scholarly journals Suppression of Hepatic Lipogenesis and Enhancement of β-oxidation in Skeletal Muscle by Betulinic Acid Lead to the Reduction of Body Adiposity and Dyslipidemia in Mice (P21-043-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Hyun Kyung Kim ◽  
Gwang-woong Go
Keyword(s):  
Skeletal Muscle ◽  
Betulinic Acid ◽  
Fruits And Vegetables ◽  
Metabolic Diseases ◽  
Final Body Weight ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Funding Sources ◽  
Body Adiposity

Abstract Objectives Betulinic acid (BA) exists as a lipophilic conformation in nature, rich in fruits and vegetables, especially the bark of birch wood. Beneficial effects of BA on cancer, oxidative stress, and inflammation were previously reported. Studies of BA for anti-obesity and dyslipidemia have been recently emerged, however the outcomes are still not conclusive. We tested if BA improves obesity and/or dyslipidemia by incorporated mechanism of liver and skeletal muscle in vivo. Methods Five-week-old male C57BL/6 mice were fed Western type diet (45% kcal from fat with 1.25% cholesterol) ad libitum for 12 weeks. Mice were allocated into five groups: (−) control, BA 5 mg/kg, BA 15 mg/kg, BA 25 mg/kg, and fenofibrate as a (+) control. BA was orally administered every day. For proved phenotype alteration, we analyzed mRNA and protein expressions linked to lipogenesis and β-oxidation. Results Growth performance including final body weight, weight gain, and feed intake were not altered by BA. Body fat mass was decreased by all BA treated groups (P < 0.01) without changes of lean mass. Energy expenditure contributed by β-oxidation was increased by BA 25 (P < 0.001). Serum lipid profiles including triglyceride, free fatty acid, total cholesterol, and LDL cholesterol were significantly improved by all BA treated groups (P < 0.001). Lipid accumulation in the liver was reduced by BA 15 and 25 (all P < 0.001). The mRNA expressions of Acc1and Scd1were dose-dependently suppressed by betulinic acid in liver (P < 0.05). SREBP1 was diminished by BA treated groups (all P < 0.05). FAS showed reduced tendency by BA (P = 0.06). In protein levels, ACC1 and SCD1 were inhibited by BA treated groups (P < 0.001 and P < 0.05). FAS and SREBP1 tended to be reduced by BA (P = 0.40 and P = 0.70). LPL and CPT1, β-oxidation markers in skeletal muscle, were activated by BA 25 (P < 0.001 and P < 0.01). The activation of CPT1 was influenced by stimulating of AMPK-pT172 and ACC1-pS79 (all P < 0.05). Taken together, BA inhibitedde novolipogenesis in the liver and upregulated key proteins related to β-oxidation in skeletal muscle, contributing to the prevention of obesity and dyslipidemia. Conclusions We suggest that BA is a potent nutraceutical for prevention and treatment of chronic metabolic diseases including obesity and dyslipidemia. Funding Sources National Research Foundation of Korea.

scholarly journals Impact of Dietary Flavanols on Microbiota, Immunity and Inflammation in Metabolic Diseases

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 850
Author(s):  
María Ángeles Martín ◽  
Sonia Ramos
Keyword(s):  
Immune System ◽  
Fruits And Vegetables ◽  
Metabolic Diseases ◽  
Nuclear Factor Κb ◽  
Low Grade ◽  
Beneficial Effects ◽  
Health And Disease ◽  
Immunological Reactions ◽  
And Function ◽  
Positive Properties

Flavanols are natural occurring polyphenols abundant in fruits and vegetables to which have been attributed to beneficial effects on health, and also against metabolic diseases, such as diabetes, obesity and metabolic syndrome. These positive properties have been associated to the modulation of different molecular pathways, and importantly, to the regulation of immunological reactions (pro-inflammatory cytokines, chemokines, adhesion molecules, nuclear factor-κB [NF-κB], inducible enzymes), and the activity of cells of the immune system. In addition, flavanols can modulate the composition and function of gut microbiome in a prebiotic-like manner, resulting in the positive regulation of metabolic pathways and immune responses, and reduction of low-grade chronic inflammation. Moreover, the biotransformation of flavanols by gut bacteria increases their bioavailability generating a number of metabolites with potential to affect human metabolism, including during metabolic diseases. However, the exact mechanisms by which flavanols act on the microbiota and immune system to influence health and disease remain unclear, especially in humans where these connections have been scarcely explored. This review seeks to summarize recent advances on the complex interaction of flavanols with gut microbiota, immunity and inflammation focus on metabolic diseases.

scholarly journals Prep1 Deficiency Induces Protection from Diabetes and Increased Insulin Sensitivity through a p160-Mediated Mechanism

2008 ◽  
Vol 28 (18) ◽  
pp. 5634-5645 ◽  
Author(s):  
Francesco Oriente ◽  
Luis Cesar Fernandez Diaz ◽  
Claudia Miele ◽  
Salvatore Iovino ◽  
Silvia Mori ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Normal Glucose Tolerance ◽  
Glucose Disposal ◽  
Protein Levels ◽  
Normal Glucose ◽  
Enhanced Expression ◽  
The Stability

ABSTRACT We have examined glucose homeostasis in mice hypomorphic for the homeotic transcription factor gene Prep1. Prep1-hypomorphic (Prep1 i / i ) mice exhibit an absolute reduction in circulating insulin levels but normal glucose tolerance. In addition, these mice exhibit protection from streptozotocin-induced diabetes and enhanced insulin sensitivity with improved glucose uptake and insulin-dependent glucose disposal by skeletal muscle. This muscle phenotype does not depend on reduced expression of the known Prep1 transcription partner, Pbx1. Instead, in Prep1 i / i muscle, we find normal Pbx1 but reduced levels of the recently identified novel Prep1 interactor p160. Consistent with this reduction, we find a muscle-selective increase in mRNA and protein levels of PGC-1α, accompanied by enhanced expression of the GLUT4 transporter, responsible for insulin-stimulated glucose uptake in muscle. Indeed, using L6 skeletal muscle cells, we induced the opposite effects by overexpressing Prep1 or p160, but not Pbx1. In vivo skeletal muscle delivery of p160 cDNA in Prep1 i / i mice also reverses the molecular phenotype. Finally, we show that Prep1 controls the stability of the p160 protein. We conclude that Prep1 controls insulin sensitivity through the p160-GLUT4 pathway.

scholarly journals Large G protein α-subunit XLαs limits clathrin-mediated endocytosis and regulates tissue iron levels in vivo

2017 ◽  
Vol 114 (45) ◽  
pp. E9559-E9568 ◽  
Author(s):  
Qing He ◽  
Richard Bouley ◽  
Zun Liu ◽  
Marc N. Wein ◽  
Yan Zhu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
G Protein ◽  
Critical Role ◽  
Hek293 Cells ◽  
Activity Levels ◽  
Α Subunit ◽  
Proteomic Screen ◽  
Protein Levels ◽  
G Protein Α Subunit

Alterations in the activity/levels of the extralarge G protein α-subunit (XLαs) are implicated in various human disorders, such as perinatal growth retardation. Encoded by GNAS, XLαs is partly identical to the α-subunit of the stimulatory G protein (Gsα), but the cellular actions of XLαs remain poorly defined. Following an initial proteomic screen, we identified sorting nexin-9 (SNX9) and dynamins, key components of clathrin-mediated endocytosis, as binding partners of XLαs. Overexpression of XLαs in HEK293 cells inhibited internalization of transferrin, a process that depends on clathrin-mediated endocytosis, while its ablation by CRISPR/Cas9 in an osteocyte-like cell line (Ocy454) enhanced it. Similarly, primary cardiomyocytes derived from XLαs knockout (XLKO) pups showed enhanced transferrin internalization. Early postnatal XLKO mice showed a significantly higher degree of cardiac iron uptake than wild-type littermates following iron dextran injection. In XLKO neonates, iron and ferritin levels were elevated in heart and skeletal muscle, where XLαs is normally expressed abundantly. XLKO heart and skeletal muscle, as well as XLKO Ocy454 cells, showed elevated SNX9 protein levels, and siRNA-mediated knockdown of SNX9 in XLKO Ocy454 cells prevented enhanced transferrin internalization. In transfected cells, XLαs also inhibited internalization of the parathyroid hormone and type 2 vasopressin receptors. Internalization of transferrin and these G protein-coupled receptors was also inhibited in cells expressing an XLαs mutant missing the Gα portion, but not Gsα or an N-terminally truncated XLαs mutant unable to interact with SNX9 or dynamin. Thus, XLαs restricts clathrin-mediated endocytosis and plays a critical role in iron/transferrin uptake in vivo.

scholarly journals Caffeic Acid Phenethyl Ester and Its Fluorinated Derivative as Natural Anti-obesity Agents (P06-089-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Srujana Rayalam ◽  
Devin Mills ◽  
Yusra Azhar ◽  
Ebony Miller ◽  
Xinyu Wang
Keyword(s):  
Life Cycle ◽  
Caffeic Acid ◽  
Lipid Content ◽  
Dose Range ◽  
Caffeic Acid Phenethyl Ester ◽  
Beneficial Effects ◽  
Funding Sources ◽  
Treatment Of Obesity ◽  
Methyl Xanthine

Abstract Objectives Caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, is well studied for its beneficial effects on cancer, inflammation and diabetes. There are however limited studies investigating the effects of CAPE on obesity. Currently, several natural products are under investigation for their effects on adipocyte life cycle. A multi-targeted approach for prevention and treatment of obesity includes targeting adipocytes at all the stages of life cycle by decreasing adipocyte differentiation, inducing lipolysis and/or by inducing adipocyte apoptosis. In this study, we examined the effects of CAPE on preadipocyte viability, adipogenesis and lipolysis. Earlier reports on CAPE indicate that CAPE is liable to enzymatic hydrolysis in vivo making this compound unstable for therapeutic applications. In the current study, we compared the anti-adipogenic effects of CAPE with its novel fluorinated derivative (FCAPE), a more stable compound. Methods 3T3-L1 pre-adipocytes were differentiated using a cocktail consisting of insulin, dexamethasone, and isobutyl methyl xanthine in DMEM supplemented with 10% FBS following adipogeneic differentiation. Pre- and mature adipocytes were incubated with CAPE or FCAPE for 24–48 hours and their effects on viability, lipolysis, and adipogenesis was tested using Prestoblue, Lipolysis assay (Zen-Bio) and AdipoRed assay respectively. Results Our results indicate that neither CAPE nor FCAPE significantly altered preadipocyte viability within the tested dose range. Although both CAPE and FCAPE significantly decreased adipogenesis compared to control, FCAPE decreased lipid content by 73.6 ± 1.6% while CAPE reduced lipid content by only 36.8 ± 9.1% at 25 μM concentration. In contrast to adipogenesis data, our preliminary results with lipolysis assay indicate that only CAPE, but not FCAPE induces lipolysis in mature adipocytes. Conclusions These findings suggest that both CAPE and FCAPE possess anti-adipogenic properties. Further studies are needed to elucidate their differential effects on adipogenesis and lipolysis. Funding Sources This study was funded by the Department of Research, PCOM.

scholarly journals The Polyphenol Pterostilbene Ameliorates the Myopathic Phenotype of Collagen VI Deficient Mice via Autophagy Induction

2020 ◽  
Vol 8 ◽  
Author(s):  
Samuele Metti ◽  
Lisa Gambarotto ◽  
Martina Chrisam ◽  
Martina La Spina ◽  
Martina Baraldo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Autophagic Flux ◽  
Collagen Vi ◽  
Beneficial Effects ◽  
Autophagy Induction ◽  
And Function ◽  
Cellular Components ◽  
Deficient Mice ◽  
Muscle Remodeling

The induction of autophagy, the catabolic pathway by which damaged or unnecessary cellular components are subjected to lysosome-mediated degradation and recycling, is impaired in Collagen VI (COL6) null mice and COL6-related myopathies. This autophagic impairment causes an accumulation of dysfunctional mitochondria, which in turn leads to myofiber degeneration. Our previous work showed that reactivation of autophagy in COL6-related myopathies is beneficial for muscle structure and function both in the animal model and in patients. Here we show that pterostilbene (Pt)—a non-toxic polyphenol, chemically similar to resveratrol but with a higher bioavailability and metabolic stability—strongly promotes in vivo autophagic flux in the skeletal muscle of both wild-type and COL6 null mice. Reactivation of autophagy in COL6-deficient muscles was also paralleled by several beneficial effects, including significantly decreased incidence of spontaneous apoptosis, recovery of ultrastructural defects and muscle remodeling. These findings point at Pt as an effective autophagy-inducing nutraceutical for skeletal muscle with great potential in counteracting the major pathogenic hallmarks of COL6-related myopathies, a valuable feature that may be also beneficial in other muscle pathologies characterized by defective regulation of the autophagic machinery.

scholarly journals Honokiol Alleviates Methionine-Choline Deficient Diet-Induced Hepatic Steatosis and Oxidative Stress in C57BL/6 Mice by Regulating CFLAR-JNK Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Ting Zhai ◽  
Wei Xu ◽  
Yayun Liu ◽  
Kun Qian ◽  
Yanling Xiong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Regulatory Gene ◽  
Deficient Diet ◽  
Jnk Pathway ◽  
Beneficial Effects ◽  
Protein Levels ◽  
And Oxidative Stress

Background. Honokiol (HNK) has been reported to possess various beneficial effects in the context of metabolic disorders, including fatty liver, insulin resistance, and oxidative stress which are closely related to nonalcoholic steatohepatitis (NASH), however with no particular reference to CFLAR or JNK. Methods. C57BL/6 mice were fed methionine-choline-deficient (MCD) diet and administered simultaneously with HNK (10 and 20 mg/kg once a day, ig) for 6 weeks, and NCTC1469 cells were pretreated, respectively, by oleic acid (OA, 0.5 mmol/L) plus palmitic acid (PA, 0.25 mmol/L) for 24 h, and adenovirus-down Cflar for 24 h, then exposed to HNK (10 and 20 μmol/L) for 24 h. Commercial kits, H&E, MT, ORO staining, RT-qPCR, and Western blotting were used to detect the biomarkers, hepatic histological changes, and the expression of key genes involved in NASH. Results. The in vivo results showed that HNK suppressed the phosphorylation of JNK (pJNK) by activating CFLAR; enhanced the mRNA expression of lipid metabolism-related genes Acox, Cpt1α, Fabp5, Gpat, Mttp, Pparα, and Scd-1; and decreased the levels of hepatic TG, TC, and MDA, as well as the levels of serum ALT and AST. Additionally, HNK enhanced the protein expression of oxidative stress-related key regulatory gene NRF2 and the activities of antioxidases HO-1, CAT, and GSH-Px and decreased the protein levels of prooxidases CYP4A and CYP2E1. The in vivo effects of HNK on the expression of CLFAR, pJNK, and NRF2 were proved by the in vitro experiments. Moreover, HNK promoted the phosphorylation of IRS1 (pIRS1) in both tested cells and increased the uptake of fluorescent glucose 2-NBDG in OA- and PA-pretreated cells. Conclusions. HNK ameliorated NASH mainly by activating the CFLAR-JNK pathway, which not only alleviated fat deposition by promoting the efflux and β-oxidation of fatty acids in the liver but also attenuated hepatic oxidative damage and insulin resistance by upregulating the expression of NRF2 and pIRS1.

scholarly journals The mTORC2 Regulator homer1 Modulates Protein Levels and Sub-Cellular Localization of the CaSR in Human Osteoblasts.

2021 ◽  
Author(s):  
Mark S Rybchyn ◽  
Tara C Brennan-Speranza ◽  
David Mor ◽  
Zhiqiang Cheng ◽  
Wenhan Chang ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Bone Cells ◽  
Cell Protein ◽  
Osteosarcoma Cell ◽  
Wild Type ◽  
Human Osteoblasts ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Mtorc1 Activation

We recently found that in human osteoblasts Homer1 complexes to CaSR and mediates AKT initiation via mTORC2 leading to beneficial effects in osteoblasts including -catenin stabilization and mTORC1 activation (doi: 10.1074/jbc.RA118.006587). Herein we further investigated the relationship between Homer1 and CaSR and demonstrate a link between the protein levels of CaSR and Homer1 in human osteoblasts in primary culture. Thus, when siRNA was used to suppress the CaSR, we observed upregulated Homer1 levels and when siRNA was used to suppress Homer1 we observed downregulated CaSR protein levels using immunofluorescence staining of cultured osteoblasts as well as western blot analyses of cell protein extracts. This finding was confirmed in vivo as the bone cells from osteoblast specific CaSR(-/-) mice showed increased Homer1 expression compared to wild-type. Furthermore, when the commonly used osteosarcoma cell lines MG63 and SAOS-2 were compared to primary osteoblasts, higher levels of Homer1 protein were associated with increased protein levels of the CaSR as well as mTOR and Rictor. CaSR and Homer1 protein were both expressed in osteocytes embedded in the long bones of wild-type mice, and immunofluorescent studies of these cells revealed that Homer1 protein sub-cellular localization was markedly altered in the osteocytes of CaSR(-/-) mice compared to wt. The study identifies additional roles for Homer1 in the control of the protein level and subcellular localization of CaSR in cells of the osteoblast lineage, in addition to its established role of mTORC2 activation downstream of the receptor.

scholarly journals Investigation of the curative effects of palm vitamin E tocotrienols on autoimmune arthritis disease in vivo

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Zaida Zainal ◽  
Afiqah Abdul Rahim ◽  
Ammu Kutty Radhakrishnan ◽  
Sui Kiat Chang ◽  
Huzwah Khaza’ai
Keyword(s):  
Vitamin E ◽  
Rat Model ◽  
Bone Erosion ◽  
Cartilage Destruction ◽  
Intradermal Injection ◽  
Dark Agouti ◽  
Therapeutic Effects ◽  
Beneficial Effects ◽  
Protein Levels

AbstractThe tocotrienol-rich fraction (TRF) from palm oil contains vitamin E, which possesses potent antioxidant and anti-inflammatory activities. Rheumatoid arthritis (RA) is a chronic joint inflammatory disease characterised by severe joint pain, cartilage destruction, and bone erosion owing to the effects of various pro-inflammatory mediators and cytokines. Here, we investigated the therapeutic effects of TRF in a rat model of collagen-induced arthritis (CIA). Arthritis was induced by a single intradermal injection of collagen type II in Dark Agouti (DA) rats. Rats were then treated with or without TRF by oral gavage from day 28 after the first collagen injection. Arthritic rats supplemented with TRF showed decreased articular index scores, ankle circumferences, paw volumes, and radiographic scores when compared with untreated rats. The untreated arthritic rats showed higher plasma C-reactive protein levels (p < 0.05) and production of pro-inflammatory cytokines than arthritic rats fed TRF. Moreover, there was a marked reduction in the severity of histopathological changes observed in arthritic rats treated with TRF compared with that in untreated arthritic rats. Overall, the results show that TRF had beneficial effects in this rat model of RA.

Rhodiola and salidroside in the treatment of metabolic disorders

2019 ◽  
Vol 19 (19) ◽  
pp. 1611-1626 ◽  
Author(s):  
Xiang-Li Bai ◽  
Xiu-Ling Deng ◽  
Guang-Jie Wu ◽  
Wen-Jing Li ◽  
Si Jin
Keyword(s):  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Ex Vivo ◽  
Treatment Strategies ◽  
Ampk Signaling ◽  
Beneficial Effects

Over the past three decades, the knowledge gained about the mechanisms that underpin the potential use of Rhodiola in stress- and ageing-associated disorders has increased, and provided a universal framework for studies that focused on the use of Rhodiola in preventing or curing metabolic diseases. Of particular interest is the emerging role of Rhodiola in the maintenance of energy homeostasis. Moreover, over the last two decades, great efforts have been undertaken to unravel the underlying mechanisms of action of Rhodiola in the treatment of metabolic disorders. Extracts of Rhodiola and salidroside, the most abundant active compound in Rhodiola, are suggested to provide a beneficial effect in mental, behavioral, and metabolic disorders. Both in vivo and ex vivo studies, Rhodiola extracts and salidroside ameliorate metabolic disorders when administered acutely or prior to experimental injury. The mechanism involved includes multi-target effects by modulating various synergistic pathways that control oxidative stress, inflammation, mitochondria, autophagy, and cell death, as well as AMPK signaling that is associated with possible beneficial effects on metabolic disorders. However, evidence-based data supporting the effectiveness of Rhodiola or salidroside in treating metabolic disorders is limited. Therefore, a comprehensive review of available trials showing putative treatment strategies of metabolic disorders that include both clinical effective perspectives and fundamental molecular mechanisms is warranted. This review highlights studies that focus on the potential role of Rhodiola extracts and salidroside in type 2 diabetes and atherosclerosis, the two most common metabolic diseases.

scholarly journals Anthocyanins Function as Anti-Inflammatory Agents in a Drosophila Model for Adipose Tissue Macrophage Infiltration

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Alice Valenza ◽  
Carola Bonfanti ◽  
Maria Enrica Pasini ◽  
Paola Bellosta
Keyword(s):  
Adipose Tissue ◽  
Fruits And Vegetables ◽  
Metabolic Diseases ◽  
Fat Body ◽  
Protective Action ◽  
Macrophage Infiltration ◽  
Tissue Macrophage ◽  
Beneficial Effects ◽  
Drosophila Model ◽  
Stress Kinase

Epidemiological and preclinical studies have demonstrated that bioactive foods like flavonoids, polyphenolic compounds derived from fruits and vegetables, exert a protective action against obesity, cardiovascular disorders, and Adipocyte Tissue Macrophage infiltration (ATM). All these pathologies are characterized by increase in reactive oxygen species (ROS) and in proinflammatory cytokines that have been shown to favor the migration of immune cells, particularly of macrophages, in metabolically active organs like the liver and adipose tissue, that in Drosophila are constituted by a unique organ: the fat body. This study, using a unique Drosophila model that mimics human ATM, reveals the beneficial effects of flavonoids to reduce tissue inflammation. Our data show that anthocyanin-rich food reduces the number of hemocytes, Drosophila macrophages, infiltrating the fat cells, a process that is associated with reduced production of ROS and reduced activation of the JNK/SAPK p46 stress kinase, suggesting a fundamental function for anthocyanins as antioxidants in chronic inflammation and in metabolic diseases.

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