22-h symmetric light–dark cycle (11 h–11 h). After 8 weeks, rats subjected to the T22 exhibited desynchrony in their locomotor activity. Although plasma glucose and insulin levels were similar in both groups, desynchronized rats demonstrated dyslipidemia, significant hypertrophy of the fasciculate zone of the adrenal gland, low IRB, IRS2, PI3K, AKT, SOD and CAT protein expression and an increased expression of phosphoenolpyruvate carboxykinase in the liver. Furthermore, though they maintained normal baseline heart rates and mean arterial pressure levels, they also presented reduced baroreflex sensitivity. The findings indicate that circadian timing desynchrony following the T22 protocol can induce cardiometabolic disruptions. Early hepatic metabolism dysfunction can trigger other disorders, though additional studies are needed to clarify the causes.
Qiongge Zhang, Chaoqun Wang, Yehua Tang, Qiangqiang Zhu, Yongcheng Li, Haiyan Chen, Yi Bao, Song Xue, Liangliang Sun, Wei Tang, Xiangfang Chen, Yongquan Shi, Lefeng Qu, Bin Lu and Jiaoyang Zheng
Hyperglycemia plays a major role in the development of diabetic macrovascular complications, including atherosclerosis and restenosis, which are responsible for the most of disability and mortality in diabetic patients. Osteopontin (OPN) is an important factor involved in atherogenesis, and hyperglycemia enhances the transcriptional activity of FoxO1 which is closely association with insulin resistance and diabetes. Here, we showed that plasma OPN levels were significantly elevated in type 2 diabetic patients and positively correlated with glycated albumin (GA). The more atherosclerotic lesions were observed in the aorta of diabetic ApoE−/− mice analyzed by Sudan IV staining. High glucose increased both the mRNA and protein expression levels of OPN and inhibited the phosphorylation of FoxO1 in RAW 264.7 cells. Overexpression of WT or constitutively active mutant FoxO1 promoted the expression levels of OPN, while the dominant-negative mutant FoxO1 decreased slightly the expression of OPN. Conversely, knockdown of FoxO1 reduced the expression of OPN. Luciferase reporter assay revealed that high glucose and overexpression of FoxO1 enhanced the activities of the OPN promoter region nt −1918 ~ −713. Furthermore, the interactions between FoxO1 and the OPN promoter were confirmed by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP). Our results suggest that high glucose upregulates OPN expression via FoxO1 activation, which would play a critical role in the development of diabetic atherogenesis.
Wenqi Chen, Siyu Lu, Cheng Shun Yang, Na Li, Xuemei Chen, Junlin He, Xueqing Liu, Yubin Ding, Chao Tong, Chuan Peng, Chen Zhang, Yan Su, Yingxiong Wang and Rufei Gao
Previous research on the role of insulin has focused on metabolism. This study investigated the effect of insulin on angiogenesis in endometrial decidualization. High insulin-treated mouse model were constructed by subcutaneous injection of insulin. Venous blood glucose, serum insulin, P4, E2, FSH and LH levels in the pregnant mice were detected by ELISA. Decidual markers, angiogenesis factors and decidual vascular network were detected during decidualization in the pregnant mouse model and an artificially induced decidualization mouse model. Tube formation ability and angiogenesis factors expression were also detected in high insulin-treated HUVECS cells. To confirm whether autophagy participates in hyperinsulinemia-impaired decidual angiogenesis, autophagy were detected in vivo and in vitro. During decidualization, in the condition of high insulin, serum insulin and blood glucose were significantly higher while ovarian steroid hormones were also disordered (p<0.05), decidual markers BMP2 and PRL was significantly lower (p<0.05). Uterine CD34 staining showed that the size of the vascular sinus was significantly smaller than that in control. Endometrial VEGFA was significantly decreased after treatment with high insulin in vivo and in vitro (p<0.05), whereas ANG-1 and TIE2 expression was significantly increased (p<0.05). In addition, aberrant expression of autophagy markers revealed that autophagy participates in endometrial angiogenesis during decidualization (p<0.05). After treated with the autophagy inhibitor 3-MA in HUVEC, the originally damaged cell tube formation ability and VEGFA expression were repaired. This study suggests that endometrial angiogenesis during decidualization was impaired by hyperinsulinemia in early pregnant mice.
Monisha Rajasekaran, Ok-Joo Sul, Eun-Kyung Choi, Ji-Eun Kim, Jae-Hee Suh and Hye-Seon Choi
Obesity is strongly associated with chronic inflammation for which adipose tissue macrophages play a critical role. The objective of this study is to identify monocyte chemoattractant protein-1 (MCP-1, CCL2) as a key player governing M1–M2 macrophage polarization and energy balance. We evaluated body weight, fat mass, adipocyte size and energy expenditure as well as core body temperature of Ccl2 knockout mice compared with wild-type mice. Adipose tissues, differentiated adipocyte and bone marrow-derived macrophages were assessed by qPCR, Western blot analysis and histochemistry. MCP-1 deficiency augmented energy expenditure by promoting browning in white adipose tissue and brown adipose tissue activity via increasing the expressions of Ucp1, Prdm16, Tnfrsf9, Ppargc1a, Nrf1 and Th and mitochondrial DNA copy number. MCP-1 abrogation promoted M2 polarization which is characterized by increased expression of Arg1, Chil3, Il10 and Klf4 whereas it decreased M1 polarization by decreased p65 nuclear translocation and attenuated expression of Itgax, Tnf and Nos2, leading to increased browning of adipocytes. Enhanced M2 polarization and attenuated M1 polarization in the absence of MCP-1 are independent. Collectively, our results suggest that the action of MCP-1 in macrophages modulates energy expenditure by impairing browning in adipose tissue.
Eloise A Bradley, Dino Premilovac, Andrew C Betik, Donghua Hu, Emily Attrill, Steve Richards, Stephen Rattigan and Michelle Keske
Insulin stimulates glucose disposal in skeletal muscle in part by increasing microvascular blood flow and this effect is blunted during insulin resistance. We aimed to determine whether metformin treatment improves insulin-mediated glucose disposal and vascular insulin responsiveness in skeletal muscle of insulin resistant rats. Sprague Dawley rats were fed a normal (ND) or high-fat (HFD) diet for four weeks. A separate HFD group was given metformin in drinking water (HFD+MF, 150 mg/kg/day) during the final two weeks. After the intervention, overnight-fasted (food and metformin removed) anaesthetised rats underwent a 2-hr euglycemic–hyperinsulinemic clamp (10 mU/min/kg) or saline infusion. Femoral artery blood flow, hindleg muscle microvascular blood flow, muscle glucose disposal and muscle signalling (Ser473-Akt and Thr172-AMPK phosphorylation) were measured. HFD rats had elevated body weight, epididymal fat pad weight, fasting plasma insulin and free fatty acid levels when compared to ND. HFD-fed animals displayed whole body and skeletal muscle insulin resistance and blunting of insulin-stimulated femoral artery blood flow, muscle microvascular blood flow and skeletal muscle insulin-stimulated Ser473-Akt phosphorylation. Metformin treatment of HFD rats reduced fasting insulin and non-esterified fatty acid concentrations and lowered body weight and adiposity. During hyperinsulinemic-euglycemic clamp, metformin-treated animals showed improved vascular responsiveness to insulin, improved insulin-stimulated muscle Ser473-Akt phosphorylation but only partially restored (60%) muscle glucose uptake. This occurred without any detectable levels of metformin in plasma or change in muscle Thr172-AMPK phosphorylation. We conclude that two-week metformin treatment is effective at improving vascular and metabolic insulin responsiveness in muscle of HFD-induced insulin resistant rats.
Oliver Claire Watkins, Mohammed Omedul Islam, Preben Selvam, Reshma Appukuttan Pillai, Amaury Cazenave-Gassiot, Anne K. Bendt, Neerja Karnani, Keith M. Godfrey, Rohan M Lewis, Markus R Wenk and Shiao-Yng Chan
We postulate that myo-inositol, a proposed intervention for gestational-diabetes, affects transplacental lipid supply to the fetus. We investigated the effect of myo-inositol on fatty-acid processing in human placental-explants from uncomplicated pregnancies. Explants were incubated with 13C-labeled palmitic-acid, 13C-oleic-acid and 13C-docosahexaenoic-acid across a range of myo-inositol concentrations for 24 h and 48 h. The incorporation of labeled-fatty-acids into individual lipids was quantified by liquid-chromatography-mass-spectrometry. At 24 h, myo-inositol increased the amount of 13C-palmitic-acid and 13C-oleic-acid labeled lipids (median fold-change relative to control=1). Significant effects were seen with 30 µM myo-inositol (physiological) for 13C-palmitic-acid-lysophosphatidylcholines (1.26) and 13C-palmitic-acid-phosphatidylethanolamines (1.17). At 48 h, myo-inositol addition increased 13C-oleic-acid-lipids but decreased 13C-palmitic-acid and 13C-docosahexaenoic-acid lipids. Significant effects were seen with 30 µM myo-inositol for 13C-oleic-acid-phosphatidylcholines (1.25), 13C-oleic-acid-phosphatidylethanolamines (1.37) and 13C-oleic-acid-triacylglycerols (1.32) and with 100 µM myo-inositol for 13C-docosahexaenoic-acid-triacylglycerols (0.78). Lipids labeled with the same 13C-fatty-acid showed similar responses when tested at the same time-point, suggesting myo-inositol alters upstream processes such as fatty-acid uptake or activation. Myo-inositol supplementation may alter placental lipid physiology with unknown clinical consequences.
Sivaporn Sivasinprasasn, Siripong Palee, Kenneth Chattipakorn, Thidarat Jaiwongkum, Nattayaporn Apaijai, Wasana Pratchayasakul, Siriporn C Chattipakorn and Nipon Chattipakorn
Myocardial damage and mitochondrial dysfunction caused by cardiac ischemia-reperfusion (I/R) injury are intensified by endogenous estrogen deprivation. Although N-acetylcysteine (NAC) exerted cardioprotective effects, its benefits when used in combination with hormone therapy are unknown. We tested the hypothesis that a combination of NAC with low-dose estrogen improves cardiometabolic function and protects cardiac mitochondria against I/R injury, to a similar extent to regular-dose estrogen treatment, in estrogen-deprived rats. Female Wistar rats had a bilateral ovariectomy (OVX) or sham operation. Twelve weeks after the operation, OVX rats were treated with regular-dose estrogen (E; 50 µg/kg/day), low-dose estrogen (e; 25 µg/kg/day), NAC (N; 100 mg/kg/day) or combined low-dose estradiol with NAC (eN) for 4 weeks (n = 6/group). Metabolic parameters, echocardiography, heart rate variability and then cardiac I/R protocol involving 30-min coronary artery ligation, followed by 120-min reperfusion, were performed. OVX rats had increased body weight, visceral fat, fasting plasma glucose, HOMA-IR index, triglycerides, cholesterol and LDL levels (P < 0.05 vs sham). Only OVX-E and OVX-eN had a similarly improved HOMA-IR index. LVEF was increased in all treatment groups, but HRV was restored only by OVX-E and OVX-eN. After I/R, myocardial infarct size was decreased in both OVX-E and OVX-eN groups. OVX-E and OVX-eN rats similarly had a reduced mitochondrial ROS level and increased mitochondrial membrane potential in the ischemic myocardium. In conclusion, combined NAC with low-dose estrogen and regular-dose estrogen therapy similarly improve cardiometabolic function, prevent cardiac mitochondrial dysfunction and reduces the infarct size in estrogen-deprived rats with cardiac I/R injury.
Joan Villarroya, Rubén Cereijo, Aleix Gavaldà-Navarro, Marion Peyrou, Marta Giralt and Francesc Villarroya
In recent years, an important secretory role of brown adipose tissue (BAT) has emerged, which is consistent, to some extent, with the earlier recognition of the important secretory role of white fat. The so-called brown adipokines or “batokines” may play an autocrine role, which may either be positive or negative in the thermogenic function of brown adipocytes. Additionally, there is a growing recognition of the signalling molecules released by brown adipocytes that target sympathetic nerve endings (such as neuregulin-4 and S100b protein), vascular cells (e.g., bone morphogenetic protein-8b), and immune cells (e.g., C-X-C motif chemokine ligand-14) to promote the tissue remodelling associated with the adaptive BAT recruitment in response to thermogenic stimuli. Moreover, existing indications of an endocrine role of BAT are being confirmed through the release of brown adipokines acting on other distant tissues and organs; a recent example is the recognition that BAT-secreted fibroblast growth factor-21 and myostatin target the heart and skeletal muscle, respectively. The application of proteomics technologies is aiding the identification of new members of the brown adipocyte secretome, such as the extracellular matrix or complement system components. In summary, BAT can no longer be considered a mere producer of heat in response to environment or dietary challenges; it is also an active secretory tissue releasing brown adipokines with a relevant local and systemic action. The identification of the major brown adipokines and their roles is highly important for the discovery of novel candidates useful in formulating intervention strategies for metabolic diseases.