1
|
Nowicka B, Polkowska I, Zeliszewska-Duk P, Torres A, Duk M. Molecular Assessment of Plasma Concentrations of Selected Adipokines and IL-8 in Horses with Back Pain and Comorbid Asthma-Based on Clinical Cases. Animals (Basel) 2025; 15:310. [PMID: 39943080 PMCID: PMC11815831 DOI: 10.3390/ani15030310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 01/08/2025] [Accepted: 01/14/2025] [Indexed: 02/16/2025] Open
Abstract
Similarly, in humans and horses, thoracic and lumbosacral back pain cause more disability and work interruptions worldwide than any other disease. Given that there are few effective treatments for back pain in humans and animals, primary prevention strategies and a reduction in pain factors may be crucial. In the analysed data obtained for the horses studied, the pattern of changes in adipocytokine concentrations, including resistin, visfatin and leptin, was noted for those with back pain compared to the control animals. Concentrations of selected adipocytokines in horses from the back pain group were different in animals with a coexisting diagnosis of asthma and back dysfunction. Very few studies are available on adipokine concentrations in horses. No information was found in relation to back pain and asthma in these animals. In humans, correlations of back pain and asthma with concentrations of selected adipokines have been described.
Collapse
Affiliation(s)
- Beata Nowicka
- Department and Clinic of Animal Surgery, University of Life Sciences in Lublin, Głęboka 30, 20-612 Lublin, Poland;
| | - Izabela Polkowska
- Department and Clinic of Animal Surgery, University of Life Sciences in Lublin, Głęboka 30, 20-612 Lublin, Poland;
| | - Paulina Zeliszewska-Duk
- Department of Horse Breeding and Use, Faculty of Animal Sciences and Bioeconomy, University of Life Sciences in Lublin, Akademicka 13, 20-950 Lublin, Poland;
| | - Anna Torres
- Department of Pediatrics and Adolescent Gynecology, Medical University of Lublin, Chodzki 4, 20-093 Lublin, Poland;
| | - Mariusz Duk
- Department of Electronics and Information Technology, Faculty of Electrical Engineering and Computer Science, Lublin University of Technology, 20-618 Lublin, Poland;
| |
Collapse
|
2
|
Soukop J, Kazdová L, Hüttl M, Malínská H, Marková I, Oliyarnyk O, Miklánková D, Gurská S, Rácová Z, Poruba M, Večeřa R. Beneficial Effect of Fenofibrate in Combination with Silymarin on Parameters of Hereditary Hypertriglyceridemia-Induced Disorders in an Animal Model of Metabolic Syndrome. Biomedicines 2025; 13:212. [PMID: 39857794 PMCID: PMC11763318 DOI: 10.3390/biomedicines13010212] [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: 12/26/2024] [Revised: 01/11/2025] [Accepted: 01/14/2025] [Indexed: 01/27/2025] Open
Abstract
Background: Hypertriglyceridemia has serious health risks such as cardiovascular disease, type 2 diabetes mellitus, nephropathy, and others. Fenofibrate is an effective hypolipidemic drug, but its benefits for ameliorating disorders associated with hypertriglyceridemia failed to be proven in clinical trials. Methods: To search for possible causes of this situation and possibilities of their favorable influence, we tested the effect of FF monotherapy and the combination of fenofibrate with silymarin on metabolic disorders in a unique model of hereditary hypertriglyceridemic rats (HHTg). Results: Fenofibrate treatment (100 mg/kg BW/day for four weeks) significantly decreased serum levels of triglyceride, (-77%) and free fatty acids (-29%), the hepatic accumulation of triglycerides, and the expression of genes encoding transcription factors involved in lipid metabolism (Srebf2, Nr1h4. Rxrα, and Slco1a1). In contrast, the hypertriglyceridemia-induced ectopic storage of lipids in muscles, the heart, and kidneys reduced glucose utilization in muscles and was not affected. In addition, fenofibrate reduced the activity of the antioxidant system, including Nrf2 expression (-35%) and increased lipoperoxidation in the liver and, to a lesser extent, in the kidneys and heart. Adding silymarin (micronized form, 600 mg/kg BW/day) to fenofibrate therapy increased the synthesis of glycogen in muscles, (+36%) and reduced hyperinsulinemia (-34%). In the liver, it increased the activity of the antioxidant system, including PON-1 activity and Nrf2 expression, and reduced the formation of lipoperoxides. The beneficial effect of combination therapy on the parameters of oxidative stress and lipoperoxidation was also observed, to a lesser extent, in the heart and kidneys. Conclusions: Our results suggest the potential beneficial use of the combination of FF with SLM in the treatment of hypertriglyceridemia-induced metabolic disorders.
Collapse
Affiliation(s)
- Jan Soukop
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77515 Olomouc, Czech Republic; (J.S.)
| | - Ludmila Kazdová
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Martina Hüttl
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Hana Malínská
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Irena Marková
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Olena Oliyarnyk
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Denisa Miklánková
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Soňa Gurská
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77515 Olomouc, Czech Republic
| | - Zuzana Rácová
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77515 Olomouc, Czech Republic; (J.S.)
| | - Martin Poruba
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77515 Olomouc, Czech Republic; (J.S.)
| | - Rostislav Večeřa
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77515 Olomouc, Czech Republic; (J.S.)
| |
Collapse
|
3
|
Marković A, Tauchmannová K, Šimáková M, Mlejnek P, Kaplanová V, Pecina P, Pecinová A, Papoušek F, Liška F, Šilhavý J, Mikešová J, Neckář J, Houštěk J, Pravenec M, Mráček T. Genetic Complementation of ATP Synthase Deficiency Due to Dysfunction of TMEM70 Assembly Factor in Rat. Biomedicines 2022; 10:276. [PMID: 35203486 PMCID: PMC8869460 DOI: 10.3390/biomedicines10020276] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/05/2022] [Accepted: 01/18/2022] [Indexed: 11/17/2022] Open
Abstract
Mutations of the TMEM70 gene disrupt the biogenesis of the ATP synthase and represent the most frequent cause of autosomal recessive encephalo-cardio-myopathy with neonatal onset. Patient tissues show isolated defects in the ATP synthase, leading to the impaired mitochondrial synthesis of ATP and insufficient energy provision. In the current study, we tested the efficiency of gene complementation by using a transgenic rescue approach in spontaneously hypertensive rats with the targeted Tmem70 gene (SHR-Tmem70ko/ko), which leads to embryonic lethality. We generated SHR-Tmem70ko/ko knockout rats expressing the Tmem70 wild-type transgene (SHR-Tmem70ko/ko,tg/tg) under the control of the EF-1α universal promoter. Transgenic rescue resulted in viable animals that showed the variable expression of the Tmem70 transgene across the range of tissues and only minor differences in terms of the growth parameters. The TMEM70 protein was restored to 16-49% of the controls in the liver and heart, which was sufficient for the full biochemical complementation of ATP synthase biogenesis as well as for mitochondrial energetic function in the liver. In the heart, we observed partial biochemical complementation, especially in SHR-Tmem70ko/ko,tg/0 hemizygotes. As a result, this led to a minor impairment in left ventricle function. Overall, the transgenic rescue of Tmem70 in SHR-Tmem70ko/ko knockout rats resulted in the efficient complementation of ATP synthase deficiency and thus in the successful genetic treatment of an otherwise fatal mitochondrial disorder.
Collapse
Affiliation(s)
- Aleksandra Marković
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; (A.M.); (K.T.); (M.Š.); (P.M.); (V.K.); (P.P.); (A.P.); (F.P.); (F.L.); (J.Š.); (J.M.); (J.N.); (J.H.)
- Faculty of Science, Charles University, 128 00 Prague, Czech Republic
| | - Kateřina Tauchmannová
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; (A.M.); (K.T.); (M.Š.); (P.M.); (V.K.); (P.P.); (A.P.); (F.P.); (F.L.); (J.Š.); (J.M.); (J.N.); (J.H.)
| | - Miroslava Šimáková
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; (A.M.); (K.T.); (M.Š.); (P.M.); (V.K.); (P.P.); (A.P.); (F.P.); (F.L.); (J.Š.); (J.M.); (J.N.); (J.H.)
| | - Petr Mlejnek
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; (A.M.); (K.T.); (M.Š.); (P.M.); (V.K.); (P.P.); (A.P.); (F.P.); (F.L.); (J.Š.); (J.M.); (J.N.); (J.H.)
| | - Vilma Kaplanová
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; (A.M.); (K.T.); (M.Š.); (P.M.); (V.K.); (P.P.); (A.P.); (F.P.); (F.L.); (J.Š.); (J.M.); (J.N.); (J.H.)
| | - Petr Pecina
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; (A.M.); (K.T.); (M.Š.); (P.M.); (V.K.); (P.P.); (A.P.); (F.P.); (F.L.); (J.Š.); (J.M.); (J.N.); (J.H.)
| | - Alena Pecinová
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; (A.M.); (K.T.); (M.Š.); (P.M.); (V.K.); (P.P.); (A.P.); (F.P.); (F.L.); (J.Š.); (J.M.); (J.N.); (J.H.)
| | - František Papoušek
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; (A.M.); (K.T.); (M.Š.); (P.M.); (V.K.); (P.P.); (A.P.); (F.P.); (F.L.); (J.Š.); (J.M.); (J.N.); (J.H.)
| | - František Liška
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; (A.M.); (K.T.); (M.Š.); (P.M.); (V.K.); (P.P.); (A.P.); (F.P.); (F.L.); (J.Š.); (J.M.); (J.N.); (J.H.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital, 128 00 Prague, Czech Republic
| | - Jan Šilhavý
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; (A.M.); (K.T.); (M.Š.); (P.M.); (V.K.); (P.P.); (A.P.); (F.P.); (F.L.); (J.Š.); (J.M.); (J.N.); (J.H.)
| | - Jana Mikešová
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; (A.M.); (K.T.); (M.Š.); (P.M.); (V.K.); (P.P.); (A.P.); (F.P.); (F.L.); (J.Š.); (J.M.); (J.N.); (J.H.)
| | - Jan Neckář
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; (A.M.); (K.T.); (M.Š.); (P.M.); (V.K.); (P.P.); (A.P.); (F.P.); (F.L.); (J.Š.); (J.M.); (J.N.); (J.H.)
| | - Josef Houštěk
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; (A.M.); (K.T.); (M.Š.); (P.M.); (V.K.); (P.P.); (A.P.); (F.P.); (F.L.); (J.Š.); (J.M.); (J.N.); (J.H.)
| | - Michal Pravenec
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; (A.M.); (K.T.); (M.Š.); (P.M.); (V.K.); (P.P.); (A.P.); (F.P.); (F.L.); (J.Š.); (J.M.); (J.N.); (J.H.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital, 128 00 Prague, Czech Republic
| | - Tomáš Mráček
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic; (A.M.); (K.T.); (M.Š.); (P.M.); (V.K.); (P.P.); (A.P.); (F.P.); (F.L.); (J.Š.); (J.M.); (J.N.); (J.H.)
| |
Collapse
|
4
|
Šilhavý J, Malínská H, Hüttl M, Marková I, Oliyarnyk O, Mlejnek P, Šimáková M, Liška F, Kazdová L, Moravcová R, Novotný J, Pravenec M. Downregulation of the Glo1 Gene Is Associated with Reduced Adiposity and Ectopic Fat Accumulation in Spontaneously Hypertensive Rats. Antioxidants (Basel) 2020; 9:antiox9121179. [PMID: 33255888 PMCID: PMC7759780 DOI: 10.3390/antiox9121179] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 12/30/2022] Open
Abstract
Methylglyoxal (MG), a potent precursor of advanced glycation end-products (AGE), is increased in metabolic disorders such as diabetes and obesity. MG and other dicarbonyl metabolites are detoxified by the glyoxalase system in which glyoxalase 1, coded by the Glo1 gene, serves as the rate-limiting enzyme. In this study, we analyzed the effects of Glo1 downregulation on glucose and lipid metabolism parameters in spontaneously hypertensive rats (SHR) by targeting the Glo1 gene (SHR-Glo1+/− heterozygotes). Compared to SHR wild-type animals, SHR-Glo1+/− rats showed significantly reduced Glo1 expression and lower GLO1 activity in tissues associated with increased MG levels. In contrast to SHR controls, SHR-Glo1+/− rats exhibited lower relative weight of epididymal fat, reduced ectopic fat accumulation in the liver and heart, and decreased serum triglycerides. In addition, compared to controls, SHR-Glo1+/− rats showed reduced serum insulin and increased basal and insulin stimulated incorporation of glucose into white adipose tissue lipids (lipogenesis). Reduced ectopic fat accumulation in the heart was associated with significantly increased pAMPK/AMPK ratio and GLUT4 activity. These results provide evidence that Glo1 downregulation in SHR is associated with reduced adiposity and ectopic fat accumulation, most likely mediated by AMPK activation in the heart.
Collapse
Affiliation(s)
- Jan Šilhavý
- Institute of Physiology of the Czech Academy of Sciences, 14220 Prague, Czech Republic; (J.Š.); (P.M.); (M.Š.); (F.L.)
| | - Hana Malínská
- Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (H.M.); (M.H.); (I.M.); (O.O.); (L.K.)
| | - Martina Hüttl
- Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (H.M.); (M.H.); (I.M.); (O.O.); (L.K.)
| | - Irena Marková
- Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (H.M.); (M.H.); (I.M.); (O.O.); (L.K.)
| | - Olena Oliyarnyk
- Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (H.M.); (M.H.); (I.M.); (O.O.); (L.K.)
| | - Petr Mlejnek
- Institute of Physiology of the Czech Academy of Sciences, 14220 Prague, Czech Republic; (J.Š.); (P.M.); (M.Š.); (F.L.)
| | - Miroslava Šimáková
- Institute of Physiology of the Czech Academy of Sciences, 14220 Prague, Czech Republic; (J.Š.); (P.M.); (M.Š.); (F.L.)
| | - František Liška
- Institute of Physiology of the Czech Academy of Sciences, 14220 Prague, Czech Republic; (J.Š.); (P.M.); (M.Š.); (F.L.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital, 12800 Prague, Czech Republic
| | - Ludmila Kazdová
- Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (H.M.); (M.H.); (I.M.); (O.O.); (L.K.)
| | - Radka Moravcová
- Department of Physiology, Faculty of Science, Charles University, 12843 Prague, Czech Republic; (R.M.); (J.N.)
| | - Jiří Novotný
- Department of Physiology, Faculty of Science, Charles University, 12843 Prague, Czech Republic; (R.M.); (J.N.)
| | - Michal Pravenec
- Institute of Physiology of the Czech Academy of Sciences, 14220 Prague, Czech Republic; (J.Š.); (P.M.); (M.Š.); (F.L.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital, 12800 Prague, Czech Republic
- Correspondence: ; Tel.: +420-241-062-297; Fax: +420-244-472-269
| |
Collapse
|
5
|
Catalina MOS, Redondo PC, Granados MP, Cantonero C, Sanchez-Collado J, Albarran L, Lopez JJ. New Insights into Adipokines as Potential Biomarkers for Type-2 Diabetes Mellitus. Curr Med Chem 2019; 26:4119-4144. [PMID: 29210636 DOI: 10.2174/0929867325666171205162248] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 10/30/2017] [Accepted: 10/30/2017] [Indexed: 02/06/2023]
Abstract
A large number of studies have been focused on investigating serum biomarkers associated with risk or diagnosis of type-2 diabetes mellitus. In the last decade, promising studies have shown that circulating levels of adipokines could be used as a relevant biomarker for diabetes mellitus progression as well as therapeutic future targets. Here, we discuss the possible use of recently described adipokines, including apelin, omentin-1, resistin, FGF-21, neuregulin-4 and visfatin, as early biomarkers for diabetes. In addition, we also include recent findings of other well known adipokines such as leptin and adiponectin. In conclusion, further studies are needed to clarify the pathophysiological significance and clinical value of these biological factors as potential biomarkers in type-2 diabetes and related dysfunctions.
Collapse
Affiliation(s)
| | - Pedro C Redondo
- Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003-Caceres, Spain
| | - Maria P Granados
- Aldea Moret's Medical Center, Extremadura Health Service, 10195-Caceres, Spain
| | - Carlos Cantonero
- Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003-Caceres, Spain
| | - Jose Sanchez-Collado
- Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003-Caceres, Spain
| | - Letizia Albarran
- Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003-Caceres, Spain
| | - Jose J Lopez
- Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003-Caceres, Spain
| |
Collapse
|
6
|
Benomar Y, Taouis M. Molecular Mechanisms Underlying Obesity-Induced Hypothalamic Inflammation and Insulin Resistance: Pivotal Role of Resistin/TLR4 Pathways. Front Endocrinol (Lausanne) 2019; 10:140. [PMID: 30906281 PMCID: PMC6418006 DOI: 10.3389/fendo.2019.00140] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 02/15/2019] [Indexed: 12/16/2022] Open
Abstract
Low-grade inflammation and insulin resistance are among the clinical features of obesity that are thought to promote the progressive onset of type 2 diabetes. However, the underlying mechanisms linking these disorders remain not fully understood. Recent reports pointed out hypothalamic inflammation as a major step in the onset of obesity-induced insulin resistance. In light of the increasing prevalence of obesity and T2D, two worldwide public health concerns, deciphering mechanisms implicated in hypothalamic inflammation constitutes a major challenge in the field of insulin-resistance/obesity. Several clinical and experimental studies have identified resistin as a key hormone linking insulin-resistance to obesity, notably through the activation of Toll Like Receptor (TLR) 4 signaling pathways. In this review, we present an overview of the molecular mechanisms underlying obesity-induced hypothalamic inflammation and insulin resistance with peculiar focus on the role of resistin/TLR4 signaling pathway.
Collapse
|
7
|
Majdi MA, Mohammadzadeh NA, Lotfi H, Mahmoudi R, Alipour FG, Shool F, Moghanloo MN, Porfaraj S, Zarghami N. Correlation of Resistin Serum Level with Fat Mass and Obesity-Associated Gene (FTO) rs9939609 Polymorphism in Obese Women with Type 2 Diabetes. Diabetes Metab Syndr 2017; 11 Suppl 2:S715-S720. [PMID: 28566238 DOI: 10.1016/j.dsx.2017.05.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 05/11/2017] [Indexed: 12/14/2022]
Abstract
AIMS The aim of this study was to detect any association of fat mass and obesity-associated (FTO) rs9939609 variant to metabolic and anthropometric parameters and resistin level as adipokines in Iranian obese women with type 2 diabetes mellitus. MATERIAL AND METHODS Totally, 42 diabetic and 36 non-diabetic women were selected. The PCR amplicons of FTO gene were sequenced and metabolic, anthropometric parameters and resistin level were measured. RESULTS Serum resistin concentrations were not different between diabetic and non-diabetic subjects (p>0.05), while resistin level in diabetic group with AA genotype was lower than that with other genotypes in the same group. In rs9939609 SNP adjusted analysis, insulin and HOMA levels were high in AA genotype. While levels of FBS and HbA1c were higher in AA and AT genotypes. In diabetic group, only TG showed significant difference among three genotypes and mean of TG was higher in TA genotype. No significant correlation between resistin and anthropometric and metabolic parameters was found except for DBP in diabetic patients. CONCLUSION There was no significant association between rs9939609 and resistin serum level in type 2 obese diabetic women while percentile ranges (25th, 50th and 75th) of resistin concentrations was high in diabetic group.
Collapse
Affiliation(s)
- Maryam Abbasi Majdi
- Department of Clinical Biochemistry. Laboratory Medicine. Faculty of Medical Science, Tabriz. University of Medical Sciences, Tabriz, Iran
| | | | - Hajie Lotfi
- Department of Medical Biotechnology. Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rasoul Mahmoudi
- Department of Clinical Biochemistry. Laboratory Medicine. Faculty of Medical Science, Tabriz. University of Medical Sciences, Tabriz, Iran
| | - Farzaneh Ghafarian Alipour
- Department of Clinical Biochemistry. Laboratory Medicine. Faculty of Medical Science, Tabriz. University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Shool
- Department of Clinical Biochemistry. Laboratory Medicine. Faculty of Medical Science, Tabriz. University of Medical Sciences, Tabriz, Iran
| | - Mehdi Niknam Moghanloo
- Department of Clinical Biochemistry. Laboratory Medicine. Faculty of Medical Science, Tabriz. University of Medical Sciences, Tabriz, Iran
| | - Sadeg Porfaraj
- Department of Clinical Biochemistry. Laboratory Medicine. Faculty of Medical Science, Tabriz. University of Medical Sciences, Tabriz, Iran
| | - Nosratollah Zarghami
- Department of Clinical Biochemistry. Laboratory Medicine. Faculty of Medical Science, Tabriz. University of Medical Sciences, Tabriz, Iran; Immunology research center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Medical Biotechnology. Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
8
|
Hajavi J, Momtazi AA, Johnston TP, Banach M, Majeed M, Sahebkar A. Curcumin: A Naturally Occurring Modulator of Adipokines in Diabetes. J Cell Biochem 2017; 118:4170-4182. [DOI: 10.1002/jcb.26121] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 05/08/2017] [Indexed: 01/30/2023]
Affiliation(s)
- Jafar Hajavi
- Immunology Research CenterMashhad University of Medical SciencesMashhadIran
| | - Amir Abbas Momtazi
- Student Research Committee, Nanotechnology Research CenterDepartment of Medical Biotechnology, School of Medicine, Mashhad University of Medical SciencesMashhadIran
| | - Thomas P. Johnston
- Division of Pharmaceutical Sciences, School of PharmacyUniversity of Missouri‐Kansas CityKansas CityMissouri
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in LodzMedical University of LodzZeromskiego 113LodzPoland
| | | | - Amirhossein Sahebkar
- Biotechnology Research CenterMashhad University of Medical SciencesMashhad9177948564Iran
- Neurogenic Inflammation Research CenterMashhad University of Medical SciencesMashhadIran
| |
Collapse
|
9
|
Rak A, Mellouk N, Froment P, Dupont J. Adiponectin and resistin: potential metabolic signals affecting hypothalamo-pituitary gonadal axis in females and males of different species. Reproduction 2017; 153:R215-R226. [DOI: 10.1530/rep-17-0002] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Revised: 03/14/2017] [Accepted: 03/22/2017] [Indexed: 12/14/2022]
Abstract
Adipokines, including adiponectin and resistin, are cytokines produced mainly by the adipose tissue. They play a significant role in metabolic functions that regulate the insulin sensitivity and inflammation. Alterations in adiponectin and resistin plasma levels, or their expression in metabolic and gonadal tissues, are observed in some metabolic pathologies, such as obesity. Several studies have shown that these two hormones and the receptors for adiponectin, AdipoR1 and AdipoR2 are present in various reproductive tissues in both sexes of different species. Thus, these adipokines could be metabolic signals that partially explain infertility related to obesity, such as polycystic ovary syndrome (PCOS). Species and gender differences in plasma levels, tissue or cell distribution and hormonal regulation have been reported for resistin and adiponectin. Furthermore, until now, it has been unclear whether adiponectin and resistin act directly or indirectly on the hypothalamo–pituitary–gonadal axis. The objective of this review was to summarise the latest findings and particularly the species and gender differences of adiponectin and resistin on female and male reproduction known to date, based on the hypothalamo–pituitary–gonadal axis.
Collapse
|
10
|
Mazaherioun M, Djalali M, Koohdani F, Javanbakht MH, Zarei M, Beigy M, Ansari S, Rezvan N, Saedisomeolia A. Beneficial Effects of n-3 Fatty Acids on Cardiometabolic and Inflammatory Markers in Type 2 Diabetes Mellitus: A Clinical Trial. Med Princ Pract 2017; 26:535-541. [PMID: 29017158 PMCID: PMC5848481 DOI: 10.1159/000484089] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 10/10/2017] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE To determine the effect of supplementation with n-3 polyunsaturated fatty acids (PUFAs) on circulatory resistin and monocyte chemoattractant protein 1 (MCP-1) levels in type 2 diabetes mellitus (T2DM) patients. SUBJECTS AND METHODS This was a 10-week, placebo-controlled, double-blind, randomized trial of n-3 PUFAs (2,700 mg/day) versus placebo (soft gels containing 900 mg of edible paraffin). Forty-four T2DM patients were supplemented with n-3 PUFAs and another 44 patients received placebo (3 patients discontinued the trial). Serum resistin, MCP-1, and the lipid profile were measured before and after supplementation. The adiponectin-resistin index (1 + log10 [resistin] - log10 [adiponectin]) and atherogenic index (log10 triglyceride/high-density lipoprotein cholesterol) of plasma (an indicator of cardiovascular complications) were assessed. The independent Student t test was used to assess the differences between the supplement and placebo groups and the paired t test to analyze the before/after changes. RESULTS In this study, n-3 PUFAs reduced serum MCP-1 levels (from 260.5 to 230.5 pg/mL; p = 0.002), but they remained unchanged in the placebo group. n-3 PUFAs could not decrease serum resistin levels. The adiponectin-resistin index was significantly reduced after supplementation with n-3 PUFAs when compared to the placebo. The atherogenic index was also significantly improved after supplementation with n-3 PUFAs (from 1.459 to 1.412; p = 0.006). CONCLUSIONS The MCP-1 levels and lipid profile were improved after supplementation with n-3 PUFAs, but resistin serum levels were not changed. Hence, the anti-inflammatory effects of n-3 PUFAs might be mediated by targeting MCP-1.
Collapse
Affiliation(s)
- Maryam Mazaherioun
- School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Djalali
- School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Fariba Koohdani
- School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mahnaz Zarei
- School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Maani Beigy
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Samaneh Ansari
- School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Rezvan
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Saedisomeolia
- School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pharmacology, School of Medicine, Western Sydney University, Sydney, New South Wales, Australia
- *Dr. Ahmad Saedisomeolia, Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran (Iran), E-Mail
| |
Collapse
|
11
|
Abstract
Malnutrition is the result of an inadequate balance between energy intake and energy expenditure that ultimately leads to either obesity or undernutrition. Several factors are associated with the onset and preservation of malnutrition. One of these factors is the gut microbiota, which has been recognized as an important pathophysiologic factor in the development and sustainment of malnutrition. However, to our knowledge, the extent to which the microbiota influences malnutrition has yet to be elucidated. In this review, we summarize the mechanisms via which the gut microbiota may influence energy homeostasis in relation to malnutrition. In addition, we discuss potential therapeutic modalities to ameliorate obesity or undernutrition.
Collapse
Affiliation(s)
- Nicolien C de Clercq
- Department of Internal and Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands;
| | - Albert K Groen
- Department of Internal and Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Johannes A Romijn
- Department of Internal and Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, Netherlands; and
- Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| |
Collapse
|
12
|
Pravenec M, Mlejnek P, Zídek V, Landa V, Šimáková M, Šilhavý J, Strnad H, Eigner S, Eigner Henke K, Škop V, Malínská H, Trnovská J, Kazdová L, Drahota Z, Mráček T, Houštěk J. Autocrine effects of transgenic resistin reduce palmitate and glucose oxidation in brown adipose tissue. Physiol Genomics 2016; 48:420-7. [PMID: 27113533 DOI: 10.1152/physiolgenomics.00122.2015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 04/06/2016] [Indexed: 12/23/2022] Open
Abstract
Resistin has been originally identified as an adipokine that links obesity to insulin resistance in mice. In our previous studies in spontaneously hypertensive rats (SHR) expressing a nonsecreted form of mouse resistin (Retn) transgene specifically in adipose tissue (SHR-Retn), we have observed an increased lipolysis and serum free fatty acids, ectopic fat accumulation in muscles, and insulin resistance. Recently, brown adipose tissue (BAT) has been suggested to play an important role in the pathogenesis of metabolic disturbances. In the current study, we have analyzed autocrine effects of transgenic resistin on BAT glucose and lipid metabolism and mitochondrial function in the SHR-Retn vs. nontransgenic SHR controls. We observed that interscapular BAT isolated from SHR-Retn transgenic rats compared with SHR controls showed a lower relative weight (0.71 ± 0.05 vs. 0.91 ± 0.08 g/100 g body wt, P < 0.05), significantly reduced both basal and insulin stimulated incorporation of palmitate into BAT lipids (658 ± 50 vs. 856 ± 45 and 864 ± 47 vs. 1,086 ± 35 nmol/g/2 h, P ≤ 0.01, respectively), and significantly decreased palmitate oxidation (37.6 ± 4.5 vs. 57 ± 4.1 nmol/g/2 h, P = 0.007) and glucose oxidation (277 ± 34 vs. 458 ± 38 nmol/g/2 h, P = 0.001). In addition, in vivo microPET imaging revealed significantly reduced (18)F-FDG uptake in BAT induced by exposure to cold in SHR-Retn vs. control SHR (232 ± 19 vs. 334 ± 22 kBq/ml, P < 0.05). Gene expression profiles in BAT identified differentially expressed genes involved in skeletal muscle and connective tissue development, inflammation and MAPK and insulin signaling. These results provide evidence that autocrine effects of resistin attenuate differentiation and activity of BAT and thus may play a role in the pathogenesis of insulin resistance in the rat.
Collapse
Affiliation(s)
- Michal Pravenec
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic;
| | - Petr Mlejnek
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Václav Zídek
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Vladimír Landa
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Miroslava Šimáková
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Jan Šilhavý
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Hynek Strnad
- Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic
| | - Sebastian Eigner
- Nuclear Physics Institute, Czech Academy of Sciences, Husinec-Řež, Czech Republic, Faculty of Pharmacy, Charles University in Prague, Hradec Králové, Czech Republic
| | | | - Vojtěch Škop
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Hana Malínská
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Jaroslava Trnovská
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Ludmila Kazdová
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Zdeněk Drahota
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Tomáš Mráček
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Josef Houštěk
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| |
Collapse
|
13
|
Feng J, Dai Z, Zhang Y, Meng L, Ye J, Ma X. Alteration of Gene Expression Profile in Kidney of Spontaneously Hypertensive Rats Treated with Protein Hydrolysate of Blue Mussel (Mytilus edulis) by DNA Microarray Analysis. PLoS One 2015; 10:e0142016. [PMID: 26517713 PMCID: PMC4627735 DOI: 10.1371/journal.pone.0142016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Accepted: 10/15/2015] [Indexed: 12/19/2022] Open
Abstract
Marine organisms are rich sources of bioactive components, which are often reported to have antihypertensive effects. However, the underlying mechanisms have yet to be fully identified. The aim of this study was to investigate the antihypertensive effect of enzymatic hydrolysis of blue mussel protein (HBMP) in rats. Peptides with in vitro ACE inhibitory activity were purified from HBMP by ultrafiltration, gel filtration chromatography and reversed-phase high performance liquid chromatography. And the amino acid sequences of isolated peptides were estimated to be Val-Trp, Leu-Gly-Trp, and Met-Val-Trp-Thr. To study its in vivo action, spontaneously hypertensive rats (SHRs) were orally administration with high- or low-dose of HBMP for 28 days. Major components of the renin-angiotensin (RAS) system in serum of SHRs from different groups were analyzed, and gene expression profiling were performed in the kidney of SHRs, using the Whole Rat Genome Oligonucleotide Microarray. Results indicated although genes involved in RAS system were not significantly altered, those related to blood coagulation system, cytokine and growth factor, and fatty acids metabolism were remarkablely changed. Several genes which were seldom reported to be implicated in pathogenesis of hypertension also showed significant expression alterations after oral administration of HBMP. These data provided valuable information for our understanding of the molecular mechanisms that underlie the potential antihypertensive activities of HBMP, and will contribute towards increased value-added utilization of blue mussel protein.
Collapse
Affiliation(s)
- Junli Feng
- Institute of Seafood, Zhejiang Gongshang University, Hangzhou, China
| | - Zhiyuan Dai
- Institute of Seafood, Zhejiang Gongshang University, Hangzhou, China
- * E-mail:
| | - Yanping Zhang
- School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, China
| | - Lu Meng
- Institute of Seafood, Zhejiang Gongshang University, Hangzhou, China
| | - Jian Ye
- Institute of Seafood, Zhejiang Gongshang University, Hangzhou, China
| | - Xuting Ma
- Institute of Seafood, Zhejiang Gongshang University, Hangzhou, China
| |
Collapse
|
14
|
Malinska H, Hüttl M, Oliyarnyk O, Bratova M, Kazdova L. Conjugated linoleic acid reduces visceral and ectopic lipid accumulation and insulin resistance in chronic severe hypertriacylglycerolemia. Nutrition 2015; 31:1045-51. [PMID: 26059381 DOI: 10.1016/j.nut.2015.03.011] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 02/25/2015] [Accepted: 03/12/2015] [Indexed: 01/16/2023]
Abstract
OBJECTIVE The metabolic health effects of conjugated linoleic acid (CLA), which is one of the principal polyunsaturated fatty acids, are controversial and still not fully accepted. The aim of this study was to examine the effects of CLA on adiposity, ectopic lipid accumulation, and insulin-resistant states in a metabolic syndrome model of non-obese hereditary rats with hypertriacylglycerolmia (HHTg). METHODS Groups of adult male HHTg rats were fed a high-carbohydrate diet (70% sucrose) with a 2% mixture of CLA isomers, or with the same amount of sunflower oil (control group) for 2 mo. RESULTS CLA supplementation decreased body weight gain (P < 0.05) and visceral adipose tissue weight (P < 0.01), and distinctively reduced serum triacylglycerols (P < 0.01) and triacylglycerol accumulation in the liver, heart, muscle, and aorta. CLA-treated rats exhibited increased insulin sensitivity in the adipose (P < 0.01), a higher release of fatty acids (P < 0.001), and increased adiponectin secretion (P < 0.01).In the skeletal muscle, CLA supplementation was associated with increased glucose oxidation (P < 0.01) and an elevated anti-inflammatory index (P < 0.05), according to phospholipid fatty acid composition. In the liver, CLA reduced the oxidized form of glutathione and elevated the activity of glutathione-dependent antioxidant enzymes. CONCLUSION Results suggest that CLA supplementation may protect against HHTg-induced dyslipidemia, ectopic lipid deposition, and insulin resistance. Increased glucose oxidation in the skeletal muscle as well as adiponectin secretion may play a role in the mechanism of the CLA action. Results suggest that CLA could reduce the negative consequences of HHTg and metabolic syndrome.
Collapse
Affiliation(s)
- Hana Malinska
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
| | - Martina Hüttl
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Olena Oliyarnyk
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Miriam Bratova
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Ludmila Kazdova
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| |
Collapse
|
15
|
Yu Z, Wang R, Fok WC, Coles A, Salmon AB, Pérez VI. Rapamycin and dietary restriction induce metabolically distinctive changes in mouse liver. J Gerontol A Biol Sci Med Sci 2014; 70:410-20. [PMID: 24755936 DOI: 10.1093/gerona/glu053] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Dietary restriction (DR) is the gold standard intervention used to delay aging, and much recent research has focused on the identification of possible DR mimetics. Energy sensing pathways, including insulin/IGF1 signaling, sirtuins, and mammalian Target of Rapamycin (mTOR), have been proposed as pathways involved in the antiaging actions of DR, and compounds that affect these pathways have been suggested to act as DR mimetics, including metformin (insulin/IGF1 signaling), resveratrol (sirtuins), and rapamycin (mTOR). Rapamycin is a promising DR mimetic because it significantly increases both health span and life span in mice. Unfortunately, rapamycin also leads to some negative effects, foremost among which is the induction of insulin resistance, potentially limiting its translation into humans. To begin clarifying the mechanism(s) involved in insulin resistance induced by rapamycin, we compared several aspects of liver metabolism in mice treated with DR or rapamycin for 6 months. Our data suggest that although both DR and rapamycin inhibit lipogenesis, activate lipolysis, and increased serum levels of nonesterified fatty acids, only DR further activates β-oxidation of the fatty acids leading to the production of ketone bodies.
Collapse
Affiliation(s)
- Zhen Yu
- Linus Pauling Institute, Oregon State University, Corvallis
| | - Rong Wang
- Linus Pauling Institute, Oregon State University, Corvallis
| | - Wilson C Fok
- Department of Geriatric Medicine, Oklahoma University Health Science Center and Oklahoma City VA Medical Center
| | - Alexander Coles
- Department of Chemistry and Biochemistry, University of Michigan-Flint
| | - Adam B Salmon
- Department of Molecular Medicine, Barshop Institute for Longevity and Aging Studies, and Audie Murphy VA Hospital, South Texas Veterans Health Care System, San Antonio, Texas
| | - Viviana I Pérez
- Linus Pauling Institute, Oregon State University, Corvallis. Department of Biochemistry and Biophysics, Oregon State University, Corvallis.
| |
Collapse
|
16
|
PRAVENEC M, KŘEN V, LANDA V, MLEJNEK P, MUSILOVÁ A, ŠILHAVÝ J, ŠIMÁKOVÁ M, ZÍDEK V. Recent Progress in the Genetics of Spontaneously Hypertensive Rats. Physiol Res 2014; 63:S1-8. [DOI: 10.33549/physiolres.932622] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and accompanying metabolic disturbances. Recent advances in sequencing of genomes of BN-Lx and SHR progenitors of the BXH/HXB recombinant inbred (RI) strains as well as accumulation of multiple data sets of intermediary phenotypes in the RI strains, including mRNA and microRNA abundance, quantitative metabolomics, proteomics, methylomics or histone modifications, will make it possible to systematically search for genetic variants involved in regulation of gene expression and in the etiology of complex pathophysiological traits. New advances in manipulation of the rat genome, including efficient transgenesis and gene targeting, will enable in vivo functional analyses of selected candidate genes to identify QTL at the molecular level or to provide insight into mechanisms whereby targeted genes affect pathophysiological traits in the SHR.
Collapse
Affiliation(s)
- M. PRAVENEC
- Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | | | | | | | | | | | | | | |
Collapse
|
17
|
HARIYA N, MOCHIZUKI K, INOUE S, MORIOKA K, SHIMADA M, OKUDA T, GODA T. Insulin Resistance in SHR/NDmc-cp Rats Correlates with Enlarged Perivascular Adipocytes and Endothelial Cell Dysfunction in Skeletal Muscle. J Nutr Sci Vitaminol (Tokyo) 2014; 60:52-9. [DOI: 10.3177/jnsv.60.52] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
|
18
|
Dong ZX, Su L, Brymora J, Bird C, Xie Q, George J, Wang JH. Resistin mediates the hepatic stellate cell phenotype. World J Gastroenterol 2013; 19:4475-4485. [PMID: 23901222 PMCID: PMC3725371 DOI: 10.3748/wjg.v19.i28.4475] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2012] [Revised: 02/13/2013] [Accepted: 03/29/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To describe the role of resistin in liver fibrosis.
METHODS: For the in vivo animal study, Sprague Dawley rats were subjected to bile duct ligation (BDL) for 4 wk. Rat liver, adipose tissue (epididymal fat) and serum were analyzed for resistin expression. For the in vitro experiment, rat primary hepatic stellate cells (HSCs) and Kupffer cells (KCs) were used. HSCs were exposed to recombinant resistin, and collagen I, transforming growth factor β1, α smooth muscle actin, tissue inhibitor of metalloproteinase 1 and connective tissue growth factor expression were analyzed. Resistin gene and protein expression was quantified as was the expression of pro-inflammatory cytokines including tumor necrosis factor α (TNFα), interleukin (IL)-1, IL-6, IL-8 and monocyte chemotactic protein-1 (MCP-1). The effects of resistin on HSC proliferation, migration and apoptosis were determined. The effects of resistin on KCs were also investigated.
RESULTS: Following BDL, rat epididymal fat and serum rather than liver showed higher resistin expression compared to control rats. In liver, resistin was expressed in quiescent HSCs and KCs. Resistin treatment resulted in enhancement of TNFα, IL-6, IL-8 and MCP-1 gene expression and increased IL-6 and MCP-1 protein in HSCs. Resistin activated HSC phospho-MAPK/p38, and p38 inhibition diminished IL-6 and MCP-1 expression. Furthermore, resistin facilitated HSC proliferation and migration, but decreased apoptosis which was via an IL-6 and MCP-1 mechanism. Finally, resistin-induced transforming growth factor β1 from KCs enhanced HSC collagen Iexpression.
CONCLUSION: Resistin directly and indirectly modulates HSC behavior towards a more pro-fibrogenic phenotype.
Collapse
|
19
|
Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3β. Gene 2013; 529:50-6. [PMID: 23860320 DOI: 10.1016/j.gene.2013.06.085] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 06/25/2013] [Accepted: 06/27/2013] [Indexed: 11/21/2022]
Abstract
The effect of mouse resistin on hepatic insulin resistance in vivo and in vitro, and its possible molecular mechanism were examined. Focusing on liver glycogen metabolism and gluconeogenesis, which are important parts of glucose metabolism, in primary cultures of rat hepatocytes we found that glycogen content was significantly lower (P<0.05) after treatment with recombinant murine resistin only in the presence of insulin plus glucose stimulation. Protein levels of factors in the insulin signaling pathway involved in glycogen synthesis were examined by Western blot analysis, with the only significant change observed being the level of phosphorylated (at Ser 9) glycogen synthase kinase-3β (GSK-3β) (P<0.001). No differences in the protein levels for the insulin receptor β (IRβ), insulin receptor substrates (IRS1 and IRS2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) or their phosphorylated forms were observed between control and resistin treated primary rat hepatocytes. In a mouse model with high liver-specific expression of resistin, fasting blood glucose levels and liver glycogen content changed. Fasting blood glucose levels were significantly higher (P<0.001) in the model mice, compared to the control mice, while the glycogen content of the liver tissue was about 60% of that of the control mice (P<0.05). The gluconeogenic response was not altered between the experimental and control mice. The level of phosphorylated GSK-3β in the liver tissue was also decreased (P<0.05) in the model mice, consistent with the results from the primary rat hepatocytes. Our results suggest that resistin reduces the levels of GSK-3β phosphorylated at Ser 9 leading to impaired hepatic insulin action in primary rat hepatocytes and in a mouse model with high liver-specific expression of resistin.
Collapse
|
20
|
Effects of alternate-day fasting on high-fat diet-induced insulin resistance in rat skeletal muscle. Life Sci 2013; 93:208-13. [PMID: 23782997 DOI: 10.1016/j.lfs.2013.06.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2013] [Revised: 05/20/2013] [Accepted: 06/06/2013] [Indexed: 02/03/2023]
Abstract
AIMS The purpose of this study was to investigate the effects of alternate-day fasting (ADF) on insulin-stimulated glucose transport activity in skeletal muscle in rats fed a high-fat diet. MAIN METHODS Male Wistar rats were placed on a high-fat diet (n=24) or standard chow diet (Chow, n=12) for 10weeks. Rats fed the high-fat diet were separated into two groups after 4weeks. One group was subjected to ADF for the subsequent 6weeks (HF-ADF, n=12), and the other group was maintained on an ad libitum diet (HF-AL, n=12). After the 10-week dietary intervention, measurements of insulin-stimulated glucose uptake and insulin tolerance test (ITT) were performed. KEY FINDINGS Whereas the total intra-abdominal fat mass in the HF-AL group was significantly higher than in the Chow and HF-ADF groups, there was no significant difference between the Chow and HF-ADF groups. However, insulin-stimulated glucose uptake in skeletal muscles was significantly lower in both high-fat fed groups than in the Chow group. Muscle GLUT-4 protein content in HF-AL is significantly lower (~30%) than in Chow, and further reduction (~42%) was observed in the HF-ADF group rats. The HF-ADF and HF-AL group rats had less reduction in glycemia than did the Chow group rats during ITT. SIGNIFICANCE ADF was unable to eliminate high-fat diet-induced muscle insulin resistance, despite a substantial decrease in total intra-abdominal fat mass. This might have resulted from a reduction in GLUT-4 protein in both HF-AL and HF-ADF rats compared to the Chow group.
Collapse
|
21
|
Bucci L, Yani SL, Fabbri C, Bijlsma AY, Maier AB, Meskers CG, Narici MV, Jones DA, McPhee JS, Seppet E, Gapeyeva H, Pääsuke M, Sipilä S, Kovanen V, Stenroth L, Musarò A, Hogrel JY, Barnouin Y, Butler-Browne G, Capri M, Franceschi C, Salvioli S. Circulating levels of adipokines and IGF-1 are associated with skeletal muscle strength of young and old healthy subjects. Biogerontology 2013; 14:261-72. [PMID: 23666343 DOI: 10.1007/s10522-013-9428-5] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Accepted: 04/29/2013] [Indexed: 01/20/2023]
Abstract
It is known that adipose tissue mass increases with age, and that a number of hormones, collectively called adipokines, are produced by adipose tissue. For most of them it is not known whether their plasmatic levels change with age. Moreover, it is known that adipose tissue infiltration in skeletal muscle is related to sarcopenia and loss of muscle strength. In this study we investigated the age-related changes of representative adipokines and insulin-like growth factor (IGF)-1 and their effect on muscle strength. We studied the association between circulating levels of adiponectin, leptin, resistin and IGF-1 and muscle strength. This cross-sectional study included 412 subjects of different age (152 subjects aged 18-30 years and 260 subjects aged 69-81 years) recruited within the framework of the European research network project "Myoage". The levels of adiponectin (both in male and female subjects) and leptin (only in males) were significantly higher in old subjects compared to young, while those of IGF-1 were lower in old subjects. In old subjects adiponectin, resistin and the resistin/IGF-1 ratio (but not IGF-1 alone) were inversely associated with quadriceps torque, while only adiponectin was inversely associated with handgrip strength independently from percentage of fat mass, height, age, gender and geographical origin. The ratio of leptin to adiponectin was directly associated with handgrip strength in both young and old subjects. These results suggest that in humans the age-associated loss of strength is associated with the levels of representative adipokines and IGF-1.
Collapse
Affiliation(s)
- Laura Bucci
- Department of Experimental, Diagnostic and Specialty Medicine and CIG-Interdepartmental Centre L. Galvani, University of Bologna, via S. Giacomo 12, 40126, Bologna, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
22
|
Benomar Y, Gertler A, De Lacy P, Crépin D, Ould Hamouda H, Riffault L, Taouis M. Central resistin overexposure induces insulin resistance through Toll-like receptor 4. Diabetes 2013; 62:102-14. [PMID: 22961082 PMCID: PMC3526022 DOI: 10.2337/db12-0237] [Citation(s) in RCA: 125] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Resistin promotes both inflammation and insulin resistance associated with energy homeostasis impairment. However, the resistin receptor and the molecular mechanisms mediating its effects in the hypothalamus, crucial for energy homeostasis control, and key insulin-sensitive tissues are still unknown. In the current study, we report that chronic resistin infusion in the lateral cerebral ventricle of normal rats markedly affects both hypothalamic and peripheral insulin responsiveness. Central resistin treatment inhibited insulin-dependent phosphorylation of insulin receptor (IR), AKT, and extracellular signal-related kinase 1/2 associated with reduced IR expression and with upregulation of suppressor of cytokine signaling-3 and phosphotyrosine phosphatase 1B, two negative regulators of insulin signaling. Additionally, central resistin promotes the activation of the serine kinases Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinase, enhances the serine phosphorylation of insulin receptor substrate-1, and increases the expression of the proinflammatory cytokine interleukin-6 in the hypothalamus and key peripheral insulin-sensitive tissues. Interestingly, we also report for the first time, to our knowledge, the direct binding of resistin to Toll-like receptor (TLR) 4 receptors in the hypothalamus, leading to the activation of the associated proinflammatory pathways. Taken together, our findings clearly identify TLR4 as the binding site for resistin in the hypothalamus and bring new insight into the molecular mechanisms involved in resistin-induced inflammation and insulin resistance in the whole animal.
Collapse
Affiliation(s)
- Yacir Benomar
- Unité Mixte de Recherche 8195, University Paris-Sud, Orsay, France
- Centre National de la Recherche Scientifique, Center of Neurosciences Paris-Sud, Unité Mixte de Recherche 8195, Orsay, France
| | - Arieh Gertler
- Faculty of Agricultural, Food and Environmental Quality Sciences, The Institute of Biochemistry, Food Science, and Nutrition, The Hebrew University of Jerusalem, Rehovot, Israel
| | | | - Delphine Crépin
- Unité Mixte de Recherche 8195, University Paris-Sud, Orsay, France
- Centre National de la Recherche Scientifique, Center of Neurosciences Paris-Sud, Unité Mixte de Recherche 8195, Orsay, France
| | - Hassina Ould Hamouda
- Unité Mixte de Recherche 8195, University Paris-Sud, Orsay, France
- Centre National de la Recherche Scientifique, Center of Neurosciences Paris-Sud, Unité Mixte de Recherche 8195, Orsay, France
| | - Laure Riffault
- Unité Mixte de Recherche 8195, University Paris-Sud, Orsay, France
- Centre National de la Recherche Scientifique, Center of Neurosciences Paris-Sud, Unité Mixte de Recherche 8195, Orsay, France
| | - Mohammed Taouis
- Unité Mixte de Recherche 8195, University Paris-Sud, Orsay, France
- Centre National de la Recherche Scientifique, Center of Neurosciences Paris-Sud, Unité Mixte de Recherche 8195, Orsay, France
- Corresponding author: Mohammed Taouis,
| |
Collapse
|
23
|
Kawamoto R, Tabara Y, Kohara K, Kusunoki T, Abe M, Miki T. Plasma Resistin Levels Are Associated with Insulin Resistance in Older Japanese Men from a Rural Village. Metab Syndr Relat Disord 2012; 10:380-6. [DOI: 10.1089/met.2012.0032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Ryuichi Kawamoto
- Department of Community Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Yasuharu Tabara
- Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Katsuhiko Kohara
- Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Tomo Kusunoki
- Department of Community Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Masanori Abe
- Department of Community Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Tetsuro Miki
- Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| |
Collapse
|
24
|
Gui Y, Silha JV, Murphy LJ. Sexual Dimorphism and Regulation of Resistin, Adiponectin, and Leptin Expression in the Mouse. ACTA ACUST UNITED AC 2012; 12:1481-91. [PMID: 15483213 DOI: 10.1038/oby.2004.185] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
OBJECTIVE To examine gender differences and hormonal regulation of resistin, adiponectin, and leptin. RESEARCH METHODS AND PROCEDURES Plasma levels were measured, and mRNA expression in perigonadal fat was quantified by RNase protection assays. RESULTS Plasma resistin declined with age despite an increase in adiposity in both genders. In male mice, plasma leptin increased, whereas adiponectin levels were constant. In females, both adiponectin and leptin levels increased with age. Resistin mRNA levels were significantly higher in female than male mice at all ages, whereas leptin and adiponectin mRNA levels were similar in fat from 6-week-old male and female mice, and sexual dimorphism was apparent only in the older mice, with higher levels apparent in females. Castration did not abolish gender differences in plasma levels or resistin, adiponectin, or leptin mRNAs. Castration of male mice did not significantly change adipokine mRNA levels or plasma levels of resistin or leptin; however, adiponectin was significantly increased. Dihydrotestosterone treatment had no effect on adipokine mRNA expression or resistin and adiponectin levels but increased leptin levels. In contrast, ovariectomy significantly increased resistin mRNA abundance and decreased leptin and adiponectin mRNAs. Plasma leptin levels were also increased by ovariectomy, whereas resistin and adiponectin levels were unchanged. Estrogen replacement significantly reduced resistin mRNA and increased leptin and adiponectin mRNA levels but had no effect on plasma adipokine levels. DISCUSSION The gender differences in adipokine mRNA expression and plasma levels were not ablated by castration and seem to be dependent on other factors in addition to gonadal steroids.
Collapse
Affiliation(s)
- Yaoting Gui
- Department of Physiology, University of Manitoba, Winnipeg, Canada
| | | | | |
Collapse
|
25
|
Luong KVQ, Nguyen LTH. The impact of thiamine treatment in the diabetes mellitus. J Clin Med Res 2012; 4:153-60. [PMID: 22719800 PMCID: PMC3376872 DOI: 10.4021/jocmr890w] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/03/2012] [Indexed: 01/19/2023] Open
Abstract
Thiamine acts as a coenzyme for transketolase (Tk) and for the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes, enzymes which play a fundamental role for intracellular glucose metabolism. The relationship between thiamine and diabetes mellitus (DM) has been reported in the literature. Thiamine levels and thiamine-dependent enzyme activities have been reduced in DM. Genetic studies provide opportunity to link the relationship between thiamine and DM (such as Tk, SLC19A2 gene, transcription factor Sp1, α-1-antitrypsin, and p53). Thiamine and its derivatives have been demonstrated to prevent the activation of the biochemical pathways (increased flux through the polyol pathway, formation of advanced glycation end-products, activation of protein kinase C, and increased flux through the hexosamine biosynthesis pathway) induced by hyperglycemia in DM.Thiamine definitively has a role in the diabetic endothelial vascular diseases (micro and macroangiopathy), lipid profile, retinopathy, nephropathy, cardiopathy, and neuropathy.
Collapse
|
26
|
Jamaluddin MS, Weakley SM, Yao Q, Chen C. Resistin: functional roles and therapeutic considerations for cardiovascular disease. Br J Pharmacol 2012. [PMID: 21545576 DOI: 10.1111/j.1476-5381.2011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
UNLABELLED Resistin, originally described as an adipocyte-specific hormone, has been suggested to be an important link between obesity, insulin resistance and diabetes. Although its expression was initially defined in adipocytes, significant levels of resistin expression in humans are mainly found in mononuclear leukocytes, macrophages, spleen and bone marrow cells. Increasing evidence indicates that resistin plays important regulatory roles apart from its role in insulin resistance and diabetes in a variety of biological processes: atherosclerosis and cardiovascular disease (CVD), non-alcoholic fatty liver disease, autoimmune disease, malignancy, asthma, inflammatory bowel disease and chronic kidney disease. As CVD accounts for a significant amount of morbidity and mortality in patients with diabetes and without diabetes, it is important to understand the role that adipokines such as resistin play in the cardiovascular system. Evidence suggests that resistin is involved in pathological processes leading to CVD including inflammation, endothelial dysfunction, thrombosis, angiogenesis and smooth muscle cell dysfunction. The modes of action and signalling pathways whereby resistin interacts with its target cells are beginning to be understood. In this review, the current knowledge about the functions and pathophysiological implications of resistin in CVD development is summarized; clinical translations, therapeutic considerations and future directions in the field of resistin research are discussed. LINKED ARTICLES This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3.
Collapse
Affiliation(s)
- Md S Jamaluddin
- Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
| | | | | | | |
Collapse
|
27
|
Jamaluddin MS, Weakley SM, Yao Q, Chen C. Resistin: functional roles and therapeutic considerations for cardiovascular disease. Br J Pharmacol 2012; 165:622-32. [PMID: 21545576 DOI: 10.1111/j.1476-5381.2011.01369.x] [Citation(s) in RCA: 339] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
UNLABELLED Resistin, originally described as an adipocyte-specific hormone, has been suggested to be an important link between obesity, insulin resistance and diabetes. Although its expression was initially defined in adipocytes, significant levels of resistin expression in humans are mainly found in mononuclear leukocytes, macrophages, spleen and bone marrow cells. Increasing evidence indicates that resistin plays important regulatory roles apart from its role in insulin resistance and diabetes in a variety of biological processes: atherosclerosis and cardiovascular disease (CVD), non-alcoholic fatty liver disease, autoimmune disease, malignancy, asthma, inflammatory bowel disease and chronic kidney disease. As CVD accounts for a significant amount of morbidity and mortality in patients with diabetes and without diabetes, it is important to understand the role that adipokines such as resistin play in the cardiovascular system. Evidence suggests that resistin is involved in pathological processes leading to CVD including inflammation, endothelial dysfunction, thrombosis, angiogenesis and smooth muscle cell dysfunction. The modes of action and signalling pathways whereby resistin interacts with its target cells are beginning to be understood. In this review, the current knowledge about the functions and pathophysiological implications of resistin in CVD development is summarized; clinical translations, therapeutic considerations and future directions in the field of resistin research are discussed. LINKED ARTICLES This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3.
Collapse
Affiliation(s)
- Md S Jamaluddin
- Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
| | | | | | | |
Collapse
|
28
|
Jean S, Landry D, Daigle M, Martin LJ. Influence of the adipose derived hormone resistin on signal transducer and activator of transcription factors, steroidogenesis and proliferation of Leydig cells. ASIAN PACIFIC JOURNAL OF REPRODUCTION 2012. [DOI: 10.1016/s2305-0500(13)60038-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
|
29
|
Makino-Wakagi Y, Yoshimura Y, Uzawa Y, Zaima N, Moriyama T, Kawamura Y. Ellagic acid in pomegranate suppresses resistin secretion by a novel regulatory mechanism involving the degradation of intracellular resistin protein in adipocytes. Biochem Biophys Res Commun 2012; 417:880-5. [DOI: 10.1016/j.bbrc.2011.12.067] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Accepted: 12/14/2011] [Indexed: 12/20/2022]
|
30
|
Čepica S, Óvilo C, Masopust M, Knoll A, Fernandez A, Lopez A, Rohrer GA, Nonneman D. Four genes located on a SSC2 meat quality QTL region are associated with different meat quality traits in Landrace × Chinese-European crossbred population. Anim Genet 2011; 43:333-6. [DOI: 10.1111/j.1365-2052.2011.02252.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
|
31
|
Terada S, Yamamoto S, Sekine S, Aoyama T. Dietary intake of medium- and long-chain triacylglycerols ameliorates insulin resistance in rats fed a high-fat diet. Nutrition 2011; 28:92-7. [PMID: 21872431 DOI: 10.1016/j.nut.2011.04.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Accepted: 04/30/2011] [Indexed: 10/17/2022]
Abstract
OBJECTIVE Excessive accumulation of visceral fat is strongly associated with insulin resistance. The present investigation examined the effects of dietary intake of medium- and long-chain triacylglycerols (MLCTs), which have been shown to induce significantly lower visceral fat accumulation in rats and humans, on high-fat diet-induced obesity and insulin resistance in rats. These effects were then compared with those observed in long-chain triacylglycerol (LCT)-fed rats. METHODS After an 8-wk feeding of a high-fat diet, which induced severe whole-body insulin resistance, male Sprague-Dawley rats were fed a standard diet containing LCTs or MLCTs for 6 wk. After the dietary treatment, an oral glucose tolerance test was performed. RESULTS Although body weight and total intra-abdominal fat mass did not differ between the two groups, mesenteric fat weight in the MLCT-fed group was significantly lower than that in the LCT group (P < 0.05). The increase in plasma insulin concentrations, but not in glucose, after glucose administration (area under the curve) was significantly smaller in the MLCT group than in the LCT group (P < 0.01) and was significantly associated with mesenteric fat weight (P < 0.05). MLCT-fed rats had significantly higher plasma adiponectin concentrations compared with LCT rats (P < 0.05). Adiponectin concentrations were negatively correlated with the area under the curve for plasma insulin (P < 0.05) and tended to be inversely related to mesenteric fat weight (P = 0.08). CONCLUSION These results suggest that dietary intake of MLCTs may improve insulin resistance in rats fed a high-fat diet, at least in part through increased adiponectin concentrations caused by a lower mesenteric fat mass.
Collapse
Affiliation(s)
- Shin Terada
- Central Research Laboratory, The Nisshin OilliO Group, Ltd., Yokosuka City, Kanagawa Prefecture, Japan.
| | | | | | | |
Collapse
|
32
|
Hsu WY, Chao YW, Tsai YL, Lien CC, Chang CF, Deng MC, Ho LT, Kwok CF, Juan CC. Resistin induces monocyte-endothelial cell adhesion by increasing ICAM-1 and VCAM-1 expression in endothelial cells via p38MAPK-dependent pathway. J Cell Physiol 2011; 226:2181-8. [PMID: 21520070 DOI: 10.1002/jcp.22555] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Resistin, firstly reported as an adipocyte-specific hormone, is suggested to be an important link between obesity and diabetes. Recent studies have suggested an association between resistin and atherogenic processes. The adhesion of circulating monocytes to endothelial cells is a critical step in the early stages of atherosclerosis. The purpose of the present study was to investigate the effect of resistin on the adhesion of THP-1 monocytes to human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. Our results showed that resistin caused a significant increase in monocyte adhesion. In exploring the underlying mechanisms of resistin action, we found that resistin-induced monocyte adhesion was blocked by inhibition of p38MAPK activation using SB203580 and SB202190. Furthermore, resistin increased the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) by HUVECs and these effects were also p38MAPK-dependent. Resistin-induced monocyte adhesion was also blocked by monoclonal antibodies against ICAM-1 and VCAM-1. Taken together, these results show that resistin increases both the expression of ICAM-1 and VCAM-1 by endothelial cells and monocyte adhesion to HUVECs via p38MAPK-dependent pathways.
Collapse
Affiliation(s)
- Wei-Yen Hsu
- Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | | | | | | | | | | | | | | | | |
Collapse
|
33
|
Pravenec M, Zídek V, Landa V, Simáková M, Mlejnek P, Silhavy J, Maxová M, Kazdová L, Seidman JG, Seidman CE, Eminaga S, Gorham J, Wang J, Kurtz TW. Age-related autocrine diabetogenic effects of transgenic resistin in spontaneously hypertensive rats: gene expression profile analysis. Physiol Genomics 2011; 43:372-9. [PMID: 21285283 DOI: 10.1152/physiolgenomics.00112.2010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Increased circulating levels of resistin have been proposed as a possible link between obesity and insulin resistance; however, many of the potential metabolic effects of resistin remain to be investigated, including systemic versus local resistin action. We investigated potential autocrine effects of resistin on lipid and glucose metabolism in 2- and 16-mo-old transgenic spontaneously hypertensive rats (SHR) expressing a nonsecreted form of mouse resistin under control of the aP2 promoter. To search for possible molecular mechanisms, we compared gene expression profiles in adipose tissue in 6-wk-old transgenic SHR versus control rats, before development of insulin resistance, by digital transcriptional profiling using high-throughput sequencing. Both young and old transgenic rats showed moderate expression of the resistin transgene in adipose tissue but had serum resistin levels similar to control SHR and undetectable levels of transgenic resistin in the circulation. Young transgenic rats exhibited mild glucose intolerance. In contrast, older transgenic rats displayed marked glucose intolerance in association with near total resistance of adipose tissue to insulin-stimulated glucose incorporation into lipids (6 ± 2 vs. 77 ± 19 nmol glucose·g(-1)·2 h(-1), P < 0.00001). Ingenuity Pathway Analysis of differentially expressed genes revealed calcium signaling, Nuclear factor-erythroid 2-related factor-2 (NRF2)-mediated oxidative stress response, and actin cytoskeletal signaling canonical pathways as those most significantly affected. Analysis using DAVID software revealed oxidative phosphorylation, glutathione metabolism, pyruvate metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling as top Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. These results suggest that with increasing age autocrine effects of resistin in fat tissue may predispose to diabetes in part by impairing insulin action in adipose tissue.
Collapse
Affiliation(s)
- Michal Pravenec
- Institute of Physiology, Czech Academy of Sciences, 14220 Prague 4, Czech Republic.
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
34
|
Li FP, Li ZZ, Zhang M, Yan L, Fu ZZ. Effects of resistin on skeletal glucose metabolism. ACTA ACUST UNITED AC 2010; 4:329-35. [PMID: 21191840 DOI: 10.1007/s11684-010-0091-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2010] [Accepted: 05/10/2010] [Indexed: 01/15/2023]
Abstract
Resistin is an adipokine highly related to insulin resistance (IR). The purpose of our research was to investigate how resistin influences skeletal glucose metabolism and explore its mechanisms. We constructed the recombinant plasmid pcDNA3.1 expressing resistin and then transfected it into C2C12 myocytes. The expression of resistin in C2C12 myocytes was detected by Western blotting. Glucose uptake was measured by 3H labeled glucose; glucose oxidation and glycogen synthesis was detected with 14C-labeled glucose. GLUT4 mRNA was measured by reverse transcription polymerase chain reaction (RT-PCR). We observed that resistin was expressed in transfected myocytes, and resistin decreased insulin induced glucose uptake rate by 28%-31% and inhibited the expression of GLUT4 mRNA. However, there was no significant difference in basal glucose uptake, and glucose oxidation and glycogen synthesis remained unchanged in all groups. It is concluded that resistin inhibits insulin induced glucose uptake in myocytes by downregulating the expression of GLUT4 and it has no effects on glucose oxidation and glycogen synthesis. Our findings may provide a clue to understand the roles of resistin in the pathogenesis of skeletal IR.
Collapse
Affiliation(s)
- Fang-Ping Li
- Department of Endocrinology, The Second Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
| | | | | | | | | |
Collapse
|
35
|
Martos-Moreno GA, Chowen JA, Argente J. Metabolic signals in human puberty: effects of over and undernutrition. Mol Cell Endocrinol 2010; 324:70-81. [PMID: 20026379 DOI: 10.1016/j.mce.2009.12.017] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2009] [Revised: 12/08/2009] [Accepted: 12/11/2009] [Indexed: 01/19/2023]
Abstract
Puberty in mammals is associated with important physical and psychological changes due to the increase in sex steroids and growth hormone (GH). Indeed, an increase in growth velocity and the attainment of sexual maturity for future reproductive function are the hallmark changes during this stage of life. Both growth and reproduction consume high levels of energy, requiring suitable energy stores to face these physiological functions. During the last two decades our knowledge concerning how peptides produced in the digestive tract (in charge of energy intake) and in adipose tissue (in charge of energy storage) provide information regarding metabolic status to the central nervous system (CNS) has increased dramatically. Moreover, these peptides have been shown to play an important role in modulating the gonadotropic axis with their absence or an imbalance in their secretion being able to disturb pubertal onset or progression. In this article we will review the current knowledge concerning the role played by leptin, the key adipokine in energy homeostasis, and ghrelin, the only orexigenic and growth-promoting peptide produced by the digestive tract, on sexual development. The normal evolutionary pattern of these peripherally produced metabolic signals throughout human puberty will be summarized. The effect of two opposite situations of chronic malnutrition, obesity and anorexia, on these signals and how they influence the course of puberty will also be discussed. Finally, we will briefly mention other peptides derived from the digestive tract (such as PYY) that may be involved in the regulatory link between energy homeostasis and sexual development.
Collapse
Affiliation(s)
- G A Martos-Moreno
- Hospital Infantil Universitario Niño Jesús, Department of Endocrinology, Universidad Autónoma de Madrid, Madrid, Spain
| | | | | |
Collapse
|
36
|
Saini V. Molecular mechanisms of insulin resistance in type 2 diabetes mellitus. World J Diabetes 2010; 1:68-75. [PMID: 21537430 PMCID: PMC3083885 DOI: 10.4239/wjd.v1.i3.68] [Citation(s) in RCA: 152] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2010] [Revised: 06/22/2010] [Accepted: 06/29/2010] [Indexed: 02/05/2023] Open
Abstract
Free fatty acids are known to play a key role in promoting loss of insulin sensitivity in type 2 diabetes mellitus but the underlying mechanism is still unclear. It has been postulated that an increase in the intracellular concentration of fatty acid metabolites activates a serine kinase cascade, which leads to defects in insulin signaling downstream to the insulin receptor. In addition, the complex network of adipokines released from adipose tissue modulates the response of tissues to insulin. Among the many molecules involved in the intracellular processing of the signal provided by insulin, the insulin receptor substrate-2, the protein kinase B and the forkhead transcription factor Foxo 1a are of particular interest, as recent data has provided strong evidence that dysfunction of these proteins results in insulin resistance in vivo. Recently, studies have revealed that phosphoinositidedependent kinase 1-independent phosphorylation of protein kinase Cε causes a reduction in insulin receptor gene expression. Additionally, it has been suggested that mitochondrial dysfunction triggers activation of several serine kinases, and weakens insulin signal transduction. Thus, in this review, the current developments in understanding the pathophysiological processes of insulin resistance in type 2 diabetes have been summarized. In addition, this study provides potential new targets for the treatment and prevention of type 2 diabetes.
Collapse
Affiliation(s)
- Vandana Saini
- Vandana Saini, Department of Biochemistry, Lady Hardinge Medical College, New Delhi 110001, India
| |
Collapse
|
37
|
Richards JC, Johnson TK, Kuzma JN, Lonac MC, Schweder MM, Voyles WF, Bell C. Short-term sprint interval training increases insulin sensitivity in healthy adults but does not affect the thermogenic response to beta-adrenergic stimulation. J Physiol 2010. [PMID: 20547683 DOI: 10.1113/jphysiol.2010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Sprint interval training (SIT) and traditional endurance training elicit similar physiological adaptations. From the perspective of metabolic function, superior glucose regulation is a common characteristic of endurance-trained adults. Accordingly, we have investigated the hypothesis that short-term SIT will increase insulin sensitivity in sedentary/recreationally active humans. Thirty one healthy adults were randomly assigned to one of three conditions: (1) SIT (n = 12): six sessions of repeated (4-7) 30 s bouts of very high-intensity cycle ergometer exercise over 14 days; (2) sedentary control (n = 10); (3) single-bout SIT (n = 9): one session of 4 x 30 s cycle ergometer sprints. Insulin sensitivity was determined (hyperinsulinaemic euglycaemic clamp) prior to and 72 h following each intervention. Compared with baseline, and sedentary and single-bout controls, SIT increased insulin sensitivity (glucose infusion rate: 6.3 +/- 0.6 vs. 8.0 +/- 0.8 mg kg(1) min(1); mean +/- s.e.m.; P = 0.04). In a separate study, we investigated the effect of SIT on the thermogenic response to beta-adrenergic receptor (beta-AR) stimulation, an important determinant of energy balance. Compared with baseline, and sedentary and single-bout control groups, SIT did not affect resting energy expenditure (EE: ventilated hood technique; 6274 +/- 226 vs. 6079 +/- 297 kJ day(1); P = 0.51) or the thermogenic response to isoproterenol (6, 12 and 24 ng (kg fat-free mass)(1) min(1): %EE 11 +/- 2, 14 +/- 3, 23 +/- 2 vs. 11 +/- 1, 16 +/- 2, 25 +/- 3; P = 0.79). Combined data from both studies revealed no effect of SIT on fasted circulating concentrations of glucose, insulin, adiponectin, pigment epithelial-derived factor, non-esterified fatty acids or noradrenaline (all P > 0.05). Sixteen minutes of high-intensity exercise over 14 days augments insulin sensitivity but does not affect the thermogenic response to beta-AR stimulation.
Collapse
Affiliation(s)
- Jennifer C Richards
- Department of Health and Exercise Science, Colorado State University, Fort Collins, CO 80523-1582, USA
| | | | | | | | | | | | | |
Collapse
|
38
|
Richards JC, Johnson TK, Kuzma JN, Lonac MC, Schweder MM, Voyles WF, Bell C. Short-term sprint interval training increases insulin sensitivity in healthy adults but does not affect the thermogenic response to beta-adrenergic stimulation. J Physiol 2010; 588:2961-72. [PMID: 20547683 DOI: 10.1113/jphysiol.2010.189886] [Citation(s) in RCA: 129] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Sprint interval training (SIT) and traditional endurance training elicit similar physiological adaptations. From the perspective of metabolic function, superior glucose regulation is a common characteristic of endurance-trained adults. Accordingly, we have investigated the hypothesis that short-term SIT will increase insulin sensitivity in sedentary/recreationally active humans. Thirty one healthy adults were randomly assigned to one of three conditions: (1) SIT (n = 12): six sessions of repeated (4-7) 30 s bouts of very high-intensity cycle ergometer exercise over 14 days; (2) sedentary control (n = 10); (3) single-bout SIT (n = 9): one session of 4 x 30 s cycle ergometer sprints. Insulin sensitivity was determined (hyperinsulinaemic euglycaemic clamp) prior to and 72 h following each intervention. Compared with baseline, and sedentary and single-bout controls, SIT increased insulin sensitivity (glucose infusion rate: 6.3 +/- 0.6 vs. 8.0 +/- 0.8 mg kg(1) min(1); mean +/- s.e.m.; P = 0.04). In a separate study, we investigated the effect of SIT on the thermogenic response to beta-adrenergic receptor (beta-AR) stimulation, an important determinant of energy balance. Compared with baseline, and sedentary and single-bout control groups, SIT did not affect resting energy expenditure (EE: ventilated hood technique; 6274 +/- 226 vs. 6079 +/- 297 kJ day(1); P = 0.51) or the thermogenic response to isoproterenol (6, 12 and 24 ng (kg fat-free mass)(1) min(1): %EE 11 +/- 2, 14 +/- 3, 23 +/- 2 vs. 11 +/- 1, 16 +/- 2, 25 +/- 3; P = 0.79). Combined data from both studies revealed no effect of SIT on fasted circulating concentrations of glucose, insulin, adiponectin, pigment epithelial-derived factor, non-esterified fatty acids or noradrenaline (all P > 0.05). Sixteen minutes of high-intensity exercise over 14 days augments insulin sensitivity but does not affect the thermogenic response to beta-AR stimulation.
Collapse
Affiliation(s)
- Jennifer C Richards
- Department of Health and Exercise Science, Colorado State University, Fort Collins, CO 80523-1582, USA
| | | | | | | | | | | | | |
Collapse
|
39
|
Zhang J, Lei T, Chen X, Peng Y, Long H, Zhou L, Huang J, Chen Z, Long Q, Yang Z. Resistin up-regulates COX-2 expression via TAK1-IKK-NF-kappaB signaling pathway. Inflammation 2010; 33:25-33. [PMID: 19774455 DOI: 10.1007/s10753-009-9155-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The hormone resistin, which was originally shown to induce insulin resistance, has been implicated in the regulation of inflammatory processes, but the molecular mechanism underlying such regulation has not been clearly defined. The goal of our study was to determine whether the expression of COX-2 can be induced by resistin and what the potential signaling pathway involved in this process is. Compared with controls, resistin significantly upregulated COX-2 expression in RAW264.7 macrophage cells. Administration of anti-resistin antibody could significantly reduce this effect. Induction of COX-2 by resistin was also markedly reduced in the presence of either dominant negative mutant IkappaBalpha or PDTC, a pharmacological inhibitor of NF-kappaB. On the other hand, NF-kappaB subunit p65 was upregulated by resistin. Moreover, we found that transforming growth factor-beta-activated kinase 1 (TAK1), a mitogen-activated protein kinase kinase kinase (MAPKKK), could be activated in response to resistin. These results suggest that resistin enhances COX-2 expression in mouse macrophage cells in a TAK1-IKK-NF-kappaB-dependent manner and therefore plays a critical role in inflammatory processes.
Collapse
Affiliation(s)
- Jian Zhang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Life Science and Technology, HuaZhong Agricultural University, Wuhan 430070, People's Republic of China
| | | | | | | | | | | | | | | | | | | |
Collapse
|
40
|
Filková M, Haluzík M, Gay S, Senolt L. The role of resistin as a regulator of inflammation: Implications for various human pathologies. Clin Immunol 2009; 133:157-70. [PMID: 19740705 DOI: 10.1016/j.clim.2009.07.013] [Citation(s) in RCA: 311] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2009] [Revised: 07/24/2009] [Accepted: 07/29/2009] [Indexed: 12/28/2022]
Abstract
Resistin was originally described as an adipocyte-secreted peptide that induced insulin resistance in rodents. Increasing evidence indicates its important regulatory roles in various biological processes, including several inflammatory diseases. Further studies have shown that resistin in humans, in contrast to its production by adipocytes in mice, is synthesized predominantly by mononuclear cells both within and outside adipose tissue. Possible roles for resistin in obesity-related subclinical inflammation, atherosclerosis and cardiovascular disease, non-alcoholic fatty liver disease, rheumatic diseases, malignant tumors, asthma, inflammatory bowel disease, and chronic kidney disease have already been demonstrated. In addition, resistin can modulate several molecular pathways involved in metabolic, inflammatory, and autoimmune diseases. In this review, current knowledge about the functions and pathophysiological implications of resistin in different human pathologies is summarized, although there is a significant lack of firm evidence regarding the specific role resistin plays in the "orchestra" of the numerous mediators of inflammation.
Collapse
Affiliation(s)
- Mária Filková
- Institute of Rheumatology and Connective Tissue Research Laboratory, Department of Rheumatology of First Faculty of Medicine, Charles University in Prague, Na Slupi 4, Prague 2, 128 50, Czech Republic
| | | | | | | |
Collapse
|
41
|
Adipokines in nonalcoholic steatohepatitis: from pathogenesis to implications in diagnosis and therapy. Mediators Inflamm 2009; 2009:831670. [PMID: 19753129 PMCID: PMC2694309 DOI: 10.1155/2009/831670] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2009] [Accepted: 04/06/2009] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and can vary from benign steatosis to end-stage liver disease. The pathogenesis of non-alcoholic steatohepatitis (NASH) is currently thought to involve a multiple-hit process with the first hit being the accumulation of liver fat which is followed by the development of necroinflammation and fibrosis. There is mounting evidence that cytokines secreted from adipose tissue, namely, adipokines, are implicated in the pathogenesis and progression of NAFLD. In the current review, we explore the role of these adipokines, particularly leptin, adiponectin, resistin, tumor necrosis factor-a, and interleukin-6 in NASH, as elucidated in experimental models and clinical practice. We also comment on their potential use as noninvasive markers for differentiating simple fatty liver from NASH as well as on their potential future therapeutic role in patients with NASH.
Collapse
|
42
|
Kuda O, Jelenik T, Jilkova Z, Flachs P, Rossmeisl M, Hensler M, Kazdova L, Ogston N, Baranowski M, Gorski J, Janovska P, Kus V, Polak J, Mohamed-Ali V, Burcelin R, Cinti S, Bryhn M, Kopecky J. n-3 fatty acids and rosiglitazone improve insulin sensitivity through additive stimulatory effects on muscle glycogen synthesis in mice fed a high-fat diet. Diabetologia 2009; 52:941-951. [PMID: 19277604 DOI: 10.1007/s00125-009-1305-z] [Citation(s) in RCA: 115] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2008] [Accepted: 02/02/2009] [Indexed: 01/09/2023]
Abstract
AIMS/HYPOTHESIS Fatty acids of marine origin, i.e. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) act as hypolipidaemics, but they do not improve glycaemic control in obese and diabetic patients. Thiazolidinediones like rosiglitazone are specific activators of peroxisome proliferator-activated receptor gamma, which improve whole-body insulin sensitivity. We hypothesised that a combined treatment with a DHA and EPA concentrate (DHA/EPA) and rosiglitazone would correct, by complementary additive mechanisms, impairments of lipid and glucose homeostasis in obesity. METHODS Male C57BL/6 mice were fed a corn oil-based high-fat diet. The effects of DHA/EPA (replacing 15% dietary lipids), rosiglitazone (10 mg/kg diet) or a combination of both on body weight, adiposity, metabolic markers and adiponectin in plasma, as well as on liver and muscle gene expression and metabolism were analysed. Euglycaemic-hyperinsulinaemic clamps were used to characterise the changes in insulin sensitivity. The effects of the treatments were also analysed in dietary obese mice with impaired glucose tolerance (IGT). RESULTS DHA/EPA and rosiglitazone exerted additive effects in prevention of obesity, adipocyte hypertrophy, low-grade adipose tissue inflammation, dyslipidaemia and insulin resistance, while inducing adiponectin, suppressing hepatic lipogenesis and decreasing muscle ceramide concentration. The improvement in glucose tolerance reflected a synergistic stimulatory effect of the combined treatment on muscle glycogen synthesis and its sensitivity to insulin. The combination treatment also reversed dietary obesity, dyslipidaemia and IGT. CONCLUSIONS/INTERPRETATION DHA/EPA and rosiglitazone can be used as complementary therapies to counteract dyslipidaemia and insulin resistance. The combination treatment may reduce dose requirements and hence the incidence of adverse side effects of thiazolidinedione therapy.
Collapse
Affiliation(s)
- O Kuda
- Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
43
|
Junkin KA, Dyck DJ, Mullen KL, Chabowski A, Thrush AB. Resistin acutely impairs insulin-stimulated glucose transport in rodent muscle in the presence, but not absence, of palmitate. Am J Physiol Regul Integr Comp Physiol 2009; 296:R944-51. [PMID: 19193939 DOI: 10.1152/ajpregu.90971.2008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Resistin is a cytokine implicated in the development of insulin resistance. However, there has been little investigation of the effects of resistin on fatty acid (FA) metabolism and insulin response in skeletal muscle, a key tissue for glucose disposal. The purpose of the present study was to examine the role of altered FA metabolism as a cause of resistin's inhibition of insulin-stimulated glucose transport in muscle. Isolated rat soleus muscles were incubated acutely (2 h) in the presence or absence of 600 ng/ml resistin, with or without 2 mM palmitate. Resistin acutely impaired insulin-stimulated glucose transport and Akt phosphorylation, but only in the presence of palmitate, implicating a role for altered FA metabolism. This impairment of glucose transport induced by resistin plus palmitate could be pharmacologically rescued by the inclusion of aimidazole carboxamide ribonucleotide, a stimulator of AMP-activated protein kinase and FA oxidation, as well as inhibitors of ceramide synthesis (myriocin, fumonisin). However, to our surprise, resistin actually blunted the palmitate-induced increase in muscle ceramide content; as expected, ceramide content was significantly lowered by fumonisin. In summary, the acute impairment of insulin response by resistin was manifested only in the presence of high palmitate and was alleviated when FA metabolism was manipulated (increased oxidation, inhibited ceramide synthesis). Resistin's acute impairment of insulin response does not appear to require an absolute increase in ceramide content; however, reducing ceramide content alleviated the impairment in glucose transport and insulin signaling.
Collapse
Affiliation(s)
- Kathryn A Junkin
- Department of Human Health and Nutritional Sciences, University of Guelph, Ontario, Canada N1G 2W1
| | | | | | | | | |
Collapse
|
44
|
Qatanani M, Szwergold NR, Greaves DR, Ahima RS, Lazar MA. Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice. J Clin Invest 2009; 119:531-9. [PMID: 19188682 DOI: 10.1172/jci37273] [Citation(s) in RCA: 160] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2008] [Accepted: 12/08/2008] [Indexed: 01/06/2023] Open
Abstract
Resistin is an adipokine that contributes to insulin resistance in mice. In humans, however, studies investigating the link between resistin and metabolic disease are conflicting. Further complicating the matter, human resistin is produced mainly by macrophages rather than adipocytes. To address this important issue, we generated mice that lack adipocyte-derived mouse resistin but produce human resistin in a pattern similar to that found in humans, i.e., in macrophages (humanized resistin mice). When placed on a high-fat diet, the humanized resistin mice rapidly developed accelerated white adipose tissue (WAT) inflammation, leading to increased lipolysis and increased serum free fatty acids. Over time, these mice accumulated lipids, including diacylglycerols, in muscle. We found that this resulted in increased Pkcq pathway activity, leading to increased serine phosphorylation of Irs-1 and insulin resistance. Thus, although the site of resistin production differs between species, human resistin exacerbates WAT inflammation and contributes to insulin resistance.
Collapse
Affiliation(s)
- Mohammed Qatanani
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6149, USA
| | | | | | | | | |
Collapse
|
45
|
van Schothorst EM, Bunschoten A, Schrauwen P, Mensink RP, Keijer J. Effects of a high-fat, low- versus high-glycemic index diet: retardation of insulin resistance involves adipose tissue modulation. FASEB J 2008; 23:1092-101. [PMID: 19029198 DOI: 10.1096/fj.08-117119] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Beneficial effects of low glycemic index (GI) diets in rodents have been studied using healthy low-fat diets, while the effects might be different on high-fat diets inducing progression of insulin resistance. We fed C57BL/6J male mice high-fat low/high-GI (LGI/HGI) diets for 13 wk. Glucose and insulin tolerance and serum substrates, including adipokines, were measured longitudinally. The LGI group showed a significantly higher glucose tolerance from wk 2 onwards, which was supported by lower serum insulin and free fatty acids levels at 8 wk, and a tendency for lower leptin levels, while resistin levels remained similar. At 11 wk, when differences in serum resistin started to increase, differences in serum insulin were diminished. Although food intake was similar throughout the study, body weights and epididymal adipose tissue mass became significantly lower in the LGI group at necropsy. Several serum substrates and adipose tissue leptin mRNA levels, as analyzed by Q-PCR, were, again, significantly lower, whereas adiponectin mRNA levels were higher. Taken together, an LGI high-fat diet maintains higher glucose tolerance and insulin sensitivity via adipose tissue modulation solely because of a difference in the type of carbohydrate, supporting a nutritional approach in the fight against insulin resistance.
Collapse
|
46
|
Rabe K, Lehrke M, Parhofer KG, Broedl UC. Adipokines and insulin resistance. Mol Med 2008; 14:741-51. [PMID: 19009016 DOI: 10.2119/2008-00058.rabe] [Citation(s) in RCA: 512] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2008] [Accepted: 09/08/2008] [Indexed: 12/27/2022] Open
Abstract
Obesity is associated with an array of health problems in adult and pediatric populations. Understanding the pathogenesis of obesity and its metabolic sequelae has advanced rapidly over the past decades. Adipose tissue represents an active endocrine organ that, in addition to regulating fat mass and nutrient homeostasis, releases a large number of bioactive mediators (adipokines) that signal to organs of metabolic importance including brain, liver, skeletal muscle, and the immune system--thereby modulating hemostasis, blood pressure, lipid and glucose metabolism, inflammation, and atherosclerosis. In the present review, we summarize current data on the effect of the adipose tissue-derived hormones adiponectin, chemerin, leptin, omentin, resistin, retinol binding protein 4, tumor necrosis factor-alpha and interleukin-6, vaspin, and visfatin on insulin resistance.
Collapse
Affiliation(s)
- Katja Rabe
- Department of Internal Medicine II, University of Munich, Munich, Germany
| | | | | | | |
Collapse
|
47
|
Singhal NS, Patel RT, Qi Y, Lee YS, Ahima RS. Loss of resistin ameliorates hyperlipidemia and hepatic steatosis in leptin-deficient mice. Am J Physiol Endocrinol Metab 2008; 295:E331-8. [PMID: 18505833 PMCID: PMC2519749 DOI: 10.1152/ajpendo.00577.2007] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Resistin has been linked to components of the metabolic syndrome, including obesity, insulin resistance, and hyperlipidemia. We hypothesized that resistin deficiency would reverse hyperlipidemia in genetic obesity. C57Bl/6J mice lacking resistin [resistin knockout (RKO)] had similar body weight and fat as wild-type mice when fed standard rodent chow or a high-fat diet. Nonetheless, hepatic steatosis, serum cholesterol, and very low-density lipoprotein (VLDL) secretion were decreased in diet-induced obese RKO mice. Resistin deficiency exacerbated obesity in ob/ob mice, but hepatic steatosis was drastically attenuated. Moreover, the levels of triglycerides, cholesterol, insulin, and glucose were reduced in ob/ob-RKO mice. The antisteatotic effect of resistin deficiency was related to reductions in the expression of genes involved in hepatic lipogenesis and VLDL export. Together, these results demonstrate a crucial role of resistin in promoting hepatic steatosis and hyperlipidemia in obese mice.
Collapse
Affiliation(s)
- Neel S Singhal
- Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania School of Medicine, 415 Curie Blvd., Philadelphia, PA 19104, USA
| | | | | | | | | |
Collapse
|
48
|
Yang Y, Xiao M, Mao Y, Li H, Zhao S, Gu Y, Wang R, Yu J, Zhang X, Irwin DM, Niu G, Tan H. Resistin and insulin resistance in hepatocytes: resistin disturbs glycogen metabolism at the protein level. Biomed Pharmacother 2008; 63:366-74. [PMID: 18672341 DOI: 10.1016/j.biopha.2008.06.033] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2008] [Accepted: 06/12/2008] [Indexed: 01/19/2023] Open
Abstract
Resistin has been considered to link obesity with type 2 diabetes. Liver glycogen metabolism plays an essential role in maintaining glucose homeostasis, we investigated the effect of resistin on liver glycogen metabolism and attempted to identify its role in initiating insulin resistance and type 2 diabetes. Primary culture of rat hepatocytes was treated by resistin and insulin. Glycogen content was determined by the anthrone-reagent method. Real-time PCR, Western blot and enzymatic activity assay were used to detect key enzymes and genes involved in glucose metabolism. Hepatocytes exposed to resistin, but only in the presence of insulin, show a decrease in insulin-stimulated glycogen content. Decreased insulin receptor expression and GS activity and elevated GP activity was observed after the treatment of hepatocytes with resistin. No significant changes in the expression of the genes for these proteins were observed. These results strongly suggest that resistin effects glycogen metabolism at the protein level, and resistin is highly associated with insulin resistance and type 2 diabetes and is a candidate for the prevention and treatment of type 2 diabetes. Our results should lead to the development of novel strategies for the treatment of type 2 diabetes.
Collapse
Affiliation(s)
- Yang Yang
- Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
49
|
Juan CC, Lien CC, Chang CL, Huang YH, Ho LT. Involvement of iNOS and NO in TNF-alpha-downregulated resistin gene expression in 3T3-L1 adipocytes. Obesity (Silver Spring) 2008; 16:1219-25. [PMID: 18369347 DOI: 10.1038/oby.2008.200] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE In order to characterize the regulation of resistin gene expression, we explore the effect of tumornecrosis factor-alpha (TNF-alpha) on resistin mRNA expression and its underlying mechanism in 3T3-L1 adipocytes. METHODS AND PROCEDURES Differentiated 3T3-L1 adipocytes were treated for 24 h with 0-10 ng/ml of TNF-alpha or with 2.5 ng/ml of TNF-alpha for 0-24 h, and then resistin mRNA levels were measured by northern blotting. To further explore the involvement of nitric oxide (NO) in TNF-alpha-regulated resistin expression, the effect of the NO donor, sodium nitroprusside (SNP), on resistin mRNA levels in adipocytes and the effect of the nitric oxide synthase (NOS) inhibitors, N(G)-nitro-L-arginine methyl ester (L-NAME), and S,S'-1,3-phenylene-bis(1,2-ethanediyl)-bis-isothiourea.2HBr (PBITU), on the TNF-alpha effect in adipocytes were examined. The effects of TNF-alpha on inducible NOS (iNOS) protein expression in adipocytes were also measured by western blotting. RESULTS Our results showed that TNF-alpha caused a dose-dependent reduction in resistin mRNA levels. This effect seemed to be associated with the TNF-alpha-induced expression of iNOS. The results showed that TNF-alpha induced iNOS expression and release of NO after 24-h treatment of differentiated 3T3-L1 adipocytes. Pretreatment with L-NAME and PBITU significantly reversed the TNF-alpha-induced downregulation of resistin expression, while treatment with SNP mimicked the inhibitory effect of TNF-alpha on resistin expression. In addition, pretreatment with protein tyrosine kinase (PTK) inhibitors, genistein and AG-1288, prevented TNF-alpha-induced iNOS expression and subsequent resistin downregulation. DISCUSSION Our data suggest that TNF-alpha suppresses resistin expression by inducing iNOS expression, thus causing overproduction of NO, which downregulates resistin gene expression.
Collapse
Affiliation(s)
- Chi-Chang Juan
- Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
| | | | | | | | | |
Collapse
|
50
|
Leptin, soluble leptin receptor, adiponectin and resistin in relation to OGTT in overweight/obese postmenopausal women. Maturitas 2008; 59:339-49. [DOI: 10.1016/j.maturitas.2008.03.012] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2007] [Revised: 02/25/2008] [Accepted: 03/27/2008] [Indexed: 11/19/2022]
|