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Daskalaki MG, Axarlis K, Tsoureki A, Michailidou S, Efraimoglou C, Lapi I, Kolliniati O, Dermitzaki E, Venihaki M, Kousoulaki K, Argiriou A, Tsatsanis C. Fish-Derived Protein Hydrolysates Increase Insulin Sensitivity and Alter Intestinal Microbiome in High-Fat-Induced Obese Mice. Mar Drugs 2023; 21:343. [PMID: 37367668 DOI: 10.3390/md21060343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 05/29/2023] [Accepted: 05/31/2023] [Indexed: 06/28/2023] Open
Abstract
Obesity and type 2 diabetes are characterized by low-grade systemic inflammation and glucose intolerance, which can be partially controlled with nutritional interventions. Protein-containing nutritional supplements possess health-promoting benefits. Herein, we examined the effect of dietary supplementation with protein hydrolysates derived from fish sidestreams on obesity and diabetes, utilizing a mouse model of High-Fat Diet-induced obesity and type 2 diabetes. We examined the effect of protein hydrolysates from salmon and mackerel backbone (HSB and HMB, respectively), salmon and mackerel heads (HSH and HMH, respectively), and fish collagen. The results showed that none of the dietary supplements affected weight gain, but HSH partially suppressed glucose intolerance, while HMB and HMH suppressed leptin increase in the adipose tissue. We further analyzed the gut microbiome, which contributes to the metabolic disease implicated in the development of type 2 diabetes, and found that supplementation with selected protein hydrolysates resulted in distinct changes in gut microbiome composition. The most prominent changes occurred when the diet was supplemented with fish collagen since it increased the abundance of beneficial bacteria and restricted the presence of harmful ones. Overall, the results suggest that protein hydrolysates derived from fish sidestreams can be utilized as dietary supplements with significant health benefits in the context of type 2 diabetes and diet-induced changes in the gut microbiome.
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Affiliation(s)
- Maria G Daskalaki
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece
- Institute of Molecular Biology and Biotechnology, FORTH, 71100 Heraklion, Greece
| | - Konstantinos Axarlis
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece
- Institute of Molecular Biology and Biotechnology, FORTH, 71100 Heraklion, Greece
| | - Antiopi Tsoureki
- Institute of Applied Biosciences (INAB), CERTH, Thermi, 57001 Thessaloniki, Greece
| | - Sofia Michailidou
- Institute of Applied Biosciences (INAB), CERTH, Thermi, 57001 Thessaloniki, Greece
| | - Christina Efraimoglou
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece
- Institute of Molecular Biology and Biotechnology, FORTH, 71100 Heraklion, Greece
| | - Ioanna Lapi
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece
- Institute of Molecular Biology and Biotechnology, FORTH, 71100 Heraklion, Greece
| | - Ourania Kolliniati
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece
- Institute of Molecular Biology and Biotechnology, FORTH, 71100 Heraklion, Greece
| | - Eirini Dermitzaki
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece
- Institute of Molecular Biology and Biotechnology, FORTH, 71100 Heraklion, Greece
| | - Maria Venihaki
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece
| | | | - Anagnostis Argiriou
- Institute of Applied Biosciences (INAB), CERTH, Thermi, 57001 Thessaloniki, Greece
- Department of Food Science and Nutrition, University of the Aegean, Myrina, 81400 Lemnos, Greece
| | - Christos Tsatsanis
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece
- Institute of Molecular Biology and Biotechnology, FORTH, 71100 Heraklion, Greece
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Park YK, Jang BC. The Receptor Tyrosine Kinase c-Met Promotes Lipid Accumulation in 3T3-L1 Adipocytes. Int J Mol Sci 2023; 24:ijms24098086. [PMID: 37175792 PMCID: PMC10179087 DOI: 10.3390/ijms24098086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/23/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
The receptor tyrosine kinase c-Met is elaborated in embryogenesis, morphogenesis, metabolism, cell growth, and differentiation. JNJ38877605 (JNJ) is an inhibitor of c-Met with anti-tumor activity. The c-Met expression and its role in adipocyte differentiation are unknown. Here, we investigated the c-Met expression and phosphorylation, knockdown (KD) effects, and pharmacological inhibition of c-Met by JNJ on fat accumulation in murine preadipocyte 3T3-L1 cells. During 3T3-L1 preadipocyte differentiation, strikingly, c-Met expression at the protein and mRNA levels and the protein phosphorylation on Y1234/1235 and Y1349 is crucial for inducing its kinase catalytic activity and activating a docking site for signal transducers were increased in a time-dependent manner. Of note, JNJ treatment at 20 μM that strongly inhibits c-Met phosphorylation without altering its total expression resulted in less lipid accumulation and triglyceride (TG) content with no cytotoxicity. JNJ further reduced the expression of adipogenic regulators, including CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), acetyl CoA carboxylase (ACC), and perilipin A. Moreover, JNJ treatment increased cAMP-activated protein kinase (AMPK) and liver kinase B-1 (LKB-1) phosphorylation but decreased ATP levels. Significantly, KD of c-Met suppressed fat accumulation and triglyceride (TG) quantity and reduced the expression of C/EBP-α, PPAR-γ, FAS, ACC, and perilipin A. Collectively, the present results demonstrate that c-Met is a novel, highly conserved mediator of adipogenesis regulating lipid accumulation in murine adipocytes.
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Affiliation(s)
- Yu-Kyoung Park
- Department of Molecular Medicine, College of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Republic of Korea
- Department of Physiology, Senotherapy-Based Metabolic Disease Control Research Center, College of Medicine, Yeungnam University, 170, Hyeonchung-ro, Nam-gu, Daegu 42415, Republic of Korea
| | - Byeong-Churl Jang
- Department of Molecular Medicine, College of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Republic of Korea
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3
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Sooriyaarachchi P, Jayawardena R, Pavey T, King NA. Shift work and the risk for metabolic syndrome among healthcare workers: A systematic review and meta-analysis. Obes Rev 2022; 23:e13489. [PMID: 35734805 PMCID: PMC9539605 DOI: 10.1111/obr.13489] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 06/09/2022] [Accepted: 06/09/2022] [Indexed: 11/27/2022]
Abstract
Shift work, defined as work occurring outside typical daytime working hours, is associated with an increased risk for metabolic syndrome (MetS) due to several biological and environmental changes. The MetS refers to the clustering of several known cardiovascular risk factors, including insulin resistance, obesity, dyslipidemia, and hypertension. This systematic review aims to evaluate the literature on the association between shift work and the risk of MetS in employees of the health sector. A systematic search was conducted in PubMed, Web of Science, and Scopus databases using appropriate keywords for studies published before September 1, 2021. Eligible studies were those that compared the prevalence of MetS between day and shift healthcare workers; had a cross-sectional, case-control, or cohort study design; provided sufficient data for calculating odds ratios or relative risks with 95% confidence intervals; and articles in English. The Joanna Briggs Institute prevalence critical appraisal tool was used for quality analysis. Risk for MetS and related measures of effect size were retrieved from studies for meta-analysis. Twelve studies met the criteria for inclusion in the review and meta-analysis. Sample sizes ranged from 42 to 738, and the age range of subjects was between 18 and 65 years. Ten studies demonstrated high methodological quality, while two studies were of average quality. Ten out of 12 studies in the review demonstrated a higher risk in shift workers for developing MetS than day workers. The pooled OR of MetS in shift workers based on 12 studies was 2.17 (95% CI = 1.31-3.60, P = 0.003; I2 = 82%, P < 0.001). Shift workers exhibited more than a twofold increase in the chance of developing MetS in comparison with day workers.
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Affiliation(s)
- Piumika Sooriyaarachchi
- School of Exercise and Nutrition Sciences, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia.,Health and Wellness Unit, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Ranil Jayawardena
- School of Exercise and Nutrition Sciences, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia.,Department of Physiology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - Toby Pavey
- School of Exercise and Nutrition Sciences, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia
| | - Neil A King
- School of Exercise and Nutrition Sciences, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia
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4
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Chen G, Harwood JL, Lemieux MJ, Stone SJ, Weselake RJ. Acyl-CoA:diacylglycerol acyltransferase: Properties, physiological roles, metabolic engineering and intentional control. Prog Lipid Res 2022; 88:101181. [PMID: 35820474 DOI: 10.1016/j.plipres.2022.101181] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 05/31/2022] [Accepted: 07/04/2022] [Indexed: 12/15/2022]
Abstract
Acyl-CoA:diacylglycerol acyltransferase (DGAT, EC 2.3.1.20) catalyzes the last reaction in the acyl-CoA-dependent biosynthesis of triacylglycerol (TAG). DGAT activity resides mainly in membrane-bound DGAT1 and DGAT2 in eukaryotes and bifunctional wax ester synthase-diacylglycerol acyltransferase (WSD) in bacteria, which are all membrane-bound proteins but exhibit no sequence homology to each other. Recent studies also identified other DGAT enzymes such as the soluble DGAT3 and diacylglycerol acetyltransferase (EaDAcT), as well as enzymes with DGAT activities including defective in cuticular ridges (DCR) and steryl and phytyl ester synthases (PESs). This review comprehensively discusses research advances on DGATs in prokaryotes and eukaryotes with a focus on their biochemical properties, physiological roles, and biotechnological and therapeutic applications. The review begins with a discussion of DGAT assay methods, followed by a systematic discussion of TAG biosynthesis and the properties and physiological role of DGATs. Thereafter, the review discusses the three-dimensional structure and insights into mechanism of action of human DGAT1, and the modeled DGAT1 from Brassica napus. The review then examines metabolic engineering strategies involving manipulation of DGAT, followed by a discussion of its therapeutic applications. DGAT in relation to improvement of livestock traits is also discussed along with DGATs in various other eukaryotic organisms.
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Affiliation(s)
- Guanqun Chen
- Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Alberta T6H 2P5, Canada.
| | - John L Harwood
- School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK
| | - M Joanne Lemieux
- Department of Biochemistry, University of Alberta, Membrane Protein Disease Research Group, Edmonton T6G 2H7, Canada
| | - Scot J Stone
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
| | - Randall J Weselake
- Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Alberta T6H 2P5, Canada
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18:0 Lyso PC Derived by Bioactivity-Based Molecular Networking from Lentil Mutant Lines and Its Effects on High-Fat Diet-Induced Obese Mice. Molecules 2021; 26:molecules26247547. [PMID: 34946633 PMCID: PMC8707596 DOI: 10.3390/molecules26247547] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/07/2021] [Accepted: 12/08/2021] [Indexed: 01/12/2023] Open
Abstract
Lentil (Lens culinaris; Fabaceae), one of the major pulse crops in the world, is an important source of proteins, prebiotics, lipids, and essential minerals as well as functional components such as flavonoids, polyphenols, and phenolic acids. To improve crop nutritional and medicinal traits, hybridization and mutation are widely used in plant breeding research. In this study, mutant lentil populations were generated by γ-irradiation for the development of new cultivars by inducing genetic diversity. Molecular networking via Global Natural Product Social Molecular Networking web platform and dipeptidyl peptide-IV inhibitor screening assay were utilized as tools for structure-based discovery of active components in active mutant lines selected among the lentil population. The bioactivity-based molecular networking analysis resulted in the annotation of the molecular class of phosphatidylcholine (PC) from the most active mutant line. Among PCs, 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (18:0 Lyso PC) was selected for further in vivo study of anti-obesity effect in a high-fat diet (HFD)-induced obese mouse model. The administration of 18:0 Lyso PC not only prevented body weight gain and decreased relative gonadal adipose tissue weight, but also attenuated the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and leptin in the sera of HFD-induced obese mice. Additionally, 18:0 Lyso PC treatment inhibited the increase of adipocyte area and crown-like structures in adipose tissue. Therefore, these results suggest that 18:0 Lyso PC is a potential compound to have protective effects against obesity, improving obese phenotype induced by HFD.
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Reijrink M, De Boer SA, Van Roon AM, Slart RHJA, Fernandez BO, Feelisch M, Heerspink HJL, Van Goor H, Hillebrands JL, Mulder DJ. Plasma Nitrate Levels Are Related to Metabolic Syndrome and Are Not Altered by Treatment with DPP-4 Inhibitor Linagliptin: A Randomised, Placebo-Controlled Trial in Patients with Early Type 2 Diabetes Mellitus. Antioxidants (Basel) 2021; 10:antiox10101548. [PMID: 34679685 PMCID: PMC8533083 DOI: 10.3390/antiox10101548] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 01/25/2023] Open
Abstract
The depletion of nitrate and nitrite, stable nitric oxide (NO) end-products, promotes adipose tissue dysfunction and insulin resistance (IR). Dipeptidyl peptidase-4 (DPP-4) inhibitors have the potentially beneficial side effect of increasing NO availability. In this study, nitrate and nitrite levels and the effects of DPP-4 inhibitor linagliptin were investigated in relation to metabolic syndrome (MetS) markers. Treatment-naive patients with early type 2 diabetes mellitus (T2DM) (n = 40, median age 63 IQR (55–67) years, 63% male, mean HbA1c 45 ± 4.4 mmol/mol) were randomized (1:1) to linagliptin (5 mg/day) or placebo. MetS-related markers (body mass index (BMI), triglycerides, HOMA-IR, gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and adiponectin), plasma levels of nitrate, nitrite, total free thiols (TFT) and vegetable intake were estimated at baseline and after 4 and 26 weeks of treatment. Plasma nitrate, but not nitrite, correlated positively with vegetable intake (r = 0.38, p = 0.018) and was inversely associated with HOMA-IR (r = −0.44, p = 0.006), BMI (r = −0.35, p = 0.028), GGT (r = −0.37, p = 0.019) and CRP (r = −0.34, p = 0.034). The relationship between nitrate and HOMA-IR remained significant after adjusting for BMI, CRP, vegetable intake and GGT. With stable vegetable intake, nitrate and nitrite, TFT, adipokines and CRP did not change after 26 weeks of linagliptin treatment. While plasma nitrate is inversely associated with MetS, linagliptin treatment does not significantly influence nitrate and nitrite concentrations, oxidative stress, adipose tissue function and systemic inflammation.
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Affiliation(s)
- Melanie Reijrink
- Medical Center Groningen, Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, 9713 Groningen, The Netherlands; (M.R.); (S.A.D.B.); (A.M.V.R.)
| | - Stefanie A. De Boer
- Medical Center Groningen, Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, 9713 Groningen, The Netherlands; (M.R.); (S.A.D.B.); (A.M.V.R.)
| | - Anniek M. Van Roon
- Medical Center Groningen, Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, 9713 Groningen, The Netherlands; (M.R.); (S.A.D.B.); (A.M.V.R.)
| | - Riemer H. J. A. Slart
- Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, 9713 Groningen, The Netherlands;
- Department of Biomedical Photoacustic Imaging (BMPI), University of Twente, 7522 Enschede, The Netherlands
| | - Bernadette O. Fernandez
- Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, SO17 1BJ Southamptonc, UK; (B.O.F.); (M.F.)
| | - Martin Feelisch
- Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, SO17 1BJ Southamptonc, UK; (B.O.F.); (M.F.)
| | - Hiddo J. L. Heerspink
- Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, University of Groningen, 9713 Groningen, The Netherlands;
| | - Harry Van Goor
- Medical Center Groningen, Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, 9713 Groningen, The Netherlands; (H.V.G.); (J.-L.H.)
| | - Jan-Luuk Hillebrands
- Medical Center Groningen, Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, 9713 Groningen, The Netherlands; (H.V.G.); (J.-L.H.)
| | - Douwe J. Mulder
- Medical Center Groningen, Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, 9713 Groningen, The Netherlands; (M.R.); (S.A.D.B.); (A.M.V.R.)
- Correspondence:
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Dickey J, Davtyan C, Davtyan D, Taegtmeyer H. Homeostasis Disrupted and Restored-A Fresh Look at the Mechanism and Treatment of Obesity During COVID-19. Front Cardiovasc Med 2021; 8:721956. [PMID: 34513959 PMCID: PMC8432610 DOI: 10.3389/fcvm.2021.721956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 08/09/2021] [Indexed: 11/13/2022] Open
Abstract
The prevalence of obesity in the United States approaches half of the adult population. The COVID-19 pandemic endangers the health of obese individuals. In addition, the metabolic syndrome poses a challenge to the health of obese adults. Bariatric surgery and diet restore metabolic homeostasis in obese individuals; however, it is still unclear which strategy is most effective. For example, intermittent fasting improves insulin sensitivity and diet alone decreases visceral adipose tissue at a disproportionately high rate compared to weight loss. Bariatric surgery causes rapid remission of type 2 diabetes and increases incretins for long-term remission of insulin resistance before meaningful weight loss has occurred. Malabsorptive surgeries have provided insight into the mechanism of altering metabolic parameters, but strong evidence to determine the duration of their effects is yet to be established. When determining the best method of weight loss, metabolic parameters, target weight loss, and risk-benefit analysis must be considered carefully. In this review, we address the pros and cons for the optimal way to restore metabolic homeostasis.
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Affiliation(s)
- Jacqueline Dickey
- McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, United States.,The University of Texas Health Science Center at Houston School of Public Health, Houston, TX, United States
| | - Camelia Davtyan
- Department of Internal Medicine, University of California Los Angeles, Los Angeles, CA, United States
| | - David Davtyan
- Department of General Surgery, Cedars-Sinai Medical Center, Glendale, CA, United States
| | - Heinrich Taegtmeyer
- McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, United States.,Department of Internal Medicine, Division of Cardiology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, United States
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Hypolipidemic Effects and Preliminary Mechanism of Chrysanthemum Flavonoids, Its Main Components Luteolin and Luteoloside in Hyperlipidemia Rats. Antioxidants (Basel) 2021; 10:antiox10081309. [PMID: 34439559 PMCID: PMC8389196 DOI: 10.3390/antiox10081309] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 07/25/2021] [Accepted: 08/12/2021] [Indexed: 12/24/2022] Open
Abstract
This study aimed to investigate the key constituents and preliminary mechanism for the hypolipidemic activity of chrysanthemum flavonoids. Hyperlipidemia (HPL) rats were divided into five groups: the model control group (MC); Chrysanthemum flavone intervention group (CF); luteolin intervention group; luteoloside intervention group and simvastatin intervention group. The body weight, organ coefficient, serum lipids, antioxidant activity, and lipid metabolism enzymes were detected. Hematoxylin and eosin (H&E) staining was used to observe the liver and adipose tissue. Chrysanthemum flavonoids, luteolin, and luteoloside can reduce the weight and levels of total cholesterol (TC), triglycerides (TG), and LDL-C, and increase the level of HDL-C in the blood and reduce liver steatosis. Indicators of liver function (AST, ALT, and ALP) improved. The antioxidant activity (GSH-Px, CAT, SOD) and enzymes associated with lipid catabolism (FAβO, CYP7A1, and HL) increased, while lipid peroxidation products (MDA) and enzymes associated with lipid synthesis (FAS, HMG-CoA, and DGAT) decreased. Chrysanthemum flavonoids had a better effect on the antioxidant level and lipid metabolism-related enzyme activity. There was no significant difference in the effects of the chrysanthemum flavonoids, luteolin, and Luteoloside on improving blood lipids and hepatic steatosis—mechanisms that may be related to antioxidant levels and regulating enzymes involved in the metabolism of fatty acids, cholesterol, and triglycerides in the liver. However, chrysanthemum flavonoids had a stronger antioxidant and lipid metabolism regulation ability, and the long-term effects may be better.
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Bas S, Oz K, Akkus A, Sizmaz M, Serin E, Durgun M, Karsidag S. Effect of Reduction Mammoplasty on Insulin and Lipid Metabolism in the Postoperative Third month: Compensatory Hip Enlargement. Aesthetic Plast Surg 2021; 47:536-543. [PMID: 34031735 PMCID: PMC8143058 DOI: 10.1007/s00266-021-02352-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 05/09/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUNDS The positive effects of reduction mammoplasty on metabolic profile have been shown in a limited number of studies. This study objective to reveal the effects of reduction mammoplasty on metabolic profile and anthropometric measurements. SUBJECTS AND METHOD The study was prospectively conducted on 42 patients who were operated between April 2019 and March 2020. Fasting plasma glucose, fasting plasma insulin, total cholesterol, triglyceride, high-density lipoprotein and low-density lipoprotein cholesterol, HgA1c, homeostasis model assessment scores, adiponectin, leptin, and resistin levels were evaluated. In addition, age, height, weight, body mass index; breast, chest, waist, hip circumference; waist-hip ratio, and bilateral breast resection tissue weights were recorded. Data and blood samples were collected one hour before the operation, 6 and 12 weeks after the operation. RESULT The patients' mean age was 43.14±10.24, and their average height was 159.42±4.96 cm. The excised bilateral dermo fatty tissue weight was 1435.85±721.16 g. At the postoperative 40th day a decrease in leptin (p = 0.001), resistin (p =0.008), glucose (p = 0.021) and insulin resistance values (p=0.013) stated. There was an increase in adiponectin (p < 0.001) and HDL (p = 0.013) levels at the postoperative 40th day. In the postoperative third month, these data returned to the previous levels that were measured before operations. However, an increase in hip circumference (p = 0.034) and a decrease in waist-hip ratio (p < 0.001) was detected in third month. Also, there was no difference in body mass index and weight compared to pre-operation. CONCLUSION After reduction mammoplasty, compensatory fat growth in the hip area, an increase in the hip circumference, and a decrease in the waist-hip ratio were observed in the postoperative third month. LEVEL OF EVIDENCE This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Affiliation(s)
- Soysal Bas
- Department of Plastic, Reconstructive and Aesthetic Surgery, University of Health Sciences, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey.
| | - Kurtulus Oz
- Department of Plastic, Reconstructive and Aesthetic Surgery, University of Health Sciences, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Anıl Akkus
- Department of Biochemistry, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Mert Sizmaz
- Department of Plastic, Reconstructive and Aesthetic Surgery, University of Health Sciences, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Erdinc Serin
- Department of Biochemistry, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Mustafa Durgun
- Department of Plastic, Reconstructive and Aesthetic Surgery, Private Clinic, Izmir, Turkey
| | - Semra Karsidag
- Department of Plastic, Reconstructive and Aesthetic Surgery, University of Health Sciences, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
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Axarlis K, Daskalaki MG, Michailidou S, Androulaki N, Tsoureki A, Mouchtaropoulou E, Kolliniati O, Lapi I, Dermitzaki E, Venihaki M, Kousoulaki K, Argiriou A, Marsni ZE, Tsatsanis C. Diet Supplementation with Fish-Derived Extracts Suppresses Diabetes and Modulates Intestinal Microbiome in a Murine Model of Diet-Induced Obesity. Mar Drugs 2021; 19:268. [PMID: 34064922 PMCID: PMC8151984 DOI: 10.3390/md19050268] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 04/29/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
Metabolic syndrome-related diseases affect millions of people worldwide. It is well established that changes in nutritional habits and lifestyle can improve or prevent metabolic-related pathologies such as type-2 diabetes and obesity. Previous reports have shown that nutritional supplements have the capacity to limit glucose intolerance and suppress diabetes development. In this study, we investigated the effect of dietary supplementation with fish-derived extracts on obesity and type 2 diabetes and their impact on gut microbial composition. We showed that nutritional supplements containing Fish Complex (FC), Fish Complex combined with Cod Powder (FC + CP), or Cod Powder combined with Collagen (CP + C) improved glucose intolerance, independent of abdominal fat accumulation, in a mouse model of diet-induced obesity and type 2 diabetes. In addition, collagen-containing supplements distinctly modulate the gut microbiome in high-fat induced obesity in mice. Our results suggest that fish-derived supplements suppress diet-induced type 2 diabetes, which may be partly mediated through changes in the gut microbiome. Thus, fish-derived supplements and particularly the ones containing fish collagen have potential beneficial properties as dietary supplements in managing type 2 diabetes and metabolic syndrome via modulation of the gut microbiome.
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Affiliation(s)
- Konstantinos Axarlis
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece; (K.A.); (M.G.D.); (N.A.); (O.K.); (I.L.); (E.D.); (M.V.)
- Institute of Molecular Biology and Biotechnology, FORTH, 71100 Heraklion, Greece
| | - Maria G. Daskalaki
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece; (K.A.); (M.G.D.); (N.A.); (O.K.); (I.L.); (E.D.); (M.V.)
- Institute of Molecular Biology and Biotechnology, FORTH, 71100 Heraklion, Greece
| | - Sofia Michailidou
- Institute of Applied Biosciences (INAB), CERTH, Thermi, 57001 Thessaloniki, Greece; (S.M.); (A.T.); (E.M.); (A.A.)
| | - Nikolais Androulaki
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece; (K.A.); (M.G.D.); (N.A.); (O.K.); (I.L.); (E.D.); (M.V.)
| | - Antiopi Tsoureki
- Institute of Applied Biosciences (INAB), CERTH, Thermi, 57001 Thessaloniki, Greece; (S.M.); (A.T.); (E.M.); (A.A.)
| | - Evangelia Mouchtaropoulou
- Institute of Applied Biosciences (INAB), CERTH, Thermi, 57001 Thessaloniki, Greece; (S.M.); (A.T.); (E.M.); (A.A.)
| | - Ourania Kolliniati
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece; (K.A.); (M.G.D.); (N.A.); (O.K.); (I.L.); (E.D.); (M.V.)
- Institute of Molecular Biology and Biotechnology, FORTH, 71100 Heraklion, Greece
| | - Ioanna Lapi
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece; (K.A.); (M.G.D.); (N.A.); (O.K.); (I.L.); (E.D.); (M.V.)
- Institute of Molecular Biology and Biotechnology, FORTH, 71100 Heraklion, Greece
| | - Eirini Dermitzaki
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece; (K.A.); (M.G.D.); (N.A.); (O.K.); (I.L.); (E.D.); (M.V.)
- Institute of Molecular Biology and Biotechnology, FORTH, 71100 Heraklion, Greece
| | - Maria Venihaki
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece; (K.A.); (M.G.D.); (N.A.); (O.K.); (I.L.); (E.D.); (M.V.)
| | - Katerina Kousoulaki
- Department of Nutrition and Feed Technology, Nofima AS, 5141 Bergen, Norway;
| | - Anagnostis Argiriou
- Institute of Applied Biosciences (INAB), CERTH, Thermi, 57001 Thessaloniki, Greece; (S.M.); (A.T.); (E.M.); (A.A.)
- Department of Food Science and Nutrition, University of the Aegean, Myrina, 81400 Lemnos, Greece
| | | | - Christos Tsatsanis
- Laboratory of Clinical Chemistry, Medical School, University of Crete, 70013 Heraklion, Greece; (K.A.); (M.G.D.); (N.A.); (O.K.); (I.L.); (E.D.); (M.V.)
- Institute of Molecular Biology and Biotechnology, FORTH, 71100 Heraklion, Greece
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11
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Yadav AK, Jang BC. Inhibition of Lipid Accumulation and Cyclooxygenase-2 Expression in Differentiating 3T3-L1 Preadipocytes by Pazopanib, a Multikinase Inhibitor. Int J Mol Sci 2021; 22:ijms22094884. [PMID: 34063048 PMCID: PMC8125232 DOI: 10.3390/ijms22094884] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 01/23/2023] Open
Abstract
Pazopanib is a multikinase inhibitor with anti-tumor activity. As of now, the anti-obesity effect and mode of action of pazopanib are unknown. In this study, we investigated the effects of pazopanib on lipid accumulation, lipolysis, and expression of inflammatory cyclooxygenase (COX)-2 in differentiating and differentiated 3T3-L1 cells, a murine preadipocyte. Of note, pazopanib at 10 µM markedly decreased lipid accumulation and triglyceride (TG) content during 3T3-L1 preadipocyte differentiation with no cytotoxicity. Furthermore, pazopanib inhibited not only expression of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), and perilipin A but also phosphorylation of signal transducer and activator of transcription (STAT)-3 during 3T3-L1 preadipocyte differentiation. In addition, pazopanib treatment increased phosphorylation of cAMP-activated protein kinase (AMPK) and its downstream effector ACC during 3T3-L1 preadipocyte differentiation. However, in differentiated 3T3-L1 adipocytes, pazopanib treatment did not stimulate glycerol release and hormone-sensitive lipase (HSL) phosphorylation, hallmarks of lipolysis. Moreover, pazopanib could inhibit tumor necrosis factor (TNF)-α-induced expression of COX-2 in both 3T3-L1 preadipocytes and differentiated cells. In summary, this is the first report that pazopanib has strong anti-adipogenic and anti-inflammatory effects in 3T3-L1 cells, which are mediated through regulation of the expression and phosphorylation of C/EBP-α, PPAR-γ, STAT-3, ACC, perilipin A, AMPK, and COX-2.
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12
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Su L, Wu R, Chen X, Hou W, Ruan BH. FITC-labeled d-glucose analog is suitable as a probe for detecting insulin-dependent glucose uptake. Bioorg Med Chem Lett 2018; 28:3560-3563. [PMID: 30293953 DOI: 10.1016/j.bmcl.2018.09.027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 09/19/2018] [Indexed: 11/28/2022]
Abstract
The detection of the insulin-dependent glucose uptake is a vital part in the research of diabetes. To establish a sensitive assay for measuring glucose uptake in living cells, we synthesized a FITC linked d-glucosamine 2 as a probe. 2 was obtained by the reaction of commercially available d-glucosamine hydrochloride and FITC and was determined as a single anomeric form by 1H NMR and 13C NMR. 2 exhibited good water solubility and stability. An uptake assay in HepG2 cells with or without insulin demonstrated that FITC showed strong cellular uptake, whereas uptake of 2 is much less but is insulin dependent. This suggests that 2 is specifically transported into cells through a receptor that is regulated by insulin and has potential application in screening of compounds or genes that regulate the insulin-dependence in cell-based assays.
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Affiliation(s)
- Lin Su
- College of Pharmaceutical Science, Institute of Drug Development & Chemical Biology (IDD & CB), Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, PR China
| | - Rui Wu
- College of Pharmaceutical Science, Institute of Drug Development & Chemical Biology (IDD & CB), Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, PR China
| | - Xinrou Chen
- College of Pharmaceutical Science, Institute of Drug Development & Chemical Biology (IDD & CB), Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, PR China
| | - Wei Hou
- College of Pharmaceutical Science, Institute of Drug Development & Chemical Biology (IDD & CB), Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, PR China
| | - Benfang Helen Ruan
- College of Pharmaceutical Science, Institute of Drug Development & Chemical Biology (IDD & CB), Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, PR China.
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13
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Park YK, Obiang-Obounou BW, Lee J, Lee TY, Bae MA, Hwang KS, Lee KB, Choi JS, Jang BC. Anti-Adipogenic Effects on 3T3-L1 Cells and Zebrafish by Tanshinone IIA. Int J Mol Sci 2017; 18:ijms18102065. [PMID: 28953247 PMCID: PMC5666747 DOI: 10.3390/ijms18102065] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 09/15/2017] [Accepted: 09/22/2017] [Indexed: 12/22/2022] Open
Abstract
Tanshinone IIA is a diterpene quinone isolated from the roots of Salviamiltiorrhiza bunge that has traditionally been used in China for the treatment of cardiovascular and cerebrovascular disorders. Although there is recent evidence showing that tanshinone IIA has an anti-obesity effect, its underlying mechanism of anti-obesity effect is poorly understood. Here, we investigated the effect of tanshinone IIA on lipid accumulation in 3T3-L1 preadipocytes and zebrafish. Notably, tanshinone IIA at 10 μM concentration greatly reduced lipid accumulation and triglyceride (TG) contents during 3T3-L1 preadipocyte differentiation, suggesting its anti-adipogenic effect. On mechanistic levels, tanshinone IIA reduced the expression levels of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), and perilipin A but also the phosphorylation levels of signal transducer and activator of transcription-3/5 (STAT-3/5) in differentiating 3T3-L1 cells. In addition, tanshinone IIA strongly inhibited leptin and resistin mRNA expression in differentiating 3T3-L1 cells. Importantly, the tanshinone IIA's lipid-reducing effect was also seen in zebrafish. In sum, these findings demonstrate that tanshinone IIA has anti-adipogenic effects on 3T3-L1 cells and zebrafish, and its anti-adipogenic effect on 3T3-L1 cells is largely attributable to the reduced expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3/5.
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Affiliation(s)
- Yu-Kyoung Park
- Department of Molecular Medicine, College of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Korea.
| | - Brice Wilfried Obiang-Obounou
- Department of Food Nutrition, College of Natural Sciences, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Korea.
| | - Jinho Lee
- Department of Chemistry, College of Natural Sciences, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Korea.
| | - Tae-Yun Lee
- Department of Microbiology, College of Medicine, Yeungnam University, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea.
| | - Myung-Ae Bae
- Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro Yuseong-gu, Daejeon 34114, Korea.
| | - Kyu-Seok Hwang
- Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro Yuseong-gu, Daejeon 34114, Korea.
| | - Kyung-Bok Lee
- Biological Disaster Analysis Group, Division of Convergence Biotechnology, Korea Basic Science Institute, 169-148 Gwahak-ro, Yuseong-gu, Daejeon 34133, Korea.
| | - Jong-Soon Choi
- Biological Disaster Analysis Group, Division of Convergence Biotechnology, Korea Basic Science Institute, 169-148 Gwahak-ro, Yuseong-gu, Daejeon 34133, Korea.
| | - Byeong-Churl Jang
- Department of Molecular Medicine, College of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Korea.
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14
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Yan J, Wang G, Dang X, Guo B, Chen W, Wang T, Zeng L, Wang H, Hu Y. Discovery of a low-systemic-exposure DGAT-1 inhibitor with a picolinoylpyrrolidine-2-carboxylic acid moiety. Bioorg Med Chem 2017; 25:4701-4714. [DOI: 10.1016/j.bmc.2017.07.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Revised: 07/01/2017] [Accepted: 07/06/2017] [Indexed: 10/19/2022]
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15
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Xia SF, Le GW, Wang P, Qiu YY, Jiang YY, Tang X. Regressive Effect of Myricetin on Hepatic Steatosis in Mice Fed a High-Fat Diet. Nutrients 2016; 8:nu8120799. [PMID: 27973423 PMCID: PMC5188454 DOI: 10.3390/nu8120799] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Revised: 12/04/2016] [Accepted: 12/05/2016] [Indexed: 12/16/2022] Open
Abstract
Myricetin is an effective antioxidant in the treatment of obesity and obesity-related metabolic disorders. The objective of this study was to explore the regressive effect of myricetin on pre-existing hepatic steatosis induced by high-fat diet (HFD). C57BL/6 mice were fed either a standard diet or a HFD for 12 weeks and then half of the mice were treated with myricetin (0.12% in the diet, w/w) while on their respective diets for further 12 weeks. Myricetin treatment significantly alleviated HFD-induced steatosis, decreased hepatic lipid accumulation and thiobarbituric acid reactive substance (TBARS) levels, and increased antioxidative enzyme activities, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Microarray analysis of hepatic gene expression profiles showed that myricetin significantly altered the expression profiles of 177 genes which were involved in 12 biological pathways, including the peroxisome proliferator activated receptor (PPAR) signaling pathway and peroxisome. Further research indicated that myricetin elevated hepatic nuclear Nrf2 translocation, increased the protein expression of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1), reduced the protein expression of PPARγ, and normalized the expressions of genes that were involved in peroxisome and the PPAR signaling pathway. Our data indicated that myricetin might represent an effective therapeutic agent to treat HFD-induced hepatic steatosis via activating the Nrf2 pathway and the PPAR signaling pathway.
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Affiliation(s)
- Shu-Fang Xia
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China.
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - Guo-Wei Le
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - Peng Wang
- COFCO Corporation Oilseeds Processing Division, Beijing 100020, China.
| | - Yu-Yu Qiu
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China.
| | - Yu-Yu Jiang
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China.
| | - Xue Tang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
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16
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Futatsugi K, Huard K, Kung DW, Pettersen JC, Flynn DA, Gosset JR, Aspnes GE, Barnes RJ, Cabral S, Dowling MS, Fernando DP, Goosen TC, Gorczyca WP, Hepworth D, Herr M, Lavergne S, Li Q, Niosi M, Orr STM, Pardo ID, Perez SM, Purkal J, Schmahai TJ, Shirai N, Shoieb AM, Zhou J, Goodwin B. Small structural changes of the imidazopyridine diacylglycerol acyltransferase 2 (DGAT2) inhibitors produce an improved safety profile. MEDCHEMCOMM 2016; 8:771-779. [PMID: 30108796 DOI: 10.1039/c6md00564k] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 11/08/2016] [Indexed: 11/21/2022]
Abstract
Small molecule DGAT2 inhibitors have shown promise for the treatment of metabolic diseases in preclinical models. Herein, we report the first toxicological evaluation of imidazopyridine-based DGAT2 inhibitors and show that the arteriopathy associated with imidazopyridine 1 can be mitigated with small structural modifications, and is thus not mechanism related.
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Affiliation(s)
- K Futatsugi
- Pfizer Inc. Medicine Design , 610 Main Street , Cambridge , Massachusetts , 02155 USA .
| | - K Huard
- Pfizer Inc. Medicine Design , 610 Main Street , Cambridge , Massachusetts , 02155 USA .
| | - D W Kung
- Pfizer Inc. Medicine Design , Eastern Point Road , Groton , Connecticut , 06340 USA .
| | - J C Pettersen
- Pfizer Inc. Drug Safety Research and Development , Eastern Point Road , Groton , Connecticut , 06340 USA
| | - D A Flynn
- Pfizer Inc. Drug Safety Research and Development , Eastern Point Road , Groton , Connecticut , 06340 USA
| | - J R Gosset
- Pfizer Inc. Medicine Design , 610 Main Street , Cambridge , Massachusetts , 02155 USA .
| | - G E Aspnes
- Pfizer Inc. Medicine Design , 610 Main Street , Cambridge , Massachusetts , 02155 USA .
| | - R J Barnes
- Pfizer Inc. Drug Safety Research and Development , Eastern Point Road , Groton , Connecticut , 06340 USA
| | - S Cabral
- Pfizer Inc. Medicine Design , Eastern Point Road , Groton , Connecticut , 06340 USA .
| | - M S Dowling
- Pfizer Inc. Medicine Design , Eastern Point Road , Groton , Connecticut , 06340 USA .
| | - D P Fernando
- Pfizer Inc. Medicine Design , Eastern Point Road , Groton , Connecticut , 06340 USA .
| | - T C Goosen
- Pfizer Inc. Medicine Design , Eastern Point Road , Groton , Connecticut , 06340 USA .
| | - W P Gorczyca
- Pfizer Inc. Drug Safety Research and Development , Eastern Point Road , Groton , Connecticut , 06340 USA
| | - D Hepworth
- Pfizer Inc. Medicine Design , 610 Main Street , Cambridge , Massachusetts , 02155 USA .
| | - M Herr
- Pfizer Inc. Medicine Design , Eastern Point Road , Groton , Connecticut , 06340 USA .
| | - S Lavergne
- Pfizer Inc. Medicine Design , Eastern Point Road , Groton , Connecticut , 06340 USA .
| | - Q Li
- Pfizer Inc. Medicine Design , Eastern Point Road , Groton , Connecticut , 06340 USA .
| | - M Niosi
- Pfizer Inc. Medicine Design , Eastern Point Road , Groton , Connecticut , 06340 USA .
| | - S T M Orr
- Pfizer Inc. Medicine Design , Eastern Point Road , Groton , Connecticut , 06340 USA .
| | - I D Pardo
- Pfizer Inc. Drug Safety Research and Development , Eastern Point Road , Groton , Connecticut , 06340 USA
| | - S M Perez
- Pfizer Inc. Cardiovascular and Metabolic Disease Research Unit , 610 Main Street , Cambridge , Massachusetts , 02155 USA
| | - J Purkal
- Pfizer Inc. Cardiovascular and Metabolic Disease Research Unit , 610 Main Street , Cambridge , Massachusetts , 02155 USA
| | - T J Schmahai
- Pfizer Inc. Drug Safety Research and Development , Eastern Point Road , Groton , Connecticut , 06340 USA
| | - N Shirai
- Pfizer Inc. Drug Safety Research and Development , Eastern Point Road , Groton , Connecticut , 06340 USA
| | - A M Shoieb
- Pfizer Inc. Drug Safety Research and Development , Eastern Point Road , Groton , Connecticut , 06340 USA
| | - J Zhou
- Pfizer Inc. Drug Safety Research and Development , Eastern Point Road , Groton , Connecticut , 06340 USA
| | - B Goodwin
- Pfizer Inc. Cardiovascular and Metabolic Disease Research Unit , 610 Main Street , Cambridge , Massachusetts , 02155 USA
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17
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Diacylglycerol acyltransferase-2 and monoacylglycerol acyltransferase-2 are ubiquitinated proteins that are degraded by the 26S proteasome. Biochem J 2016; 473:3621-3637. [DOI: 10.1042/bcj20160418] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 08/16/2016] [Indexed: 01/20/2023]
Abstract
Acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT)-2 is one of the two DGAT enzymes that catalyzes the synthesis of triacylglycerol, which is an important form of stored energy for eukaryotic organisms. There is currently limited information available regarding how DGAT2 and triacylglycerol synthesis are regulated. Recent studies have indicated that DGAT2 can be regulated by changes in gene expression. How DGAT2 is regulated post-transcriptionally remains less clear. In this study, we demonstrated that DGAT2 is a very unstable protein and is rapidly degraded in an ubiquitin-dependent manner via the proteasome. Many of the 25 lysines present in DGAT2 appeared to be involved in promoting its degradation. However, the six C-terminal lysines were the most important in regulating stability. We also demonstrated that acyl-CoA:monoacylglycerol acyltransferase (MGAT)-2, an enzyme with extensive sequence homology to DGAT2 that catalyzes the synthesis of diacylglycerol, was also ubiquitinated. However, MGAT2 was found to be much more stable than DGAT2. Interestingly, when co-expressed, MGAT2 appeared to stabilize DGAT2. Finally, we found that both DGAT2 and MGAT2 are substrates of the endoplasmic reticulum-associated degradation pathway.
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18
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Lam T, Harmancey R, Vasquez H, Gilbert B, Patel N, Hariharan V, Lee A, Covey M, Taegtmeyer H. Reversal of intramyocellular lipid accumulation by lipophagy and a p62-mediated pathway. Cell Death Discov 2016; 2:16061. [PMID: 27625792 PMCID: PMC4993124 DOI: 10.1038/cddiscovery.2016.61] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 06/19/2016] [Indexed: 12/16/2022] Open
Abstract
We have previously observed the reversal of lipid droplet deposition in skeletal muscle of morbidly obese patients following bariatric surgery. We now investigated whether activation of autophagy is the mechanism underlying this observation. For this purpose, we incubated rat L6 myocytes over a period of 6 days with long-chain fatty acids (an equimolar, 1.0 mM, mixture of oleate and palmitate in the incubation medium). At day 6, the autophagic inhibitor (bafilomycin A1, 200 nM) and the autophagic activator (rapamycin, 1 μM) were added separately or in combination for 48 h. Intracellular triglyceride (TG) accumulation was visualized and quantified colorimetrically. Protein markers of autophagic flux (LC3 and p62) and cell death (caspase-3 cleavage) were measured by immunoblotting. Inhibition of autophagy by bafilomycin increased TG accumulation and also increased lipid-mediated cell death. Conversely, activation of autophagy by rapamycin reduced both intracellular lipid accumulation and cell death. Unexpectedly, treatment with both drugs added simultaneously resulted in decreased lipid accumulation. In this treatment group, immunoblotting revealed p62 degradation (autophagic flux), immunofluorescence revealed the colocalization of p62 with lipid droplets, and co-immunoprecipitation confirmed the interaction of p62 with ADRP (adipose differentiation-related protein), a lipid droplet membrane protein. Thus the association of p62 with lipid droplet turnover suggests a novel pathway for the breakdown of lipid droplets in muscle cells. In addition, treatment with rapamycin and bafilomycin together also suggested the export of TG into the extracellular space. We conclude that lipophagy promotes the clearance of lipids from myocytes and switches to an alternative, p62-mediated, lysosomal-independent pathway in the context of chronic lipid overload (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001).
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Affiliation(s)
- T Lam
- Internal Medicine/Cardiology, McGovern Medical School at The University of Texas Health Science Center at Houston, TX, USA
| | - R Harmancey
- University of Mississippi School of Medicine, Jackson, MS, USA
| | - H Vasquez
- Internal Medicine/Cardiology, McGovern Medical School at The University of Texas Health Science Center at Houston, TX, USA
| | - B Gilbert
- Internal Medicine/Cardiology, McGovern Medical School at The University of Texas Health Science Center at Houston, TX, USA
| | - N Patel
- Internal Medicine/Cardiology, McGovern Medical School at The University of Texas Health Science Center at Houston, TX, USA
| | | | - A Lee
- Keck School of Medicine of USC, Los Angeles, CA, USA
| | - M Covey
- Internal Medicine/Cardiology, McGovern Medical School at The University of Texas Health Science Center at Houston, TX, USA
| | - H Taegtmeyer
- Internal Medicine/Cardiology, McGovern Medical School at The University of Texas Health Science Center at Houston, TX, USA
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19
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Derosa G, Maffioli P, Sahebkar A. Improvement of plasma adiponectin, leptin and C-reactive protein concentrations by orlistat: a systematic review and meta-analysis. Br J Clin Pharmacol 2016; 81:819-834. [PMID: 26717446 PMCID: PMC4834599 DOI: 10.1111/bcp.12874] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Revised: 12/07/2015] [Accepted: 12/14/2015] [Indexed: 12/27/2022] Open
Abstract
AIMS To conduct a systematic review and meta-analysis of relevant randomized clinical trials (RCTs) to ascertain the effect size of orlistat in modulating plasma levels of adipokines, ghrelin and C-reactive protein (CRP). METHODS Medline, SCOPUS, Web of Science and Google Scholar databases were searched. A random-effects model and the generic inverse variance method were used for quantitative data synthesis. Heterogeneity was quantitatively assessed using I(2) index. Sensitivity analyses were conducted using the one-study remove approach. Random-effects meta-regression was performed using unrestricted maximum likelihood method to evaluate the impact of duration of treatment, percentage change in body mass index (BMI) and baseline BMI values as potential confounders of the estimated effect size. RESULTS Meta-analysis suggested a significant increase in plasma levels of adiponectin [weighted mean difference (WMD): 19.18%, 95% confidence interval (CI): 5.80, 32.57, p = 0.005] and significant reductions in plasma levels of leptin (WMD: -13.24%, 95% CI: -20.69, -5.78, p = 0.001) and CRP (WMD: -11.52%, 95% CI: -16.55, -6.49, p < 0.001) following treatment with orlistat. In meta-regression, changes in plasma concentrations of adiponectin, leptin and CRP were associated with duration of treatment, but not with either change in BMI or baseline BMI values. CONCLUSION Orlistat is effective in increasing plasma concentrations of adiponectin and decreasing those of leptin and CRP.
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Affiliation(s)
- Giuseppe Derosa
- Department of Internal Medicine and TherapeuticsUniversity of Pavia and Fondazione IRCCS Policlinico S. MatteoPaviaItaly
- Center for the Study of Endocrine‐Metabolic Pathophysiology and Clinical ResearchUniversity of PaviaPaviaItaly
- Molecular Medicine LaboratoryUniversity of PaviaPaviaItaly
| | - Pamela Maffioli
- Department of Internal Medicine and TherapeuticsUniversity of Pavia and Fondazione IRCCS Policlinico S. MatteoPaviaItaly
- PhD School in Experimental MedicineUniversity of PaviaPaviaItaly
| | - Amirhossein Sahebkar
- Biotechnology Research CenterMashhad University of Medical SciencesMashhadIran
- Metabolic Research Centre, Royal Perth HospitalSchool of Medicine and Pharmacology, University of Western AustraliaPerthAustralia
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Parvaiz F, Manzoor S, Iqbal J, Sarkar-Dutta M, Imran M, Waris G. Hepatitis C virus NS5A promotes insulin resistance through IRS-1 serine phosphorylation and increased gluconeogenesis. World J Gastroenterol 2015; 21:12361-12369. [PMID: 26604643 PMCID: PMC4649119 DOI: 10.3748/wjg.v21.i43.12361] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 02/21/2014] [Accepted: 05/14/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the mechanisms of insulin resistance in human hepatoma cells expressing hepatitis C virus (HCV) nonstructural protein 5A (NS5A).
METHODS: The human hepatoma cell lines, Huh7 and Huh7.5, were infected with HCV or transiently-transfected with a vector expressing HCV NS5A. The effect of HCV NS5A on the status of the critical players involved in insulin signaling was analyzed using real-time quantitative polymerase chain reaction and Western blot assays. Data were analyzed using Graph Pad Prism version 5.0.
RESULTS: To investigate the effect of insulin treatment on the players involved in insulin signaling pathway, we analyzed the status of insulin receptor substrate-1 (IRS-1) phosphorylation in HCV infected cells or Huh7.5 cells transfected with an HCV NS5A expression vector. Our results indicated that there was an increased phosphorylation of IRS-1 (Ser307) in HCV infected or NS5A transfected Huh7.5 cells compared to their respective controls. Furthermore, an increased phosphorylation of Akt (Ser473) was observed in HCV infected and NS5A transfected cells compared to their mock infected cells. In contrast, we observed decreased phosphorylation of Akt Thr308 phosphorylation in HCV NS5A transfected cells. These results suggest that Huh7.5 cells either infected with HCV or ectopically expressing HCV NS5A alone have the potential to induce insulin resistance by the phosphorylation of IRS-1 at serine residue (Ser307) followed by decreased phosphorylation of Akt Thr308, Fox01 Ser256 and GSK3β Ser9, the downstream players of the insulin signaling pathway. Furthermore, increased expression of PECK and glucose-6-phosphatase, the molecules involved in gluconeogenesis, in HCV NS5A transfected cells was observed.
CONCLUSION: Taken together, our results suggest the role of HCV NS5A in the induction of insulin resistance by modulating various cellular targets involved in the insulin signaling pathway.
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Huard K, Londregan AT, Tesz G, Bahnck KB, Magee TV, Hepworth D, Polivkova J, Coffey SB, Pabst BA, Gosset JR, Nigam A, Kou K, Sun H, Lee K, Herr M, Boehm M, Carpino PA, Goodwin B, Perreault C, Li Q, Jorgensen CC, Tkalcevic GT, Subashi TA, Ahn K. Discovery of Selective Small Molecule Inhibitors of Monoacylglycerol Acyltransferase 3. J Med Chem 2015; 58:7164-72. [PMID: 26258602 DOI: 10.1021/acs.jmedchem.5b01008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Inhibition of triacylglycerol (TAG) biosynthetic enzymes has been suggested as a promising strategy to treat insulin resistance, diabetes, dyslipidemia, and hepatic steatosis. Monoacylglycerol acyltransferase 3 (MGAT3) is an integral membrane enzyme that catalyzes the acylation of both monoacylglycerol (MAG) and diacylglycerol (DAG) to generate DAG and TAG, respectively. Herein, we report the discovery and characterization of the first selective small molecule inhibitors of MGAT3. Isoindoline-5-sulfonamide (6f, PF-06471553) selectively inhibits MGAT3 with high in vitro potency and cell efficacy. Because the gene encoding MGAT3 (MOGAT3) is found only in higher mammals and humans, but not in rodents, a transgenic mouse model expressing the complete human MOGAT3 was used to characterize the effects of 6f in vivo. In the presence of a combination of diacylglycerol acyltransferases 1 and 2 (DGAT1 and DGAT2) inhibitors, an oral administration of 6f exhibited inhibition of the incorporation of deuterium-labeled glycerol into TAG in this mouse model. The availability of a potent and selective chemical tool and a humanized mouse model described in this report should facilitate further dissection of the physiological function of MGAT3 and its role in lipid homeostasis.
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Affiliation(s)
- Kim Huard
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Allyn T Londregan
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Gregory Tesz
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Kevin B Bahnck
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Thomas V Magee
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - David Hepworth
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Jana Polivkova
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Steven B Coffey
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Brandon A Pabst
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - James R Gosset
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Anu Nigam
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Kou Kou
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Hao Sun
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Kyuha Lee
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Michael Herr
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Markus Boehm
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Philip A Carpino
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Bryan Goodwin
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Christian Perreault
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Qifang Li
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Csilla C Jorgensen
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - George T Tkalcevic
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Timothy A Subashi
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
| | - Kay Ahn
- Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.,Worldwide Medicinal Chemistry, ∥Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States
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22
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Reducing Liver Fat by Low Carbohydrate Caloric Restriction Targets Hepatic Glucose Production in Non-Diabetic Obese Adults with Non-Alcoholic Fatty Liver Disease. J Clin Med 2015; 3:1050-63. [PMID: 25411646 PMCID: PMC4234060 DOI: 10.3390/jcm3031050] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) impairs liver functions, the organ responsible for the regulation of endogenous glucose production and thus plays a key role in glycemic homeostasis. Therefore, interventions designed to normalize liver fat content are needed to improve glucose metabolism in patients affected by NAFLD such as obesity. Objective: this investigation is designed to determine the effects of caloric restriction on hepatic and peripheral glucose metabolism in obese humans with NAFLD. Methods: eight non-diabetic obese adults were restricted for daily energy intake (800 kcal) and low carbohydrate (<10%) for 8 weeks. Body compositions, liver fat and hepatic glucose production (HGP) and peripheral glucose disposal before and after the intervention were determined. Results: the caloric restriction reduced liver fat content by 2/3 (p = 0.004). Abdominal subcutaneous and visceral fat, body weight, BMI, waist circumference and fasting plasma triglyceride and free fatty acid concentrations all significantly decreased (p < 0.05). The suppression of post-load HGP was improved by 22% (p = 0.002) whereas glucose disposal was not affected (p = 0.3). Fasting glucose remained unchanged and the changes in the 2-hour plasma glucose and insulin concentration were modest and statistically insignificant (p > 0.05). Liver fat is the only independent variable highly correlated to HGP after the removal of confounders. Conclusion: NAFLD impairs HGP but not peripheral glucose disposal; low carbohydrate caloric restriction effectively lowers liver fat which appears to directly correct the HGP impairment.
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23
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Hung YH, Linden MA, Gordon A, Rector RS, Buhman KK. Endurance exercise training programs intestinal lipid metabolism in a rat model of obesity and type 2 diabetes. Physiol Rep 2015; 3:3/1/e12232. [PMID: 25602012 PMCID: PMC4387752 DOI: 10.14814/phy2.12232] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Endurance exercise has been shown to improve metabolic outcomes in obesity and type 2 diabetes; however, the physiological and molecular mechanisms for these benefits are not completely understood. Although endurance exercise has been shown to decrease lipogenesis, promote fatty acid oxidation (FAO), and increase mitochondrial biosynthesis in adipose tissue, muscle, and liver, its effects on intestinal lipid metabolism remain unknown. The absorptive cells of the small intestine, enterocytes, mediate the highly efficient absorption and processing of nutrients, including dietary fat for delivery throughout the body. We investigated how endurance exercise altered intestinal lipid metabolism in obesity and type 2 diabetes using Otsuka Long‐Evans Tokushima Fatty (OLETF) rats. We assessed mRNA levels of genes associated with intestinal lipid metabolism in nonhyperphagic, sedentary Long‐Evans Tokushima Otsuka (LETO) rats (L‐Sed), hyperphagic, sedentary OLETF rats (O‐Sed), and endurance exercised OLETF rats (O‐EndEx). O‐Sed rats developed hyperphagia‐induced obesity (HIO) and type 2 diabetes compared with L‐Sed rats. O‐EndEx rats gained significantly less weight and fat pad mass, and had improved serum metabolic parameters without change in food consumption compared to O‐Sed rats. Endurance exercise resulted in dramatic up‐regulation of a number of genes in intestinal lipid metabolism and mitochondrial content compared with sedentary rats. Overall, this study provides evidence that endurance exercise programs intestinal lipid metabolism, likely contributing to its role in improving metabolic outcomes in obesity and type 2 diabetes. Endurance exercise has been shown to improve metabolic outcomes in obesity and type 2 diabetes; however, the physiological and molecular mechanisms for these benefits are not completely understood. Although endurance exercise has been shown to decrease lipogenesis, promote fatty acid oxidation (FAO), and increase mitochondrial biosynthesis in adipose tissue, muscle, and liver, its effects on intestinal lipid metabolism remain unknown. Endurance exercise resulted in dramatic up‐regulation of a number of genes in intestinal lipid metabolism and mitochondrial content compared with sedentary rats. Overall, this study provides evidence that endurance exercise programs intestinal lipid metabolism, likely contributing to its role in improving metabolic outcomes in obesity and type 2 diabetes.
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Affiliation(s)
- Yu-Han Hung
- Department of Nutrition Science, Purdue University, West Lafayette, Indiana
| | - Melissa A Linden
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri Research Service, Harry S Truman Memorial Veterans Hospital, Columbia, Missouri
| | - Alicia Gordon
- Department of Clinical Medicine, University of Dublin, Dublin, Ireland School of Biological Sciences, Dublin Institute of Technology, Dublin, Ireland
| | - R Scott Rector
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri Research Service, Harry S Truman Memorial Veterans Hospital, Columbia, Missouri Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, Missouri
| | - Kimberly K Buhman
- Department of Nutrition Science, Purdue University, West Lafayette, Indiana
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24
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Wells SA. Quantification of Hepatic Fat and Iron with Magnetic Resonance Imaging. Magn Reson Imaging Clin N Am 2014; 22:397-416. [PMID: 25086936 DOI: 10.1016/j.mric.2014.04.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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25
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Kurek K, Piotrowska DM, Wiesiołek-Kurek P, Łukaszuk B, Chabowski A, Górski J, Zendzian-Piotrowska M. Inhibition of ceramide de novo synthesis reduces liver lipid accumulation in rats with nonalcoholic fatty liver disease. Liver Int 2014; 34:1074-83. [PMID: 24106929 DOI: 10.1111/liv.12331] [Citation(s) in RCA: 100] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Accepted: 09/06/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is an insulin resistance-related hepatic disorder which can transform to cirrhosis. Insulin resistance deregulates hepatic lipid metabolism, leading to accumulation of cytotoxic lipids including ceramide and diacylglycerols. Myriocin, obtained from fungi traditionally used in Chinese medicine in an effort to attain eternal youth, is a potent pharmacological inhibitor of ceramide de novo synthesis. We examined whether inhibition of ceramide de novo synthesis with myriocin ameliorate hepatic lipid accumulation and reverse NAFLD. METHODS The experiment was carried out on male Wistar rats. The animals were divided into four groups: (i) control group, fed standard rodent diet, (ii) group, fed standard diet also treated with myriocin for 7 days, (iii) group, fed high-fat diet for 5 weeks, (iv) group, fed high-fat diet and treated with myriocin. In liver samples sphingolipids: ceramide, sphingosine and sphingosine-1-phosphatate and neutral lipids, such as diacylglycerols and triacylglycerols were measured. In peripheral blood samples, glucose and insulin levels and aminotransferases activities were measured. RESULTS High-fat diet feeding caused NAFLD, confirmed by histological assessment, with increased hepatic lipids accumulation and whole-body insulin resistance. After treating with inhibitor of ceramide de novo synthesis, decrease in hepatic ceramide and other toxic lipids were noticed. Moreover, histological analysis of liver samples revealed that inhibition of ceramide de novo synthesis reduced hepatic steatosis. CONCLUSIONS Inhibition of ceramide de novo synthesis reduced hepatic lipid accumulation in rats with NAFLD, this led to amelioration of hepatic steatosis.
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Affiliation(s)
- Krzysztof Kurek
- Department of Physiology, Medical University of Bialystok, Białystok, Poland
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26
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Naik R, Obiang-Obounou BW, Kim M, Choi Y, Lee HS, Lee K. Therapeutic Strategies for Metabolic Diseases: Small-Molecule Diacylglycerol Acyltransferase (DGAT) Inhibitors. ChemMedChem 2014; 9:2410-24. [DOI: 10.1002/cmdc.201402069] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2014] [Indexed: 11/07/2022]
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27
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Ozguven I, Ersoy B, Ozguven A, Ozkol M, Onur E. Factors affecting carotid intima media thickness predicts early atherosclerosis in overweight and obese adolescents. Obes Res Clin Pract 2013; 4:e1-e82. [PMID: 24345625 DOI: 10.1016/j.orcp.2009.06.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2009] [Revised: 06/15/2009] [Accepted: 06/16/2009] [Indexed: 11/24/2022]
Abstract
SUMMARY OBJECTIVE Aims of this study were to compare serum leptin levels, atherosclerotic markers and carotid intima media thickness (IMT) among the overweight, obese and normal weight healthy adolescents and to investigate the association of carotid IMT with leptin and atherosclerotic markers in adolescence. METHODS Seventy obese-overweight adolescents (27 of them obese, 43 of them overweight) and 72 two normal weight adolescents aged 14-18 years were included in this study. Leptin and homocysteine levels and lipid profiles were determined and carotid IMT were measured in all adolescents. Subjects were evaluated as obese-overweight and normal weight and obese, overweight and normal weight. RESULTS Carotid IMT was significantly different among the overweight adolescents, obese adolescents and the control group (p < 0.001). Leptin levels were significantly higher in obese-overweight adolescents compared to the control group (p < 0.001). Apolipoprotein (Apo) B levels were significantly higher in obese adolescents than the overweight ones and the control group (p < 0.016). There were significantly positive correlations of carotid IMT with leptin, homocysteine and Apo B levels (p < 0.05, r = 0.33, 0.28, 021, respectively). The factors associated with carotid IMT were leptin and ApoB levels (β = 0.632, p < 0.04, β = 0.264, p = 0.019, respectively). CONCLUSION Subclinical atherosclerosis determined by carotid IMT begins in overweight adolescents. Elevated leptin and Apo B levels are independent predictors of subclinical atherosclerosis. Leptin resistance, which is related to subclinical atherosclerosis, also begins in overweight adolescents. High Apo B levels, which promote development of atherosclerosis are more prominent in obese adolescents than other groups. For these reasons, all necessary precautions should be taken in overweight adolescents to prevent atherosclerosis as well as in obese adolescents.
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Affiliation(s)
- Isıl Ozguven
- Celal Bayar University, Medical School, Department of Clinical Biochemistry, Manisa, Turkey
| | - Betul Ersoy
- Celal Bayar University, Medical School, Department of Clinical Biochemistry, Manisa, Turkey.
| | - Aykan Ozguven
- Celal Bayar University, Medical School, Department of Clinical Biochemistry, Manisa, Turkey
| | - Mine Ozkol
- Celal Bayar University, Medical School, Department of Clinical Biochemistry, Manisa, Turkey
| | - Ece Onur
- Celal Bayar University, Medical School, Department of Clinical Biochemistry, Manisa, Turkey
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28
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Yadav A, Kataria MA, Saini V, Yadav A. Role of leptin and adiponectin in insulin resistance. Clin Chim Acta 2012; 417:80-4. [PMID: 23266767 DOI: 10.1016/j.cca.2012.12.007] [Citation(s) in RCA: 440] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Revised: 11/30/2012] [Accepted: 12/02/2012] [Indexed: 12/21/2022]
Abstract
Adipose tissue is a major source of energy for the human body. It is also a source of major adipocytokines adiponectin and leptin. Insulin resistance is a condition in which insulin action is impaired in adipose tissue and is more strongly linked to intra-abdominal fat than to fat in other depots. The expression of adiponectin decreases with increase in the adiposity. Adiponectin mediates insulin-sensitizing effect through binding to its receptors AdipoR1 and AdipoR2, leading to activation of adenosine monophosphate dependent kinase (AMPK), PPAR-α, and presumably other yet-unknown signalling pathways. Weight loss significantly elevates plasma adiponectin levels. Reduction of adiponectin has been associated with insulin resistance, dyslipidemia, and atherosclerosis in humans. The other major adipokine is leptin. Leptin levels increase in obesity and subcutaneous fat has been a major determinant of circulating leptin levels. The leptin signal is transmitted by the Janus kinase, signal transducer and activator of transcription ((JAK-STAT) pathway. The net action of leptin is to inhibit appetite, stimulate thermogenesis, enhance fatty acid oxidation, decrease glucose, and reduce body weight and fat.
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Affiliation(s)
- Amita Yadav
- Department of Biochemistry, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India.
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29
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Srivastava RAK, Pinkosky SL, Filippov S, Hanselman JC, Cramer CT, Newton RS. AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases. J Lipid Res 2012; 53:2490-514. [PMID: 22798688 DOI: 10.1194/jlr.r025882] [Citation(s) in RCA: 220] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor of energy metabolism at the cellular as well as whole-body level. It is activated by low energy status that triggers a switch from ATP-consuming anabolic pathways to ATP-producing catabolic pathways. AMPK is involved in a wide range of biological activities that normalizes lipid, glucose, and energy imbalances. These pathways are dysregulated in patients with metabolic syndrome (MetS), which represents a clustering of major cardiovascular risk factors including diabetes, lipid abnormalities, and energy imbalances. Clearly, there is an unmet medical need to find a molecule to treat alarming number of patients with MetS. AMPK, with multifaceted activities in various tissues, has emerged as an attractive drug target to manage lipid and glucose abnormalities and maintain energy homeostasis. A number of AMPK activators have been tested in preclinical models, but many of them have yet to reach to the clinic. This review focuses on the structure-function and role of AMPK in lipid, carbohydrate, and energy metabolism. The mode of action of AMPK activators, mechanism of anti-inflammatory activities, and preclinical and clinical findings as well as future prospects of AMPK as a drug target in treating cardio-metabolic disease are discussed.
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30
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Sanderson MC, Venable ME. A NOVEL ASSAY OF ACYL-COA:DIACYLGLYCEROL ACYLTRANSFERASE ACTIVITY UTILIZING FLUORESCENT SUBSTRATE(1). JOURNAL OF PHYCOLOGY 2012; 48:580-4. [PMID: 27011073 DOI: 10.1111/j.1529-8817.2012.01137.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
Common methods for assaying acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymatic activity rely upon radiolabeled substrates or product assay. We developed a novel assay that directly quantifies endogenous DGAT activity through the use of a fluorescently labeled substrate. We performed this assay with microsomal protein, 2-(6-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoyl-1-hexadecanoyl-sn-glycero-3-diacylglycerol (NBD-DAG), and oleoyl-CoA substrates. DGAT activity was analyzed in three species of algae as well as rat liver. The protocol proved to be sensitive and reliable. This assay may be used to facilitate research in the areas of biodiesel, oilseed crops, and triacylglycerol-related human pathologies.
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Affiliation(s)
- Matthew C Sanderson
- Department of Biology, Appalachian State University, 572 Rivers Street, Boone, NC 28608-2027, USA
| | - Mark E Venable
- Department of Biology, Appalachian State University, 572 Rivers Street, Boone, NC 28608-2027, USA
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31
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Uchida A, Whitsitt MC, Eustaquio T, Slipchenko MN, Leary JF, Cheng JX, Buhman KK. Reduced triglyceride secretion in response to an acute dietary fat challenge in obese compared to lean mice. Front Physiol 2012; 3:26. [PMID: 22375122 PMCID: PMC3285805 DOI: 10.3389/fphys.2012.00026] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2011] [Accepted: 02/03/2012] [Indexed: 11/13/2022] Open
Abstract
Obesity results in abnormally high levels of triglyceride (TG) storage in tissues such as liver, heart, and muscle, which disrupts their normal functions. Recently, we found that lean mice challenged with high levels of dietary fat store TGs in cytoplasmic lipid droplets in the absorptive cells of the intestine, enterocytes, and that this storage increases and then decreases over time after an acute dietary fat challenge. The goal of this study was to investigate the effects of obesity on intestinal TG metabolism. More specifically we asked whether TG storage in and secretion from the intestine are altered in obesity. We investigated these questions in diet-induced obese (DIO) and leptin-deficient (ob/ob) mice. We found greater levels of TG storage in the intestine of DIO mice compared to lean mice in the fed state, but similar levels of TG storage after a 6-h fast. In addition, we found similar TG storage in the intestine of lean and DIO mice at multiple time points after an acute dietary fat challenge. Surprisingly, we found remarkably lower TG secretion from both DIO and ob/ob mice compared to lean controls in response to an acute dietary fat challenge. Furthermore, we found altered mRNA levels for genes involved in regulation of intestinal TG metabolism in lean and DIO mice at 6 h fasting and in response to an acute dietary fat challenge. More specifically, we found that many of the genes related to TG synthesis, chylomicron synthesis, TG storage, and lipolysis were induced in response to an acute dietary fat challenge in lean mice, but this induction was not observed in DIO mice. In fact, we found a significant decrease in intestinal mRNA levels of genes related to lipolysis and fatty acid oxidation in DIO mice in response to an acute dietary fat challenge. Our findings demonstrate altered TG handling by the small intestine of obese compared to lean mice.
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Affiliation(s)
- Aki Uchida
- Interdisciplinary Life Science Program, Purdue University West Lafayette, IN, USA
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32
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Algahim MF, Sen S, Taegtmeyer H. Bariatric surgery to unload the stressed heart: a metabolic hypothesis. Am J Physiol Heart Circ Physiol 2012; 302:H1539-45. [PMID: 22307676 DOI: 10.1152/ajpheart.00626.2011] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Obesity is an independent risk factor for cardiovascular disease. Data from the Framingham Study have reported a higher incidence of heart failure in obese individuals compared with a normal cohort. The body initially copes with the abundance of fuel present in an obese milieu by storing it in adipose tissue. However, when the storage capacity is exceeded, the excess energy is taken up and stored ectopically as fat in vital organs such as the heart. Indeed, intramyocardial lipid overload is present in hearts of obese patients, as well as in hearts of animal models of obesity, and is associated with a distinct gene expression profile and cardiac dysfunction. By imposing a metabolic stress on the heart, obesity causes it to hypertrophy and ultimately to fail. Conventional measures to treat obesity include diet, exercise, and drugs. More recently, weight loss surgery (WLS) has achieved increasing prominence because of its ability to reduce the neurohumoral load, normalize metabolic dysregulation, and improve overall survival. The effects of WLS on systemic metabolic, neurohumoral, and hemodynamic parameters are well described and include an early normalization of serum glucose and insulin levels as well as reduction in blood pressure. WLS is also associated with reverse cardiac remodeling, regression of left ventricular hypertrophy, and improved left ventricular and right ventricular function. By targeting the source of the excess energy, we hypothesize that WLS improves contractile function by limiting exogenous substrate availability to the metabolically overloaded heart. These changes have also been found to be associated with increased levels of adiponectin and improved insulin sensitivity. Taken together, the sustained beneficial effects of WLS on left ventricular mass and function highlight the need to better understand the mechanism by which obesity regulates cardiovascular physiology.
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Affiliation(s)
- Mohamed F Algahim
- Division of Cardiology, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas 77030, USA
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Mori T, Kondo H, Hase T, Murase T. Dietary phospholipids ameliorate fructose-induced hepatic lipid and metabolic abnormalities in rats. J Nutr 2011; 141:2003-9. [PMID: 21940513 DOI: 10.3945/jn.111.143602] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Overconsumption of fructose results in hepatic dyslipidemia, which has a documented correlation with metabolic syndrome. We examined whether the ingestion of phospholipids (PL) from soybeans prevents fructose-induced metabolic abnormalities. Rats were fed either a fructose-free diet (C), a 60% fructose diet (F), or a 60% fructose plus 3% PL diet (F-PL) for 10 wk. At wk 8, plasma glucose concentrations after glucose loading were significantly higher in rats fed the F diet than in rats fed the C and F-PL diets, which did not differ from one another. The concentrations of hepatic TG, diglycerides, ceramides, and oleates in rats fed the F diet for 10 wk was significantly higher than those in rats fed the C diet. The increases were prevented by concurrent PL ingestion; concentrations did not differ between the F-PL and C groups. Dietary fructose increased the mRNA expression of SREBP1, ChREBP, and genes related to lipogenesis. PL completely inhibited these increases. Furthermore, reflecting the difference at the mRNA level, lipogenic enzyme activities were greater in rats fed the F diet than in rats fed the C diet, and PL ingestion suppressed the increased activities by fructose feeding. Treatment of cultured Hep-G2 cells with fructose for 24 h increased the levels of SREBP1 and ChREBP nuclear proteins, which were suppressed by culture with purified PL components, especially phosphatidylethanolamine and phosphatidylinositol. These findings indicate that PL prevents fructose-induced metabolic abnormalities in association with alterations of the hepatic lipid profile by inhibiting de novo lipogenesis.
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Affiliation(s)
- Takuya Mori
- Biological Science Laboratories, Kao Corporation, Tochigi, Japan
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Turpin SM, Hoy AJ, Brown RD, Rudaz CG, Honeyman J, Matzaris M, Watt MJ. Adipose triacylglycerol lipase is a major regulator of hepatic lipid metabolism but not insulin sensitivity in mice. Diabetologia 2011; 54:146-56. [PMID: 20842343 DOI: 10.1007/s00125-010-1895-5] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2010] [Accepted: 08/04/2010] [Indexed: 01/04/2023]
Abstract
AIMS/HYPOTHESIS Hepatic steatosis is characterised by excessive triacylglycerol accumulation and is strongly associated with insulin resistance. An inability to efficiently mobilise liver triacylglycerol may be a key event mediating hepatic steatosis. Adipose triacylglycerol lipase (ATGL) is a key triacylglycerol lipase in the liver and we hypothesised that liver-specific overproduction of ATGL would reduce steatosis and enhance insulin action in obese rodents. METHODS Studies of fatty acid metabolism were conducted in primary hepatocytes isolated from wild-type and Atgl (also known as Pnpla2)⁻(/)⁻ mice. An ATGL adenovirus was utilised to overproduce ATGL in the livers of obese insulin-resistant C57Bl/6 mice (Ad-ATGL). Blood chemistry, hepatic lipid content and insulin sensitivity were assessed in mice. RESULTS Triacylglycerol content was increased in Atgl⁻(/)⁻ hepatocytes and was associated with increased fatty acid uptake and impaired fatty acid oxidation. ATGL adenovirus administration in obese mice increased the production of hepatic ATGL protein and reduced triacylglycerol, diacylglycerol and ceramide content in the liver. Overproduction of ATGL improved insulin signal transduction in the liver but did not affect fasting glycaemia or insulinaemia. Inflammatory signalling was not suppressed by ATGL overproduction. While ATGL overproduction increased plasma non-esterified fatty acids, neither lipid deposition nor insulin-stimulated glucose uptake were affected in skeletal muscle. CONCLUSIONS/INTERPRETATION Liver ATGL overproduction decreases hepatic steatosis and mildly enhances liver insulin sensitivity. These effects are not sufficient to improve fasting glycaemia or insulinaemia in rodent obesity.
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Affiliation(s)
- S M Turpin
- Department of Physiology, Monash University, Clayton, Victoria, Australia
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McFie PJ, Stone SL, Banman SL, Stone SJ. Topological orientation of acyl-CoA:diacylglycerol acyltransferase-1 (DGAT1) and identification of a putative active site histidine and the role of the n terminus in dimer/tetramer formation. J Biol Chem 2010; 285:37377-87. [PMID: 20876538 DOI: 10.1074/jbc.m110.163691] [Citation(s) in RCA: 115] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Acyl CoA:diacylglycerol acyltransferase (DGAT) is an integral membrane protein of the endoplasmic reticulum that catalyzes the synthesis of triacylglycerols. Two DGAT enzymes have been identified (DGAT1 and DGAT2) with unique roles in lipid metabolism. DGAT1 is a multifunctional acyltransferase capable of synthesizing diacylglycerol, retinyl, and wax esters in addition to triacylglycerol. Here, we report the membrane topology for murine DGAT1 using protease protections assays and indirect immunofluorescence in conjunction with selective permeabilization of cellular membranes. Topology models based on prediction algorithms suggested that DGAT1 had eight transmembrane domains. In contrast, our data indicate that DGAT1 has three transmembrane domains with the N terminus oriented toward the cytosol. The C-terminal region of DGAT1, which accounts for ∼50% of the protein, is present in the endoplasmic reticulum lumen and contains a highly conserved histidine residue (His-426) that may be part of the active site. Mutagenesis of His-426 to alanine impaired the ability of DGAT1 to synthesize triacylglycerols as well as retinyl and wax esters in an in vitro acyltransferase assay. Finally, we show that the N-terminal domain of DGAT1 is not required for the catalytic activity of DGAT1 but, instead, may be involved in regulating enzyme activity and dimer/tetramer formation.
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Affiliation(s)
- Pamela J McFie
- Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
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Moreno M, Lombardi A, Silvestri E, Senese R, Cioffi F, Goglia F, Lanni A, de Lange P. PPARs: Nuclear Receptors Controlled by, and Controlling, Nutrient Handling through Nuclear and Cytosolic Signaling. PPAR Res 2010; 2010:435689. [PMID: 20814433 PMCID: PMC2929508 DOI: 10.1155/2010/435689] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2010] [Revised: 05/31/2010] [Accepted: 06/30/2010] [Indexed: 12/31/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs), which are known to regulate lipid homeostasis, are tightly controlled by nutrient availability, and they control nutrient handling. In this paper, we focus on how nutrients control the expression and action of PPARs and how cellular signaling events regulate the action of PPARs in metabolically active tissues (e.g., liver, skeletal muscle, heart, and white adipose tissue). We address the structure and function of the PPARs, and their interaction with other nuclear receptors, including PPAR cross-talk. We further discuss the roles played by different kinase pathways, including the extracellular signal-regulated kinases/mitogen-activated protein kinase (ERK MAPK), AMP-activated protein kinase (AMPK), Akt/protein kinase B (Akt/PKB), and the NAD+-regulated protein deacetylase SIRT1, serving to control the activity of the PPARs themselves as well as that of a key nutrient-related PPAR coactivator, PPARgamma coactivator-1alpha (PGC-1alpha). We also highlight how currently applied nutrigenomic strategies will increase our understanding on how nutrients regulate metabolic homeostasis through PPAR signaling.
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Affiliation(s)
- Maria Moreno
- Dipartimento di Scienze Biologiche ed Ambientali, Università degli Studi del Sannio, Via Port'Arsa 11, 82100 Benevento, Italy
| | - Assunta Lombardi
- Dipartimento delle Scienze Biologiche, Sezione Fisiologia ed Igiene, Università degli Studi di Napoli “Federico II”, Via Mezzocannone 8, 80134 Napoli, Italy
| | - Elena Silvestri
- Dipartimento di Scienze Biologiche ed Ambientali, Università degli Studi del Sannio, Via Port'Arsa 11, 82100 Benevento, Italy
| | - Rosalba Senese
- Dipartimento di Scienze della Vita, Seconda Università degli Studi di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
| | - Federica Cioffi
- Dipartimento di Scienze della Vita, Seconda Università degli Studi di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
| | - Fernando Goglia
- Dipartimento di Scienze Biologiche ed Ambientali, Università degli Studi del Sannio, Via Port'Arsa 11, 82100 Benevento, Italy
| | - Antonia Lanni
- Dipartimento di Scienze della Vita, Seconda Università degli Studi di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
| | - Pieter de Lange
- Dipartimento di Scienze della Vita, Seconda Università degli Studi di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
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Bayol SA, Simbi BH, Fowkes RC, Stickland NC. A maternal "junk food" diet in pregnancy and lactation promotes nonalcoholic Fatty liver disease in rat offspring. Endocrinology 2010; 151:1451-61. [PMID: 20207831 PMCID: PMC2850233 DOI: 10.1210/en.2009-1192] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
With rising obesity rates, nonalcoholic fatty liver disease is predicted to become the main cause of chronic liver disease in the next decades. Rising obesity prevalence is attributed to changes in dietary habits with increased consumption of palatable junk foods, but maternal malnutrition also contributes to obesity in progeny. This study examines whether a maternal junk food diet predisposes offspring to nonalcoholic fatty liver disease. The 144 rat offspring were fed either a balanced chow diet alone or with palatable junk foods rich in energy, fat, sugar, and/or salt during gestation, lactation, and/or after weaning up to the end of adolescence. Offspring fed junk food throughout the study exhibited exacerbated hepatic steatosis, hepatocyte ballooning, and oxidative stress response compared with offspring given free access to junk food after weaning only. These offspring also displayed sex differences in their hepatic molecular metabolic adaptation to diet-induced obesity with increased expression of genes associated with insulin sensitivity, de novo lipogenesis, lipid oxidation, and antiinflammatory properties in males, whereas the gene expression profile in females was indicative of hepatic insulin resistance. Hepatic inflammation and fibrosis were not detected indicating that offspring had not developed severe steatohepatitis by the end of adolescence. Hepatic steatosis and increased oxidative stress response also occurred in offspring born to junk food-fed mothers switched to a balanced chow diet from weaning, highlighting a degree of irreversibility. This study shows that a maternal junk food diet in pregnancy and lactation contributes to the development of nonalcoholic fatty liver disease in offspring.
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Affiliation(s)
- Stéphanie A Bayol
- Department of Veterinary Basic Sciences, The Royal Veterinary College, Royal College Street, London NW1 0TU, United Kingdom.
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Larter CZ, Chitturi S, Heydet D, Farrell GC. A fresh look at NASH pathogenesis. Part 1: the metabolic movers. J Gastroenterol Hepatol 2010; 25:672-90. [PMID: 20492324 DOI: 10.1111/j.1440-1746.2010.06253.x] [Citation(s) in RCA: 124] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The strong relationship between over-nutrition, central obesity, insulin resistance/metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) suggest pathogenic interactions, but key questions remain. NAFLD starts with over-nutrition, imbalance between energy input and output for which the roles of genetic predisposition and environmental factors (diet, physical activity) are being redefined. Regulation of energy balance operates at both central nervous system and peripheral sites, including adipose and liver. For example, the endocannabinoid system could potentially be modulated to provide effective pharmacotherapy of NAFLD. The more profound the metabolic abnormalities complicating over-nutrition (glucose intolerance, hypoadiponectinemia, metabolic syndrome), the more likely is NAFLD to take on its progressive guise of non-alcoholic steatohepatitis (NASH). Interactions between steatosis and insulin resistance, visceral adipose expansion and subcutaneous adipose failure (with insulin resistance, inflammation and hypoadiponectinemia) trigger amplifying mechanisms for liver disease. Thus, transition from simple steatosis to NASH could be explained by unmitigated hepatic lipid partitioning with failure of local adaptive mechanisms leading to lipotoxicity. In part one of this review, we discuss newer concepts of appetite and metabolic regulation, bodily lipid distribution, hepatic lipid turnover, insulin resistance and adipose failure affecting adiponectin secretion. We review evidence that NASH only occurs when over-nutrition is complicated by insulin resistance and a highly disordered metabolic milieu, the same 'metabolic movers' that promote type 2 diabetes and atheromatous cardiovascular disease. The net effect is accumulation of lipid molecules in the liver. Which lipids and how they cause injury, inflammation and fibrosis will be discussed in part two.
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Abstract
Fifty years of the Gastroenterological Society of Australia have witnessed the changing appearance of Australians. Asian immigration has transformed the dominant urban culture from European to Eurasian, with some unique Australian attributes. Meanwhile, global conditions have altered body shape, and our sports-proud country is now fat! Thus, as in North America, Europe, China, and affluent Asia-Pacific countries, prosperity and lifestyle, cheap processed foods coupled with reduced physical activity have created an epidemic of over-nutrition resulting in overweight/obesity. Additional genetic factors are at the core of the apple shape (central obesity) that typifies over-nourished persons with metabolic syndrome. Indigenous Australians, once the leanest and fittest humans, now have exceedingly high rates of obesity and type 2 diabetes, contributing to shorter life expectancy; Asian Australians are also at higher risk. Like non-steroidal anti-inflammatory drugs (NSAIDs) and cigarette smoking, obesity now contributes much to gastrointestinal morbidity and mortality (gastroesophageal reflux disease, cancers, gallstones, endoscopy complications). This review focuses on Australian research about fatty liver, particularly roles of central obesity/insulin resistance in non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH). The outputs include many highly cited original articles and reviews and the first book on NAFLD. Studies have identified community prevalence, clinical outcomes, association with insulin resistance, metabolic syndrome and hypoadiponectinemia, developed and explored animal models for mechanisms of inflammation and fibrosis, conceptualized etiopathogenesis, and demonstrated that NASH can be reversed by lowering body weight and increasing physical activity. The findings have led to development of regional guidelines on NAFLD, the first internationally, and should now inform daily practice of gastroenterologists.
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Yang G, Badeanlou L, Bielawski J, Roberts AJ, Hannun YA, Samad F. Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome. Am J Physiol Endocrinol Metab 2009; 297:E211-24. [PMID: 19435851 PMCID: PMC2711669 DOI: 10.1152/ajpendo.91014.2008] [Citation(s) in RCA: 243] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Although obesity is associated with multiple features of the metabolic syndrome (insulin resistance, leptin resistance, hepatic steatosis, chronic inflammation, etc.), the molecular changes that promote these conditions are not completely understood. Here, we tested the hypothesis that elevated ceramide biosynthesis contributes to the pathogenesis of obesity and the metabolic syndrome. Chronic treatment for 8 wk of genetically obese (ob/ob), and, high-fat diet-induced obese (DIO) mice with myriocin, an inhibitor of de novo ceramide synthesis, decreased circulating ceramides. Decreased ceramide was associated with reduced weight, enhanced metabolism and energy expenditure, decreased hepatic steatosis, and improved glucose hemostasis via enhancement of insulin signaling in the liver and muscle. Inhibition of de novo ceramide biosynthesis decreased adipose expression of suppressor of cytokine signaling-3 (SOCS-3) and induced adipose uncoupling protein-3 (UCP3). Moreover, ceramide directly induced SOCS-3 and inhibited UCP3 mRNA in cultured adipocytes suggesting a direct role for ceramide in regulation of metabolism and energy expenditure. Inhibition of de novo ceramide synthesis had no effect on adipose tumor necrosis factor-alpha (TNF-alpha) expression but dramatically reduced adipose plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattactant protein-1 (MCP-1). This study highlights a novel role for ceramide biosynthesis in body weight regulation, energy expenditure, and the metabolic syndrome.
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Affiliation(s)
- Guang Yang
- Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121, USA
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Savage DB, Semple RK, Clatworthy MR, Lyons PA, Morgan BP, Cochran EK, Gorden P, Raymond-Barker P, Murgatroyd PR, Adams C, Scobie I, Mufti GJ, Alexander GJM, Thiru S, Murano I, Cinti S, Chaudhry AN, Smith KGC, O'Rahilly S. Complement abnormalities in acquired lipodystrophy revisited. J Clin Endocrinol Metab 2009; 94:10-16. [PMID: 18854390 DOI: 10.1210/jc.2008-1703] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
CONTEXT Lipodystrophy is a heterogeneous condition characterized by an inherited or acquired deficiency in the number of adipocytes required for the storage of energy as triglycerides. Acquired lipodystrophy is frequently associated with other autoimmune disorders. One well-studied form is characterized by the selective loss of upper body fat in association with activation of the alternative complement pathway by C3 nephritic factor, low complement factor C3, and mesangiocapillary glomerulonephritis. OBJECTIVE We now describe an immunologically distinct form of acquired generalized lipodystrophy, with evidence of activation of the classical complement pathway (low C4) and autoimmune hepatitis. Patients and Research Design: Three unrelated patients with acquired lipodystrophy and low complement C4 levels are described. In vitro analysis of the complement pathway was undertaken to determine the reason for the low C4 complement levels. Biopsies were obtained from liver, bone marrow, and adipose tissue for histological analysis. RESULTS All three patients manifested near-total lipodystrophy, chronic hepatitis with autoimmune features, and low C4 complement levels. Additional autoimmune diseases, including severe hemolytic anemia, autoimmune thyroid disease, and polyneuropathy, were variably present. Detailed studies of complement pathways suggested constitutive classical pathway activation. CONCLUSIONS Although the previously described syndrome, which typically results in a cephalad pattern of partial lipodystrophy, results from activation of the alternative complement pathway, this form, in which lipodystrophy is generalized, is associated with activation of the classical pathway. Future therapeutic approaches to these disorders may benefit from being tailored to their distinct immunopathogenesis.
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Affiliation(s)
- David B Savage
- Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom.
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Yen CLE, Stone SJ, Koliwad S, Harris C, Farese RV. Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J Lipid Res 2008; 49:2283-301. [PMID: 18757836 PMCID: PMC3837458 DOI: 10.1194/jlr.r800018-jlr200] [Citation(s) in RCA: 810] [Impact Index Per Article: 47.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2008] [Revised: 08/29/2008] [Indexed: 12/18/2022] Open
Abstract
Triacylglycerols (triglycerides) (TGs) are the major storage molecules of metabolic energy and FAs in most living organisms. Excessive accumulation of TGs, however, is associated with human diseases, such as obesity, diabetes mellitus, and steatohepatitis. The final and the only committed step in the biosynthesis of TGs is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. The genes encoding two DGAT enzymes, DGAT1 and DGAT2, were identified in the past decade, and the use of molecular tools, including mice deficient in either enzyme, has shed light on their functions. Although DGAT enzymes are involved in TG synthesis, they have distinct protein sequences and differ in their biochemical, cellular, and physiological functions. Both enzymes may be useful as therapeutic targets for diseases. Here we review the current knowledge of DGAT enzymes, focusing on new advances since the cloning of their genes, including possible roles in human health and diseases.
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Affiliation(s)
- Chi-Liang Eric Yen
- Department of Nutritional Sciences, University of Wisconsin, Madison, WI
53706
| | - Scot J. Stone
- Department of Biochemistry, University of Saskatchewan, Saskatoon,
Saskatchewan, Canada
| | - Suneil Koliwad
- Gladstone Institute of Cardiovascular Disease, University of California, San
Francisco, San Francisco, CA 94141
- Cardiovascular Research Institute, University of California, San
Francisco, San Francisco, CA 94141
- Department of Medicine, University of California, San Francisco,
San Francisco, CA 94141
| | - Charles Harris
- Gladstone Institute of Cardiovascular Disease, University of California, San
Francisco, San Francisco, CA 94141
- Cardiovascular Research Institute, University of California, San
Francisco, San Francisco, CA 94141
- Department of Medicine, University of California, San Francisco,
San Francisco, CA 94141
| | - Robert V. Farese
- Gladstone Institute of Cardiovascular Disease, University of California, San
Francisco, San Francisco, CA 94141
- Cardiovascular Research Institute, University of California, San
Francisco, San Francisco, CA 94141
- Department of Medicine, University of California, San Francisco,
San Francisco, CA 94141
- Department of Biochemistry and Biophysics, University of
California, San Francisco, San Francisco, CA 94141
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Dramatic reversal of derangements in muscle metabolism and left ventricular function after bariatric surgery. Am J Med 2008; 121:966-73. [PMID: 18954843 PMCID: PMC2604808 DOI: 10.1016/j.amjmed.2008.06.033] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2008] [Revised: 06/23/2008] [Accepted: 06/26/2008] [Indexed: 01/14/2023]
Abstract
OBJECTIVE The study objective was to define muscle metabolic and cardiovascular changes after surgical intervention in clinically severe obese patients. METHODS Obesity is a state of metabolic dysregulation that can lead to maladaptive changes in heart and skeletal muscle, including insulin resistance and heart failure. In a prospective longitudinal study, 43 consecutive patients underwent metabolic profiling, skeletal muscle biopsies, and resting echocardiograms at baseline and 3 and 9 months after bariatric surgery. RESULTS Body mass index decreased (mean changes, 95% confidence interval [CI]): 7.7 kg/m(2) (95% CI, 6.70-8.89) at 3 months and 5.6 kg/m(2) (95% CI, 4.45-6.80; P<.0001) at 9 months after surgery, with restoration of insulin sensitivity and decreases in plasma leptin at the same time points. Concurrent with these changes were dramatic decreases in skeletal muscle transcript levels of stearoyl coenzyme-A desaturase and pyruvate dehydrogenase kinase-4 at 3 and 9 months (P<.0001, for both) and a significant decrease in peroxisome proliferation activated receptor-alpha-regulated genes at 9 months. Left ventricular relaxation impairment, assessed by tissue Doppler imaging, normalized 9 months after surgery. CONCLUSION Weight loss results in the reversal of systemic and muscle metabolic derangements and is accompanied by a normalization of left ventricular diastolic function.
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Bayol SA, Simbi BH, Bertrand JA, Stickland NC. Offspring from mothers fed a 'junk food' diet in pregnancy and lactation exhibit exacerbated adiposity that is more pronounced in females. J Physiol 2008; 586:3219-30. [PMID: 18467362 PMCID: PMC2538787 DOI: 10.1113/jphysiol.2008.153817] [Citation(s) in RCA: 153] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
We have shown previously that a maternal junk food diet during pregnancy and lactation plays a role in predisposing offspring to obesity. Here we show that rat offspring born to mothers fed the same junk food diet rich in fat, sugar and salt develop exacerbated adiposity accompanied by raised circulating glucose, insulin, triglyceride and/or cholesterol by the end of adolescence (10 weeks postpartum) compared with offspring also given free access to junk food from weaning but whose mothers were exclusively fed a balanced chow diet in pregnancy and lactation. Results also showed that offspring from mothers fed the junk food diet in pregnancy and lactation, and which were then switched to a balanced chow diet from weaning, exhibited increased perirenal fat pad mass relative to body weight and adipocyte hypertrophy compared with offspring which were never exposed to the junk food diet. This study shows that the increased adiposity was more enhanced in female than male offspring and gene expression analyses showed raised insulin-like growth factor-1 (IGF-1), insulin receptor substrate (IRS)-1, vascular endothelial growth factor (VEGF)-A, peroxisome proliferator-activated receptor-gamma (PPARgamma), leptin, adiponectin, adipsin, lipoprotein lipase (LPL), Glut 1, Glut 3, but not Glut 4 mRNA expression in females fed the junk food diet throughout the study compared with females never given access to junk food. Changes in gene expression were not as marked in male offspring with only IRS-1, VEGF-A, Glut 4 and LPL being up-regulated in those fed the junk food diet throughout the study compared with males never given access to junk food. This study therefore shows that a maternal junk food diet promotes adiposity in offspring and the earlier onset of hyperglycemia, hyperinsulinemia and/or hyperlipidemia. Male and female offspring also display a different metabolic, cellular and molecular response to junk-food-diet-induced adiposity.
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Affiliation(s)
- S A Bayol
- The Royal Veterinary College, Department of Veterinary Basic Sciences, Royal College Street, London NW1 0TU, UK.
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Leichman JG, Lavis VR, Aguilar D, Wilson CR, Taegtmeyer H. The metabolic syndrome and the heart--a considered opinion. Clin Res Cardiol 2008; 95 Suppl 1:i134-41. [PMID: 16598541 DOI: 10.1007/s00392-006-1119-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The metabolic syndrome (MS) is a multifactorial, heterogeneous group of risk factors for the development of cardiovascular disease. Here we review the evidence in support of the hypothesis that metabolic dysregulation of the body as a whole leads to contractile dysfunction of the heart due to an imbalance of substrate uptake (increased) and substrate oxidation (decreased). The consequences of this imbalance were already recognized 150 years ago by Virchow when he described "fatty atrophy" of the heart as a "true metamorphosis of the heart muscle cell."
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Affiliation(s)
- J G Leichman
- The University of Texas Houston Medical School, Department of Internal Medicine, Division of Cardiology, 6431 Fannin Street, MSB 1.246, Houston, TX 77030, USA
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Yoneda M, Endo H, Nozaki Y, Tomimoto A, Fujisawa T, Fujita K, Yoneda K, Takahashi H, Saito S, Iwasaki T, Yamamoto S, Tsutsumi S, Aburatani H, Wada K, Hotta K, Nakajima A. Life style-related diseases of the digestive system: gene expression in nonalcoholic steatohepatitis patients and treatment strategies. J Pharmacol Sci 2007; 105:151-6. [PMID: 17928738 DOI: 10.1254/jphs.fm0070063] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a subset of nonalcoholic fatty liver disease (NAFLD) and sometimes progresses to cirrhosis and liver failure. We analyzed the expression profiles of approximately 50,000 genes and biological pathways in NASH patients in comparison with simple steatosis patients by using the analytical technique of GSEA (Gene Set Enrichment Analysis) by DNA microarrays. Although expressions of various genes were altered, GSEA showed clearly lower expression of nuclear receptors, including the peroxisome proliferator-activated receptor gamma (PPARgamma) pathway. In a preliminary study we therefore investigated the therapeutic effect of low-dose pioglitazone (15 mg/day per body for 24 weeks), a synthetic ligand for PPARgamma, in 12 NASH patients. A decrease in aminotransferase (ALT) values to within the normal range was observed in 7 (58.3%) of the patients, and because the dose of pioglitazone was lower than that ordinarily used, no side effects, such as fatigue, lower extremity edema, or weight gain, were observed. In conclusion, the results confirmed involvement of the PPARgamma pathway in NASH and the therapeutic utility of a PPARgamma ligand.
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Affiliation(s)
- Masato Yoneda
- Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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48
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Pawlik TM, Olino K, Gleisner AL, Torbenson M, Schulick R, Choti MA. Preoperative chemotherapy for colorectal liver metastases: impact on hepatic histology and postoperative outcome. J Gastrointest Surg 2007; 11:860-8. [PMID: 17492335 DOI: 10.1007/s11605-007-0149-4] [Citation(s) in RCA: 178] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Some investigators have suggested that preoperative chemotherapy for hepatic colorectal metastases may cause hepatic injury and increase perioperative morbidity and mortality. The objective of the current study was to examine whether treatment with preoperative chemotherapy was associated with hepatic injury of the nontumorous liver and whether such injury, if present, was associated with increased morbidity or mortality after hepatic resection. Two-hundred and twelve eligible patients who underwent hepatic resection for colorectal liver metastases between January 1999 and December 2005 were identified. Data on demographics, clinicopathologic characteristics, and preoperative chemotherapy details were collected and analyzed. The majority of patients received preoperative chemotherapy (n = 153; 72.2%). Chemotherapy consisted of fluoropyrimidine-based regimens: 5-FU monotherapy, 31.6%; irinotecan, 25.9%; and oxaliplatin, 14.6%. Among those patients who received chemotherapy, the type of chemotherapy regimen predicted distinct patterns of liver injury. Oxaliplatin was associated with increased likelihood of grade 3 sinusoidal dilatation (p = 0.017). Steatosis >30% was associated with irinotecan (27.3%) compared with no chemotherapy, 5-FU monotherapy, and oxaliplatin (all p < 0.05). Irinotecan also was associated with steatohepatitis, as two of the three patients with steatohepatitis had received irinotecan preoperatively. Overall, the perioperative complication rate was similar between the no-chemotherapy group (30.5%) and the chemotherapy group (35.3%) (p = 0.79). Preoperative chemotherapy was also not associated with 60-day mortality. In patients with hepatic colorectal metastases, preoperative chemotherapy is associated with hepatic injury in about 20 to 30% of patients. Furthermore, the type of hepatic injury after preoperative chemotherapy was regimen-specific.
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Affiliation(s)
- Timothy M Pawlik
- Department of Surgery, Johns Hopkins Hospital, 600 North Wolfe Street, Halsted 614, Baltimore, MD 22187-6681, USA
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Monetti M, Levin MC, Watt MJ, Sajan MP, Marmor S, Hubbard BK, Stevens RD, Bain JR, Newgard CB, Farese RV, Hevener AL, Farese RV. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab 2007; 6:69-78. [PMID: 17618857 DOI: 10.1016/j.cmet.2007.05.005] [Citation(s) in RCA: 421] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2006] [Revised: 03/07/2007] [Accepted: 05/10/2007] [Indexed: 01/12/2023]
Abstract
Hepatic steatosis, the accumulation of lipids in the liver, is widely believed to result in insulin resistance. To test the causal relationship between hepatic steatosis and insulin resistance, we generated mice that overexpress acyl-CoA:diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step of triacylglycerol (TG) biosynthesis, in the liver (Liv-DGAT2 mice). Liv-DGAT2 mice developed hepatic steatosis, with increased amounts of TG, diacylglycerol, ceramides, and unsaturated long-chain fatty acyl-CoAs in the liver. However, they had no abnormalities in plasma glucose and insulin levels, glucose and insulin tolerance, rates of glucose infusion and hepatic glucose production during hyperinsulinemic-euglycemic clamp studies, or activities of insulin-stimulated signaling proteins in the liver. DGAT1 overexpression in the liver also failed to induce glucose or insulin intolerance. Our results indicate that DGAT-mediated lipid accumulation in the liver is insufficient to cause insulin resistance and show that hepatic steatosis can occur independently of insulin resistance.
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Affiliation(s)
- Mara Monetti
- Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA
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Clark RF, Zhang T, Wang X, Wang R, Zhang X, Camp HS, Beutel BA, Sham HL, Gu YG. Phenoxy thiazole derivatives as potent and selective acetyl-CoA carboxylase 2 inhibitors: Modulation of isozyme selectivity by incorporation of phenyl ring substituents. Bioorg Med Chem Lett 2007; 17:1961-5. [PMID: 17267221 DOI: 10.1016/j.bmcl.2007.01.022] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2006] [Accepted: 01/09/2007] [Indexed: 11/24/2022]
Abstract
A phenyl ring substitution strategy was employed to optimize the ACC2 potency and selectivity profiles of a recently discovered phenoxy thiazolyl series of acetyl-CoA carboxylase inhibitors. Ring substituents were shown to dramatically affect isozyme selectivity. Modifications that generally impart high levels of ACC2 selectivity (>3000-fold) while maintaining excellent ACC2 potency (IC50s approximately 9-20 nM) were identified.
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Affiliation(s)
- Richard F Clark
- Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
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