Dietary component isorhamnetin is a PPAR? antagonist and ameliorates metabolic disorders induced by diet or leptin deficiency.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhang Y
PROVIDER: S-EPMC4726074 | biostudies-literature | 2016 Jan
REPOSITORIES: biostudies-literature
Publications
Dietary component isorhamnetin is a PPARγ antagonist and ameliorates metabolic disorders induced by diet or leptin deficiency.
Zhang Yu Y Gu Ming M Cai Wujie W Yu Lijing L Feng Li L Zhang Lu L Zang Qingqing Q Wang Yahui Y Wang Dongshan D Chen Hui H Tong Qingchun Q Ji Guang G Huang Cheng C
Scientific reports 20160118
Studies on peroxisome proliferator-activated receptor (PPAR)-γ ligands have been focused on agonists. However, PPARγ activation may induce obesity and nonalcoholic fatty liver disease (NAFLD), one of the most challenging medical conditions. Here, we identified that isorhamnetin, a naturally occurring compound in fruits and vegetables and the metabolite of quercetin, is a novel antagonist of PPARγ. Isorhamnetin treatment inhibited the adipocyte differentiation induced by the PPARγ agonist rosigli ...[more]
Similar Datasets
Project description: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.
| S-EPMC6885115 | biostudies-literature
Project description:The hormone leptin modulates a diverse range of biological functions, including energy homeostasis and reproduction. Leptin promotes GnRH function via an indirect action on forebrain neurons. We tested whether leptin deficiency or leptin resistance due to a high-fat diet (HFD) can regulate the potent reproductive neuropeptide kisspeptin. In mice with normalized levels of estradiol, leptin deficiency markedly reduced kisspeptin gene expression, particularly in the arcuate nucleus (ARC), and kisspeptin immunoreactive cell numbers in the rostral periventricular region of the third ventricle (RP3V). The HFD model was used to determine the effects of diet-induced obesity and central leptin resistance on kisspeptin cell number and gene expression. DBA/2J mice, which are prone to HFD-induced infertility, showed a marked decrease in kisspeptin expression in both the RP3V and ARC and cell numbers in the RP3V after HFD. This is the first evidence that kisspeptin can be regulated by HFD and/or increased body weight. Next we demonstrated that leptin does not signal (via signal transducer and activator of transcription 3 or 5, or mammalian target of rapamycin) directly on kisspeptin-expressing neurons in the RP3V. Lastly, in leptin receptor-deficient mice, neither GnRH nor kisspeptin neurons were activated during a preovulatory-like GnRH/LH surge induction regime, indicating that leptin's actions on GnRH may be upstream of kisspeptin neurons. These data provide evidence that leptin's effects on reproductive function are regulated by kisspeptin neurons in both the ARC and RP3V, although in the latter site the effects are likely to be indirect.
| S-EPMC3206710 | biostudies-literature
Project description:The anti-inflammatory phytohormone abscisic acid (ABA) modulates immune and inflammatory responses in mouse models of colitis and obesity. ABA has been identified as a ligand of lanthionine synthetase C-like 2, a novel therapeutic target upstream of the peroxisome proliferator-activated receptor ? (PPAR?) pathway. The goal of this study was to investigate the immune modulatory mechanisms underlying the anti-inflammatory efficacy of ABA against influenza-associated pulmonary inflammation. Wild-type (WT) and conditional knockout mice with defective PPAR? expression in lung epithelial and hematopoietic cells (cKO) treated orally with or without ABA (100 mg/kg diet) were challenged with influenza A/Udorn (H3N2) to assess ABA's impact in disease, lung lesions and gene expression. Dietary ABA ameliorated disease activity and lung inflammatory pathology, accelerated recovery and increased survival in WT mice. ABA suppressed leukocyte infiltration and monocyte chemotactic protein 1 mRNA expression in WT mice through PPAR? since this effect was abrogated in cKO mice. ABA ameliorated disease when administered therapeutically on the same day of the infection to WT but not mice lacking PPAR? in myeloid cells. We also show that ABA's greater impact is between days 7 and 10 postchallenge when it regulates the expression of genes involved in resolution, like 5-lipoxygenase and other members of the 5-lipoxygenase pathway. Furthermore, ABA significantly increased the expression of the immunoregulatory cytokine interleukin-10 in WT mice. Our results show that ABA, given preventively or therapeutically, ameliorates influenza-virus-induced pathology by activating PPAR? in pulmonary immune cells, suppressing initial proinflammatory responses and promoting resolution.
| S-EPMC3529771 | biostudies-literature
Project description:Background and purposeThe amelioration of insulin resistance by bilobetin is closely related to its hypolipidaemic effect. The aim of the present study was to determine the insulin-sensitizing mechanism of bilobetin by elucidating its effect on lipid metabolism.Experimental approachRats fed a high-fat diet were treated with bilobetin for either 4 or 14 days before applying a hyperinsulinaemic-euglycaemic clamp. Triglyceride and fatty acids labelled with radioactive isotopes were used to track the transportation and the fate of lipids in tissues. The activity of lipid metabolism-related enzymes and ?-oxidation rate were measured. Western blot was used to investigate the phosphorylation, translocation and expression of PPAR? in several tissues and cultured cells. The location of amino acid residues subjected to phosphorylation in PPAR? was also studied.Key resultsBilobetin ameliorated insulin resistance, increased the hepatic uptake and oxidation of lipids, reduced very-low-density lipoprotein triglyceride secretion and blood triglyceride levels, enhanced the expression and activity of enzymes involved in ?-oxidation and attenuated the accumulation of triglycerides and their metabolites in tissues. Bilobetin also increased the phosphorylation, nuclear translocation and activity of PPAR? accompanied by elevated cAMP level and PKA activity. Threonine-129-alanine and/or serine-163-alanine mutations on the PPAR? genes and PKA inhibitors prevented the effects of bilobetin on PPAR?. However, cells overexpressing PKA appeared to stimulate the phosphorylation, nuclear translocation and activity of PPAR?.Conclusions and implicationsBilobetin treatment ameliorates hyperlipidaemia, lipotoxicity and insulin resistance in rats by stimulating PPAR?-mediated lipid catabolism. PKA activation is crucial for this process.
| S-EPMC3423259 | biostudies-literature
Project description:Effective and safe pharmacological interventions for hyperlipidemia remains badly needed. By incorporating the key pharmacophore of fibrates into the natural scaffold of resveratrol, a novel structural compound ZBH was constructed. In present study, we found ZBH reserved approximately one third of the sirtuin 1 (SIRT1) activation produced by resveratrol at in-vitro enzyme activity assay, directly bound to and activated all three peroxisome proliferator-activated receptor (PPAR) subtypes respectively in PPAR binding and transactivation assays. Moreover, ZBH (EC₅₀, 1.75 µM) activate PPARα 21 fold more efficiently than the well-known PPAR pan agonist bezafibrate (EC₅₀ 37.37 µM) in the cellular transactivation assays. In the high fat diet induced hyperlipidemic hamsters, 5-week treatment with ZBH significantly lowered serum triglyceride, total cholesterol, LDL-C, FFA, hyperinsulinemia, and improved insulin sensitivity more potently than bezafibrate. Meanwhile, serum transaminases, creatine phosphokinase and CREA levels were found not altered by ZBH intervention. Mechanism study indicated ZBH promoted the expression of PPARα target genes and SIRT1 mRNA. Hepatic lipogenesis was markedly decreased via down-regulation of lipogenic genes, and fatty acid uptake and oxidation was simultaneously increased in the liver and skeletal muscle via up-regulation of lipolysis genes. Glucose uptake and utilization was also significantly promoted in skeletal muscle. These results suggested that ZBH significantly lowered hyperlipidemia and ameliorated insulin resistance more efficiently than bezafibrate in the hyperlipidemic hamsters primarily by activating of PPARα, and SIRT1 promotion and activation. ZBH thus presents a potential new agent to combat hyperlipidemia.
| S-EPMC3997506 | biostudies-literature
Project description:Recent studies reveal that bile acid metabolite composition and its metabolism are changed in metabolic disorders, such as obesity, type 2 diabetes and metabolic associated fatty liver disease (MAFLD), yet its role and the mechanism remain largely unknown. In the present study, metabolomic analysis of 163 serum and stool samples of our metabolic disease cohort was performed, and we identified glycoursodeoxycholic acid (GUDCA), glycine-conjugated bile acid produced from intestinal bacteria, was decreased in both serum and stool samples from patients with hyperglycemia. RNA-sequencing and quantitative PCR results indicated that GUDCA alleviated endoplasmic reticulum (ER) stress in livers of high fat diet (HFD)-fed mice without alteration of liver metabolism. In vitro, GUDCA reduced palmitic acid induced-ER stress and -apoptosis, as well as stabilized calcium homeostasis. In vivo, GUDCA exerted effects on amelioration of HFD-induced insulin resistance and hepatic steatosis. In parallel, ER stress and apoptosis were decreased in GUDCA-treated mice as compared with vehicle-treated mice in liver. These findings demonstrate that reduced GUDCA is an indicator of hyperglycemia. Supplementation of GUDCA could be an option for the treatment of diet-induced metabolic disorders, including insulin resistance and hepatic steatosis, with inhibiting ER stress.
| S-EPMC8302808 | biostudies-literature
Project description:Beige adipocytes are a new type of recruitable brownish adipocytes, with highly mitochondrial membrane uncoupling protein 1 expression and thermogenesis. Beige adipocytes were found among white adipocytes, especially in subcutaneous white adipose tissue (sWAT). Therefore, beige adipocytes may be involved in the regulation of energy metabolism and fat deposition. Transient receptor potential melastatin 8 (TRPM8), a Ca2+-permeable non-selective cation channel, plays vital roles in the regulation of various cellular functions. It has been reported that TRPM8 activation enhanced the thermogenic function of brown adiposytes. However, the involvement of TRPM8 in the thermogenic function of WAT remains unexplored. Our data revealed that TRPM8 was expressed in mouse white adipocytes at mRNA, protein and functional levels. The mRNA expression of Trpm8 was significantly increased in the differentiated white adipocytes than pre-adipocytes. Moreover, activation of TRPM8 by menthol enhanced the expression of thermogenic genes in cultured white aidpocytes. And menthol-induced increases of the thermogenic genes in white adipocytes was inhibited by either KT5720 (a protein kinase A inhibitor) or BAPTA-AM. In addition, high fat diet (HFD)-induced obesity in mice was significantly recovered by co-treatment with menthol. Dietary menthol enhanced WAT "browning" and improved glucose metabolism in HFD-induced obesity mice as well. Therefore, we concluded that TRPM8 might be involved in WAT "browning" by increasing the expression levels of genes related to thermogenesis and energy metabolism. And dietary menthol could be a novel approach for combating human obesity and related metabolic diseases.
| S-EPMC5650405 | biostudies-literature
Project description:Although aging is a physiological process to which all organisms are subject, the presence of obesity and type 2 diabetes accelerates biological aging. Recent studies have demonstrated the causal relationships between dietary interventions suppressing obesity and type 2 diabetes and delaying the onset of age-related endocrine changes. Curcumin, a natural antioxidant, has putative therapeutic properties such as reinstating insulin sensitivity in obese mice. However, how curcumin contributes to maintaining insulin homeostasis in aged organisms largely remains unclear. Thus, the objective of this study is to examine the pleiotropic effect of dietary curcumin on insulin homeostasis in a diet-induced obese (DIO) aged mouse model. Aged (18-20 months old) male mice given a high-fat high-sugar diet supplemented with curcumin displayed a different metabolic phenotype compared to mice given a high-fat high-sugar diet alone. Furthermore, curcumin supplementation altered hepatic gene expression profiling, especially insulin signaling and senescence pathways. We then mechanistically investigated how curcumin functions to fine-tune insulin sensitivity. We found that curcumin supplementation increased hepatic insulin degrading enzyme (IDE) expression levels and preserved islet integrity, both of which are beneficial during aging. Our findings suggest that the multifaceted therapeutic potential of curcumin can be used as a protective agent for age-induced metabolic diseases.
2021-11-04 | GSE186971 | GEO
Project description:Food restriction and weight loss result in reduced plasma leptin, which is associated with a pleiotropic biologic response. However, because weight loss itself is also associated with changes in numerous other humoral and metabolic signals, it can be difficult to determine the precise features of the biologic response to acute leptin deficiency. To study this response in the absence of changes in nutritional state, we have developed a protocol that allows such analysis in normal, non-food-restricted animals. Wild-type mice are treated with high-dose leptin until fat mass is depleted and, as a consequence, endogenous leptin production is reduced. At this point, exogenous leptin is abruptly withdrawn, thus inducing a state of leptin deficiency in otherwise normal mice. Leptin deficiency is sustained by feeding the animals only as much as they consumed voluntarily before leptin withdrawal. The biologic response to leptin deficiency induced in this manner includes altered neuropeptide levels, decreased energy expenditure, and impaired reproductive and immune function. Replacement of leptin at physiological concentrations after withdrawal of high-dosage leptin blunts, but does not completely block, the hyperphagia and weight regain caused by acute leptin deficiency, nor does it correct the resulting reproductive and immune dysfunction. This suggests that high-dosage leptin treatment induces a state of partial leptin resistance. In aggregate, these studies establish the role of acute hypoleptinemia in regulating energy balance, the immune system, and reproductive function, and further suggest that high-dosage leptin treatment can induce a state of acquired leptin resistance.
| S-EPMC548993 | biostudies-literature
Project description:Obesity is a risk factor for ischemic necrosis of the femoral head (INFH). The purpose of this study was to determine if leptin treatment of INFH stimulates new bone formation to preserve femoral head shape in rats with diet-induced obesity. Rats were fed a high-fat diet (HFD) or normal chow diet (NCD) for 16 weeks to induce progressive development of obesity. Avascular necrosis of the femoral head (AVN) was surgically induced. Adenovirus-mediated introduction of the leptin gene was by intravenous injection 2 days before surgery-induced AVN. At 6 weeks post-surgery, radiologic and histomorphometric assessments were performed. Leptin signaling in tissues was examined by Western blot. Osteogenic markers were analyzed by real-time RT-PCR. Radiographs showed better preservation of femoral head architecture in the HFD-AVN-Leptin group than the HFD-AVN and HFD-AVN-LacZ groups. Histology and immunohistochemistry revealed the HFD-AVN-Leptin group had significantly increased osteoblastic proliferation and vascularity in infarcted femoral heads compared with the HFD-AVN and HFD-AVN-LacZ groups. Intravenous injection of leptin enhanced serum VEGF levels and activated HIF-1α pathways. Runx 2 and its target genes were significantly upregulated in the HFD-AVN-Leptin group. These results indicate that leptin resistance is important in INFH pathogenesis. Leptin therapy could be a new strategy for INFH.
| S-EPMC4369691 | biostudies-literature