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Ward K, Mulder E, Frings-Meuthen P, O'Gorman DJ, Cooper D. The effect of 60 days of 6° head-down-tilt bed rest on circulating adropin, irisin, retinol binding protein-4 (RBP4) and individual metabolic responses in young, healthy males. Front Physiol 2024; 15:1435448. [PMID: 39318364 PMCID: PMC11420021 DOI: 10.3389/fphys.2024.1435448] [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: 05/20/2024] [Accepted: 08/26/2024] [Indexed: 09/26/2024] Open
Abstract
Background Alterations in the circulating concentrations and target-tissue action of organokines underpin the development of insulin resistance in microgravity and gravity deprivation. The purpose of this study was to examine changes in circulating adropin, irisin, retinol binding protein-4 (RBP4), and the metabolic response of healthy young males following 60 days of 6° head-down-tilt (HDT) bed rest, with and without reactive jump training (RJT), to explore links with whole-body and tissue-specific insulin sensitivity. To our knowledge, this is the first time that adropin, irisin, and RBP4 have been studied in HDT bed rest. Methods A total of 23 male subjects (29 ± 6 years, 181 ± 6 cm, 77 ± 7 kg) were exposed to 60 days of 6° HDT bed rest and randomized to a control (CTRL, n = 11) or a RJT (JUMP, n = 12) group (48 sessions with ≤4 min total training time per session). Circulating adropin, irisin, and RBP4 were quantified in fasting serum before and after HDT bed rest. A subanalysis was performed a posteriori to investigate individual metabolic responses post-HDT bed rest based on subjects that showed an increase or decrease in whole-body insulin sensitivity (Matsuda index). Results There were significant main effects of time, but not group, for decreases in adropin, irisin, Matsuda index, and liver insulin sensitivity following HDT bed rest (p < 0.05), whereas RBP4 did not change. The subanalysis identified that in a subgroup with decreased whole-body insulin sensitivity (n = 17), RBP4 increased significantly, whereas adropin, irisin, and liver insulin sensitivity were all decreased significantly following HDT bed rest. Conversely, in a subgroup with increased whole-body insulin sensitivity (n = 6), liver insulin sensitivity increased significantly after HDT bed rest, whereas adropin, irisin, and RBP4 did not change. Conclusion Investigating individual metabolic responses has provided insights into changes in circulating adropin, irisin, RBP4, in relation to insulin sensitivity following HDT bed rest. We conclude that adropin, irisin, and RBP4 are candidate biomarkers for providing insights into whole-body and tissue-specific insulin sensitivity to track changes in physiological responsiveness to a gravity deprivation intervention in a lean male cohort.
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Affiliation(s)
- Kiera Ward
- Faculty of Science and Health, Technological University of the Shannon, Athlone Campus, Athlone, Ireland
| | - Edwin Mulder
- Department of Muscle and Bone Metabolism, Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany
| | - Petra Frings-Meuthen
- Department of Muscle and Bone Metabolism, Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany
| | - Donal J O'Gorman
- 3U Diabetes Partnership, School of Health and Human Performance, Dublin City University, Dublin, Ireland
- National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland
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Ghorbanian B, Wong A, Iranpour A. The effect of dietary carbohydrate restriction and aerobic exercise on retinol binding protein 4 (RBP4) and fatty acid binding protein 5 (FABP5) in middle-aged men with metabolic syndrome. Br J Nutr 2023; 130:553-563. [PMID: 36373560 DOI: 10.1017/s0007114522003580] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Exercise and dietary interventions have been described to positively affect metabolic syndrome (MetS) via molecular-induced changes. The purpose of this study was to investigate the effects of dietary carbohydrate restriction and aerobic exercise (AE) on retinol binding protein 4 (RBP4) and fatty acid binding protein 5 (FABP5) in middle-aged men with MetS. The study had a randomised, double-blinded, parallel-controlled design. Forty middle-aged men with MetS (age: 53·97 ± 2·85 years, BMI = 31·09 ± 1·04 kg/m2) were randomly assigned to four groups, AE (n 10), ketogenic diet (KD; n 10), AE combined with KD (AE + KD; n 10) or control (C; n 10). RBP4, FABP5, body composition (body mass, BMI and body fat), insulin resistance, insulin sensitivity and MetS factors were evaluated prior to and after the 12-week intervention. AE + KD significantly decreased the body fat percentage (P = 0·006), BMI (P = 0·001), Zmets (P = 0·017), RBP4 (P = 0·017) and the homeostasis model of insulin resistance (HOMA-IR) (P = 0·001) as compared with control group and marginally significantly decreased the Zmets as compared with exercise group (P = 0·086). KD significantly decreased RBP4 levels as compared with control group (P = 0·041). Only the AE intervention (P = 0·045) significantly decreased FABP5 levels. Combining intervention of carbohydrate restriction with AE compared with carbohydrate restriction and AE alone improved RBP4, HOMA-IR as well as different body composition and MetS factors in middle-aged men with MetS.
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Affiliation(s)
- Bahloul Ghorbanian
- Department of Physical Education, Faculty of Educational Sciences and Psychology, Azarbaijan Shahid Madani University, Tabriz, Iran
| | - Alexei Wong
- Department of Health and Human Performance, Marymount University, Arlington, VA, USA
| | - Asgar Iranpour
- Department of Sports Physiology, Faculty of Educational Sciences and Psychology, University of Mohaghegh Ardabili, Ardabil, Iran
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Thromboinflammatory Processes at the Nexus of Metabolic Dysfunction and Prostate Cancer: The Emerging Role of Periprostatic Adipose Tissue. Cancers (Basel) 2022; 14:cancers14071679. [PMID: 35406450 PMCID: PMC8996963 DOI: 10.3390/cancers14071679] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/03/2022] [Accepted: 03/04/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary As overweight and obesity increase among the population worldwide, a parallel increase in the number of individuals diagnosed with prostate cancer was observed. There appears to be a relationship between both diseases where the increase in the mass of fat tissue can lead to inflammation. Such a state of inflammation could produce many factors that increase the aggressiveness of prostate cancer, especially if this inflammation occurred in the fat stores adjacent to the prostate. Another important observation that links obesity, fat tissue inflammation, and prostate cancer is the increased production of blood clotting factors. In this article, we attempt to explain the role of these latter factors in the effect of increased body weight on the progression of prostate cancer and propose new ways of treatment that act by affecting how these clotting factors work. Abstract The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states.
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Zhao YX, Borjigin S, Yan ZL. Functional annotation and enrichment analysis of differentially expressed serum proteins in patients with type 2 diabetes after dapagliflozin. World J Diabetes 2022; 13:224-239. [PMID: 35432754 PMCID: PMC8984562 DOI: 10.4239/wjd.v13.i3.224] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 01/29/2022] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Only 50% of patients with type 2 diabetes mellitus (T2DM) can control their blood glucose levels. Dapagliflozin is a selective inhibitor of sodium-glucose co-transporter 2 (SGLT-2) that improves the insulin sensitivity of the liver and peripheral tissues. Many studies confirmed that SGLT2 inhibitors reduce blood glucose and have multiple beneficial effects such as weight loss, lipid regulation, and kidney protection. Nevertheless, the mechanisms of the renal and cardiovascular protective effects of dapagliflozin from the perspective of differentially expressed proteins in the serum of T2DM patients have not been intensively explored so far.
AIM To identify differentially expressed proteins associated with dapagliflozin treatment in patients with T2DM.
METHODS Twenty T2DM patients [hemoglobin A1c (HbA1c) 7.0%-10.0%] were enrolled at The Affiliated Hospital of Inner Mongolia Medical University between January 1, 2017 and December 1, 2018. They received dapagliflozin (10 mg/d) for 3 mo, and the HbA1c < 7.0% target was achieved. The changes in clinical indexes were compared before and after treatments. Label-free quantitative proteomics was used to identify differentially expressed proteins using the serum samples of five patients. The identified differentially expressed proteins were analyzed using various bioinformatics tools.
RESULTS Dapagliflozin significantly improved the clinical manifestation of the patients. There were 18 downregulated proteins and one upregulated protein in the serum samples of patients after dapagliflozin administration. Bioinformatics analyses, including subcellular localization, EuKaryotic Orthologous Groups, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes annotations, were used to profile the biological characteristics of the 19 differentially expressed proteins. Based on the literature and function enrichment analysis, two downregulated proteins, myeloperoxidase (MPO) and alpha II B integrin (ITGA2B), and one upregulated protein, podocalyxin (PCX), were selected for enzyme linked immunosorbent assay validation. These validated differentially expressed proteins had multiple correlations with clinical indexes, including HbAc1 and fasting C-peptide.
CONCLUSION Dapagliflozin has hypoglycemic effects and regulates the serum expressions of MPO, ITGA2B, and PCX, possibly contributing to the effects of dapagliflozin on oxidative stress, insulin resistance, and lipid metabolism.
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Affiliation(s)
- Yan-Xue Zhao
- Basic Building Laboratory, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010000, Inner Mongolia, China
| | - Sarul Borjigin
- Department of Endocrinology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010000, Inner Mongolia, China
| | - Zhao-Li Yan
- Department of Endocrinology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010000, Inner Mongolia, China
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Nono Nankam PA, Blüher M. Retinol-binding protein 4 in obesity and metabolic dysfunctions. Mol Cell Endocrinol 2021; 531:111312. [PMID: 33957191 DOI: 10.1016/j.mce.2021.111312] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 12/11/2022]
Abstract
Excessive increased adipose tissue mass in obesity is associated with numerous co-morbid disorders including increased risk of type 2 diabetes, fatty liver disease, hypertension, dyslipidemia, cardiovascular diseases, dementia, airway disease and some cancers. The causal mechanisms explaining these associations are not fully understood. Adipose tissue is an active endocrine organ that secretes many adipokines, cytokines and releases metabolites. These biomolecules referred to as adipocytokines play a significant role in the regulation of whole-body energy homeostasis and metabolism by influencing and altering target tissues function. Understanding the mechanisms of adipocytokine actions represents a hot topic in obesity research. Among several secreted bioactive signalling molecules from adipose tissue and liver, retinol-binding protein 4 (RBP4) has been associated with systemic insulin resistance, dyslipidemia, type 2 diabetes and other metabolic diseases. Here, we aim to review and discuss the current knowledge on RBP4 with a focus on its role in the pathogenesis of obesity comorbid diseases.
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Affiliation(s)
- Pamela A Nono Nankam
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Germany.
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Germany; Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Germany
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Rajesh Y, Sarkar D. Association of Adipose Tissue and Adipokines with Development of Obesity-Induced Liver Cancer. Int J Mol Sci 2021; 22:ijms22042163. [PMID: 33671547 PMCID: PMC7926723 DOI: 10.3390/ijms22042163] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/20/2022] Open
Abstract
Obesity is rapidly dispersing all around the world and is closely associated with a high risk of metabolic diseases such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD), leading to carcinogenesis, especially hepatocellular carcinoma (HCC). It results from an imbalance between food intake and energy expenditure, leading to an excessive accumulation of adipose tissue (AT). Adipocytes play a substantial role in the tumor microenvironment through the secretion of several adipokines, affecting cancer progression, metastasis, and chemoresistance via diverse signaling pathways. AT is considered an endocrine organ owing to its ability to secrete adipokines, such as leptin, adiponectin, resistin, and a plethora of inflammatory cytokines, which modulate insulin sensitivity and trigger chronic low-grade inflammation in different organs. Even though the precise mechanisms are still unfolding, it is now established that the dysregulated secretion of adipokines by AT contributes to the development of obesity-related metabolic disorders. This review focuses on several obesity-associated adipokines and their impact on obesity-related metabolic diseases, subsequent metabolic complications, and progression to HCC, as well as their role as potential therapeutic targets. The field is rapidly developing, and further research is still required to fully understand the underlying mechanisms for the metabolic actions of adipokines and their role in obesity-associated HCC.
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Affiliation(s)
- Yetirajam Rajesh
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Devanand Sarkar
- Massey Cancer Center, Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA
- Correspondence: ; Tel.: +1-804-827-2339
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Huang R, Bai X, Li X, Wang X, Zhao L. Retinol-Binding Protein 4 Activates STRA6, Provoking Pancreatic β-Cell Dysfunction in Type 2 Diabetes. Diabetes 2021; 70:449-463. [PMID: 33199363 DOI: 10.2337/db19-1241] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 11/05/2020] [Indexed: 11/13/2022]
Abstract
Pancreatic β-cell dysfunction plays a decisive role in the progression of type 2 diabetes. Retinol-binding protein 4 (RBP4) is a prominent adipokine in type 2 diabetes, although its effect on β-cell function remains elusive, and the underlying mechanisms are unknown. Here, we found that elevated circulating RBP4 levels were inversely correlated with pancreatic β-cell function in db/db mice across different glycemic stages. RBP4 directly suppressed glucose-stimulated insulin secretion (GSIS) in primary isolated islets and INS-1E cells in a dose- and time-dependent manner. RBP4 transgenic (RBP4-Tg) overexpressing mice showed a dynamic decrease of GSIS, which appeared as early as 8 weeks old, preceding the impairment of insulin sensitivity and glucose tolerance. Islets isolated from RBP4-Tg mice showed a significant decrease of GSIS. Mechanistically, we demonstrated that the stimulated by retinoic acid 6 (STRA6), RBP4's only known specific membrane receptor, is expressed in β-cells and mediates the inhibitory effect of RBP4 on insulin synthesis through the Janus kinase 2/STAT1/ISL-1 pathway. Moreover, decreasing circulating RBP4 level could effectively restore β-cell dysfunction and ameliorate hyperglycemia in db/db mice. These observations revealed a role of RBP4 in pancreatic β-cell dysfunction, which provides new insight into the diabetogenic effect of RBP4.
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Affiliation(s)
- Rong Huang
- Guangdong Provincial Key Laboratory of Food, Nutrition, and Health and Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China
| | - Xinxiu Bai
- Guangdong Provincial Key Laboratory of Food, Nutrition, and Health and Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China
| | - Xueyan Li
- Guangdong Provincial Key Laboratory of Food, Nutrition, and Health and Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China
| | - Xiaohui Wang
- Guangdong Provincial Key Laboratory of Food, Nutrition, and Health and Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China
| | - Lina Zhao
- Guangdong Provincial Key Laboratory of Food, Nutrition, and Health and Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China
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DNA methylation in adipocytes from visceral and subcutaneous adipose tissue influences insulin-signaling gene expression in obese individuals. Int J Obes (Lond) 2021; 45:650-658. [PMID: 33414486 DOI: 10.1038/s41366-020-00729-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 10/19/2020] [Accepted: 12/09/2020] [Indexed: 01/01/2023]
Abstract
OBJECTIVE Both obesity and insulin resistance are characterized by severe long-term changes in the expression of many genes of importance in the regulation of metabolism. Because these changes occur throughout life, as a result of external factors, the disorders of gene expression could be epigenetically regulated. MATERIALS/METHODS We analyzed the relationship between obesity and insulin resistance in enrolled patients by means of evaluation of the expression rate of numerous genes involved in the regulation of adipocyte metabolism and energy homeostasis in subcutaneous and visceral adipose tissue depots. We also investigated global and site-specific DNA methylation as one of the main regulators of gene expression. Visceral and subcutaneous adipose tissue biopsies were collected from 45 patients during abdominal surgery in an age range of 40-60 years. RESULTS We demonstrated hypermethylation of PPARG, INSR, SLC2A4, and ADIPOQ promoters in obese patients with insulin resistance. Moreover, the methylation rate showed a negative correlation with the expression of the investigated genes. More, we showed a correlation between the expression of PPARG and the expression of numerous genes important for proper insulin action. Given the impact of PPARγ on the regulation of the cell insulin sensitivity through modulation of insulin pathway genes expression, hypermethylation in the PPARG promoter region may constitute one of the epigenetic pathways in the development of insulin resistance in obesity. CONCLUSIONS Our research shows that epigenetic regulation through excessive methylation may constitute a link between obesity and subsequent insulin resistance.
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Li C, Kong W, Kang L, Zhang T, Zhang W, Wang W. Study on the correlation between urinary retinol-binding protein and nonalcoholic fatty liver disease. J Med Biochem 2021; 40:86-91. [PMID: 33584144 PMCID: PMC7857848 DOI: 10.5937/jomb0-24666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 02/22/2020] [Indexed: 11/23/2022] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) affects human health worldwide. Our objective was to explore the correlation between urinary retinol-binding protein (URBP) and NAFLD. Methods This cross-sectional study included 445 NAFLD patients and 911 healthy controls. The URBP level and other parameters were measured. Results The URBP level (expressed by the RBP/creatinine ratio) was higher in the NAFLD patients compared with the non-NAFLD patients. The urinary RBP/creatinine ratio was an independent risk factor for NAFLD after univariate and multivariate regression analysis, with the or values of 2.271 (1.795-2.872, P < 0.001) and 2.338 (1.775-3.080, P < 0.001), respectively. The prevalence of the urinary RBP/creatinine ratio (groups 1, 2, 3, 4) was 20.0%, 17.3%, 27.3%, and 35.4%, respectively (P < 0.001), and the prevalence of NAFLD in the high urinary RBP/creatinine ratio group was significantly higher than that in the low urinary RBP/creatinine ratio group. Conclusions Our results revealed that the urinary RBP/creatinine ratio was an independent risk factor for NAFLD.
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Affiliation(s)
- Chuang Li
- Xinxiang Medical University, The Third Affiliated Hospital, Department of Laboratory Medicine, Xinxiang, Henan, China
| | - Weiwei Kong
- Xinxiang Medical University, The Third Affiliated Hospital, Department of Laboratory Medicine, Xinxiang, Henan, China
| | - Lixia Kang
- Xinxiang Medical University, The Third Affiliated Hospital, Department of Laboratory Medicine, Xinxiang, Henan, China
| | - Tiehan Zhang
- Xinxiang Medical University, The Third Affiliated Hospital, Department of Laboratory Medicine, Xinxiang, Henan, China
| | - Weiqun Zhang
- Xinxiang Medical University, The Third Affiliated Hospital, Department of Laboratory Medicine, Xinxiang, Henan, China
| | - Weidong Wang
- Xinxiang Medical University, The Third Affiliated Hospital, Department of Laboratory Medicine, Xinxiang, Henan, China
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Shin SJ, Chen CH, Kuo WC, Chan HC, Chan HC, Lin KD, Ke LY. Disruption of retinoid homeostasis induces RBP4 overproduction in diabetes: O-GlcNAcylation involved. Metabolism 2020; 113:154403. [PMID: 33065162 DOI: 10.1016/j.metabol.2020.154403] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 08/10/2020] [Accepted: 10/09/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Retinol-binding protein 4 (RBP4) is elevated and associated with inflammation in metabolic diseases. Disruption of the retinol cascade and O-GlcNAcylation of the RBP4 receptor (STRA6) are found in diabetic kidneys. OBJECTIVES We investigated whether the disruption of the retinol cascade induces RBP4 overproduction and if O-linked GlcNAc modification targets RBPR2 and contributes to the disruption of retinol cascades in diabetic livers. METHODS Western blot or immunohistochemistry for RBPR2, CRBP1, LRAT, RALDH, RARα, RARγ, RXRα, RBP4, GFAT, OGT, OGA and inflammatory markers, as well as ELISA for RBP4, were performed in livers of db/db and ob/ob mice and high glucose-cultured hepatocytes. Immunoprecipitation and dual fluorescence staining were used to explore O-GlcNAc-modified RBPR2 and RBP4 binding activity on RBPR2. Transfection of the CRBP1 gene was done to verify whether a disrupted retinol cascade induces RBP4 overproduction. OGT silencing was done to investigate the association of O-GlcNAcylation with the disruption of retinol cascade. RESULTS Disruption of retinol cascade, RBP4 overproduction, O-GlcNAcylation of RBPR2, decreased RBP4 binding activity on RBPR2 and inflammation were found in livers of db/db and ob/ob mice and high glucose-cultured hepatocytes. CRBP1 gene transfection reversed the suppression of the cellular retinol cascade and simultaneously attenuated the RBP4 overproduction and inflammation in high glucose-treated hepatocytes. The silencing of OGT reversed the disruption of the cellular retinol cascade, RBP4 overproduction and inflammation induced by high glucose in hepatocytes. CONCLUSIONS This study indicates that the disruption of cellular retinol cascade is strongly associated with RBP4 overproduction and inflammation in diabetic livers. RBPR2 is one target for high glucose-mediated O-linked GlcNAc modification, which causes liver retinol dyshomeostasis.
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Affiliation(s)
- Shyi-Jang Shin
- Grander Clinic, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chao-Hung Chen
- The Graduate Institute of Animal Vaccine Technology, National Pingtung University of Science and Technology, Pingtung, Taiwan; General Research Service Center, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Wen-Chen Kuo
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Hua-Chen Chan
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Hsiu-Chuan Chan
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Kun-Der Lin
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Liang-Yin Ke
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Wang X, Chen X, Zhang H, Pang J, Lin J, Xu X, Yang L, Ma J, Ling W, Chen Y. Circulating retinol-binding protein 4 is associated with the development and regression of non-alcoholic fatty liver disease. DIABETES & METABOLISM 2020; 46:119-128. [DOI: 10.1016/j.diabet.2019.04.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/28/2019] [Accepted: 04/28/2019] [Indexed: 02/07/2023]
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Funcke JB, Scherer PE. Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication. J Lipid Res 2019; 60:1648-1684. [PMID: 31209153 PMCID: PMC6795086 DOI: 10.1194/jlr.r094060] [Citation(s) in RCA: 211] [Impact Index Per Article: 35.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 06/17/2019] [Indexed: 01/10/2023] Open
Abstract
The breakthrough discoveries of leptin and adiponectin more than two decades ago led to a widespread recognition of adipose tissue as an endocrine organ. Many more adipose tissue-secreted signaling mediators (adipokines) have been identified since then, and much has been learned about how adipose tissue communicates with other organs of the body to maintain systemic homeostasis. Beyond proteins, additional factors, such as lipids, metabolites, noncoding RNAs, and extracellular vesicles (EVs), released by adipose tissue participate in this process. Here, we review the diverse signaling mediators and mechanisms adipose tissue utilizes to relay information to other organs. We discuss recently identified adipokines (proteins, lipids, and metabolites) and briefly outline the contributions of noncoding RNAs and EVs to the ever-increasing complexities of adipose tissue inter-organ communication. We conclude by reflecting on central aspects of adipokine biology, namely, the contribution of distinct adipose tissue depots and cell types to adipokine secretion, the phenomenon of adipokine resistance, and the capacity of adipose tissue to act both as a source and sink of signaling mediators.
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Affiliation(s)
- Jan-Bernd Funcke
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX
| | - Philipp E Scherer
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX
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Hasannejad M, Samsamshariat SZ, Esmaili A, Jahanian-Najafabadi A. Klotho induces insulin resistance possibly through interference with GLUT4 translocation and activation of Akt, GSK3β, and PFKfβ3 in 3T3-L1 adipocyte cells. Res Pharm Sci 2019; 14:369-377. [PMID: 31516514 PMCID: PMC6714116 DOI: 10.4103/1735-5362.263627] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Klotho is considered as an anti-aging factor inducing insulin resistance and involved in type 2 diabetes. However, mechanisms by which klotho induces insulin resistance remain to be understood. Thus, in this study, we aimed to evaluate possible interference points of klotho with insulin signaling pathways in 3T3-L1 adipocyte cells by focusing on phosphorylation levels of Akt, GSK3β, PFK-fβ3, and GLUT4 translocation. Differentiation of 3T3-L1 cells to the adipocyte-like cells were performed using specific differentiation kit and confirmed by mRNA expression assay of PPARγ using qRT-PCR, and Sudan black staining of lipid droplets. Then cells were co-treated with klotho and insulin. Expression and translocation of GLUT4 mRNA were evaluated using qRT-PCR and Alexa flour 488 conjugated GLUT4 antibody, respectively. P-Akt/Akt, p-GSK3β/GSK3β, and p-PFKfβ3/PFKfβ3 ratios were determined in insulin and klotho/insulin treated cells using western blot. Our result indicated that GLUT4 expression were decreased to 0.72 ± 0.16 fold in insulin treated cells, however it was calculated 1.12 ± 0.25 fold in klotho/insulin treated cells. In addition, klotho prevented GLUT4 membrane translocation by 27.2% in comparison with insulin-treated cells (P < 0.05). Interestingly, in insulin/klotho co-treated cells, phospho-levels of Akt, GSK3β, and PFKfβ3 proteins was decreased to 2.34 ± 0.14, 2.29 ± 0.63, and 1.95 ± 0.37 fold in comparison with the insulin cells, (P < 0.05). In conclusion, our study indicated that klotho induces insulin resistance in adipocytes possibly through prevention of GLUT4 translocation, and interfere with phosphorylation of Akt, GSK3β, and PFKf3β intracellular signaling mediators by insulin.
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Affiliation(s)
- Mohamad Hasannejad
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Seyed Ziaaldin Samsamshariat
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Armita Esmaili
- Department of Pathology, Mehrgan hospital, Kerman University of Medical Sciences and Health services, Kerman, I.R. Iran
| | - Ali Jahanian-Najafabadi
- Department of Pharmaceutical Biotechnology, Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
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14
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Wang F, Chang C, Li R, Zhang Z, Jiang H, Zeng N, Li D, Chen L, Xiao Y, Chen W, Wang Q. Retinol binding protein 4 mediates MEHP-induced glucometabolic abnormalities in HepG2 cells. Toxicology 2019; 424:152236. [DOI: 10.1016/j.tox.2019.06.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 06/12/2019] [Accepted: 06/12/2019] [Indexed: 12/15/2022]
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15
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Adipose Tissue-Derived Signatures for Obesity and Type 2 Diabetes: Adipokines, Batokines and MicroRNAs. J Clin Med 2019; 8:jcm8060854. [PMID: 31208019 PMCID: PMC6617388 DOI: 10.3390/jcm8060854] [Citation(s) in RCA: 113] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 06/07/2019] [Accepted: 06/11/2019] [Indexed: 12/13/2022] Open
Abstract
: Obesity is one of the main risk factors for type 2 diabetes mellitus (T2DM). It is closely related to metabolic disturbances in the adipose tissue that primarily functions as a fat reservoir. For this reason, adipose tissue is considered as the primary site for initiation and aggravation of obesity and T2DM. As a key endocrine organ, the adipose tissue communicates with other organs, such as the brain, liver, muscle, and pancreas, for the maintenance of energy homeostasis. Two different types of adipose tissues-the white adipose tissue (WAT) and brown adipose tissue (BAT)-secrete bioactive peptides and proteins, known as "adipokines" and "batokines," respectively. Some of them have beneficial anti-inflammatory effects, while others have harmful inflammatory effects. Recently, "exosomal microRNAs (miRNAs)" were identified as novel adipokines, as adipose tissue-derived exosomal miRNAs can affect other organs. In the present review, we discuss the role of adipose-derived secretory factors-adipokines, batokines, and exosomal miRNA-in obesity and T2DM. It will provide new insights into the pathophysiological mechanisms involved in disturbances of adipose-derived factors and will support the development of adipose-derived factors as potential therapeutic targets for obesity and T2DM.
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16
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Liu Y, Albrecht E, Dannenberger D, Hammon HM, Kuehn C, Sauerwein H, Yang R, Zhao Z, Maak S. Retinol binding protein 4 abundance in plasma and tissues is related to body fat deposition in cattle. Sci Rep 2019; 9:8056. [PMID: 31147589 PMCID: PMC6542835 DOI: 10.1038/s41598-019-44509-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 05/17/2019] [Indexed: 01/10/2023] Open
Abstract
Retinol binding protein 4 (RBP4) facilitates the transport of retinol in the body but is also an adipokine and fatty acid transporter. Our study was aimed at investigating the associations between RBP4 abundance and fat deposition in cattle. Blood samples of 246 crossbred bulls were taken at 8 months of age and at slaughter at 18 months of age for the determination of RBP4, hormone levels, and fatty acid composition. Significant correlations between plasma RBP4 abundance at 8 months of age and carcass traits at 18 months of age were detected (e.g., r = 0.3; P < 0.001 to carcass fat). Furthermore, RBP4 abundances in the plasma and subcutaneous fat were higher (P < 0.05) in bulls with increased fat deposition, whereas the liver RBP4 expression was not (P > 0.05). Retinol binding protein 4 was immunohistochemically localized in or close to adipocytes within muscle and adipose tissue and in liver stellate cells but not in hepatocytes. Overall, our results indicate that increased RBP4 levels were associated with increased fat deposition and altered fatty acid composition, but not with altered glucose tolerance, in crossbred bulls. Moreover, our results suggest that adipose-tissue-derived RBP4 may contribute to the circulating RBP4 level.
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Affiliation(s)
- Yinuo Liu
- College of Animal Science, Jilin University, Changchun, Jilin, 130062, P.R. China.,Institute of Muscle Biology and Growth, Leibniz Institute for Farm Animal Biology (FBN), 18196, Dummerstorf, Germany
| | - Elke Albrecht
- Institute of Muscle Biology and Growth, Leibniz Institute for Farm Animal Biology (FBN), 18196, Dummerstorf, Germany.
| | - Dirk Dannenberger
- Institute of Muscle Biology and Growth, Leibniz Institute for Farm Animal Biology (FBN), 18196, Dummerstorf, Germany
| | - Harald M Hammon
- Institute of Nutritional Physiology "Oskar Kellner", Leibniz Institute for Farm Animal Biology (FBN), 18196, Dummerstorf, Germany
| | - Christa Kuehn
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), 18196, Dummerstorf, Germany
| | - Helga Sauerwein
- Institute for Animal Science, Physiology and Hygiene Unit, University of Bonn, 53115, Bonn, Germany
| | - Runjun Yang
- College of Animal Science, Jilin University, Changchun, Jilin, 130062, P.R. China
| | - Zhihui Zhao
- College of Animal Science, Jilin University, Changchun, Jilin, 130062, P.R. China.,College of Agriculture, Guangdong Ocean University, Zhanjiang, 523088, P.R. China
| | - Steffen Maak
- Institute of Muscle Biology and Growth, Leibniz Institute for Farm Animal Biology (FBN), 18196, Dummerstorf, Germany
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17
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Abstract
Much evidence has accumulated in the literature over the last fifteen years that indicates vitamin A has a role in metabolic disease prevention and causation. This literature proposes that vitamin A can affect obesity development and the development of obesity-related diseases including insulin resistance, type 2 diabetes, hepatic steatosis and steatohepatitis, and cardiovascular disease. Retinoic acid, the transcriptionally active form of vitamin A, accounts for many of the reported associations. However, a number of proteins involved in vitamin A metabolism, including retinol-binding protein 4 (RBP4) and aldehyde dehydrogenase 1A1 (ALDH1A1, alternatively known as retinaldehyde dehydrogenase 1 or RALDH1), have also been identified as being associated with metabolic disease. Some of the reported effects of these vitamin A-related proteins are proposed to be independent of their roles in assuring normal retinoic acid homeostasis. This review will consider both human observational data as well as published data from molecular studies undertaken in rodent models and in cells in culture. The primary focus of the review will be on the effects that vitamin A per se and proteins involved in vitamin A metabolism have on adipocytes, adipose tissue biology, and adipose-related disease, as well as on early stage liver disease, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
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Affiliation(s)
- William S Blaner
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
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18
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Atawia RT, Bunch KL, Toque HA, Caldwell RB, Caldwell RW. Mechanisms of obesity-induced metabolic and vascular dysfunctions. FRONT BIOSCI-LANDMRK 2019; 24:890-934. [PMID: 30844720 PMCID: PMC6689231 DOI: 10.2741/4758] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Obesity has reached epidemic proportions and its prevalence is climbing. Obesity is characterized by hypertrophied adipocytes with a dysregulated adipokine secretion profile, increased recruitment of inflammatory cells, and impaired metabolic homeostasis that eventually results in the development of systemic insulin resistance, a phenotype of type 2 diabetes. Nitric oxide synthase (NOS) is an enzyme that converts L-arginine to nitric oxide (NO), which functions to maintain vascular and adipocyte homeostasis. Arginase is a ureohydrolase enzyme that competes with NOS for L-arginine. Arginase activity/expression is upregulated in obesity, which results in diminished bioavailability of NO, impairing both adipocyte and vascular endothelial cell function. Given the emerging role of NO in the regulation of adipocyte physiology and metabolic capacity, this review explores the interplay between arginase and NO, and their effect on the development of metabolic disorders, cardiovascular diseases, and mitochondrial dysfunction in obesity. A comprehensive understanding of the mechanisms involved in the development of obesity-induced metabolic and vascular dysfunction is necessary for the identification of more effective and tailored therapeutic avenues for their prevention and treatment.
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Affiliation(s)
- Reem T Atawia
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University. Augusta, GA 30904, USA
| | - Katharine L Bunch
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University. Augusta, GA 30904, USA
| | - Haroldo A Toque
- Department of Pharmacology and Toxicology,and Vascular Biology Center, Medical College of Georgia, Augusta University. Augusta, GA 30904, USA
| | - Ruth B Caldwell
- Vascular Biology Center, Medical College of Georgia, Augusta University. Augusta, GA 30904, USA
| | - Robert W Caldwell
- Vascular Biology Center, Medical College of Georgia, Augusta University. Augusta, GA 30904,USA,
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19
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Gonzalez LL, Garrie K, Turner MD. Type 2 diabetes - An autoinflammatory disease driven by metabolic stress. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3805-3823. [PMID: 30251697 DOI: 10.1016/j.bbadis.2018.08.034] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 08/27/2018] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes has traditionally been viewed as a metabolic disorder characterised by chronic high glucose levels, insulin resistance, and declining insulin secretion from the pancreas. Modern lifestyle, with abundant nutrient supply and reduced physical activity, has resulted in dramatic increases in the rates of obesity-associated disease conditions, including diabetes. The associated excess of nutrients induces a state of systemic low-grade chronic inflammation that results from production and secretion of inflammatory mediators from the expanded pool of activated adipocytes. Here, we review the mechanisms by which obesity induces adipose tissue dysregulation, detailing the roles of adipose tissue secreted factors and their action upon other cells and tissues central to glucose homeostasis and type 2 diabetes. Furthermore, given the emerging importance of adipokines, cytokines and chemokines in disease progression, we suggest that type 2 diabetes should now be viewed as an autoinflammatory disease, albeit one that is driven by metabolic dysregulation.
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Affiliation(s)
- Laura L Gonzalez
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, United Kingdom
| | - Karin Garrie
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, United Kingdom
| | - Mark D Turner
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, United Kingdom.
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20
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Oikonomou EK, Antoniades C. Immunometabolic Regulation of Vascular Redox State: The Role of Adipose Tissue. Antioxid Redox Signal 2018; 29:313-336. [PMID: 28657335 DOI: 10.1089/ars.2017.7017] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
SIGNIFICANCE Vascular oxidative stress plays a crucial role in atherogenesis and cardiovascular disease (CVD). Recent evidence suggests that vascular redox state is under the control of complex pathophysiological mechanisms, ranging from inflammation to obesity and insulin resistance (IR). Recent Advances: Adipose tissue (AT) is now recognized as a dynamic endocrine and paracrine organ that secretes several bioactive molecules, called adipokines. AT has recently been shown to regulate vascular redox state in both an endocrine and a paracrine manner through the secretion of adipokines, therefore providing a mechanistic link for the association between obesity, IR, inflammation, and vascular disease. Importantly, AT behaves as a sensor of cardiovascular oxidative stress, modifying its secretory profile in response to cardiovascular oxidative injury. CRITICAL ISSUES The present article presents an up-to-date review of the association between AT and vascular oxidative stress. We focus on the effects of individual adipokines on modulating reactive oxygen species production and scavenging in the vascular wall. In addition, we highlight how inflammation, obesity, and IR alter the biology and secretome of AT leading to a more pro-oxidant phenotype with a particular focus on the local regulatory mechanisms of perivascular AT driven by vascular oxidation. FUTURE DIRECTIONS The complex and dynamic biology of AT, as well as its importance in the regulation of vascular redox state, provides numerous opportunities for the development of novel, targeted treatments in the management of CVD. Therapeutic modulation of AT biology could improve vascular redox state affecting vascular disease pathogenesis. Antioxid. Redox Signal. 29, 313-336.
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Affiliation(s)
- Evangelos K Oikonomou
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford , Oxford, United Kingdom
| | - Charalambos Antoniades
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford , Oxford, United Kingdom
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21
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Nteeba J, Ganesan S, Madden JA, Dickson MJ, Keating AF. Progressive obesity alters ovarian insulin, phosphatidylinositol-3 kinase, and chemical metabolism signaling pathways and potentiates ovotoxicity induced by phosphoramide mustard in mice. Biol Reprod 2018; 96:478-490. [PMID: 28203716 DOI: 10.1095/biolreprod.116.143818] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 12/02/2016] [Accepted: 12/21/2016] [Indexed: 01/01/2023] Open
Abstract
Mechanisms underlying obesity-associated reproductive impairment are ill defined. Hyperinsulinemia is a metabolic perturbation often observed in obese subjects. Insulin activates phosphatidylinositol 3-kinase (PI3K) signaling, which regulates ovarian folliculogenesis, steroidogenesis, and xenobiotic metabolism. The impact of progressive obesity on ovarian genes encoding mRNA involved in insulin-mediated PI3K signaling and xenobiotic biotransformation [insulin receptor (Insr), insulin receptor substrate 1 (Irs1), 2 (Irs2), and 3 (Irs3); kit ligand (Kitlg), stem cell growth factor receptor (Kit), protein kinase B (AKT) alpha (Akt1), beta (Akt2), forkhead transcription factor (FOXO) subfamily 1 (Foxo1), and subfamily 3 (Foxo3a), microsomal epoxide hydrolase (Ephx1), cytochrome P450 family 2, subfamily E, polypeptide 1 (Cyp2e1), glutathione S-transferase (GST) class Pi (Gstp1) and class mu 1 (Gstm1)] was determined in normal wild-type nonagouti (a/a; lean) and lethal yellow mice (KK.CG-Ay/J; obese) at 6, 12, 18, or 24 weeks of age. At 6 weeks, ovaries from obese mice had increased (P < 0.05) Insr and Irs3 but decreased (P < 0.05) Kitlg, Foxo1, and Cyp2e1 mRNA levels. Interestingly, at 12 weeks, an increase (P < 0.05) in Kitlg and Kit mRNA, pIRS1Ser302, pAKTThr308, EPHX1, and GSTP1 protein level was observed due to obesity, while Cyp2e1 mRNA and protein were reduced. A phosphoramide mustard (PM) challenge increased (P < 0.05) ovarian EPHX1 protein abundance in lean but not obese females. In addition, lung tissue from PM-exposed animals had increased (P < 0.05) EPHX1 protein with no impact of obesity thereon. Taken together, progressive obesity affected ovarian signaling pathways potentially involved in obesity-associated reproductive disorders.
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Affiliation(s)
- Jackson Nteeba
- Department of Animal Science, 2356 Kildee Hall, Iowa State University, Ames, IA, USA
| | - Shanthi Ganesan
- Department of Animal Science, 2356 Kildee Hall, Iowa State University, Ames, IA, USA
| | - Jill A Madden
- Department of Animal Science, 2356 Kildee Hall, Iowa State University, Ames, IA, USA
| | - Mackenzie J Dickson
- Department of Animal Science, 2356 Kildee Hall, Iowa State University, Ames, IA, USA
| | - Aileen F Keating
- Department of Animal Science, 2356 Kildee Hall, Iowa State University, Ames, IA, USA
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22
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Lin WT, Lin PC, Lee CY, Chen YL, Chan TF, Tsai S, Huang HL, Wu PW, Chin YT, Lin HY, Lee CH. Effects of insulin resistance on the association between the circulating retinol-binding protein 4 level and clustering of pediatric cardiometabolic risk factors. Pediatr Diabetes 2018; 19:611-621. [PMID: 29383816 DOI: 10.1111/pedi.12639] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 11/22/2017] [Accepted: 12/20/2017] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVES Retinol-binding protein 4 (RBP4) and insulin resistance (IR) are clinical parameters associated with cardiometabolic diseases. The mediating and modifying roles of IR on children's susceptibility to cardiometabolic disorders are undetermined. This study investigated the mediating and modifying effects of the homeostatic model assessment of IR (HOMA-IR) on the relationship between the serum RBP4 level and clustering of pediatric cardiometabolic risk factors. METHODS We assessed the diet, physical activity, cardiometabolic risk factors, and clinical parameters of 272 randomly selected adolescents from a large-scale cross-sectional study (n = 2727). Two HOMA-IRs (HOMA1-IR and HOMA2-IR) were used to evaluate the designated effects. RESULTS Levels of serum RBP4 positively correlated with the levels of the 2 HOMA-based-IRs, and HOMA-IR correlated to all components of pediatric metabolic syndrome (MetS), the number of abnormal components, and a body-weight-weighted principal component score extracted from 12 cardiometabolic risk factors. Increased RBP4 levels had positive effects on waist circumference (WC), triglyceride, and the number of abnormal MetS components (0.310 cm, 1.384 μg/dL, and 0.021 item elevations, respectively), and the HOMA-IRs explained 17.7% to 21.9%, 11.8% to 27.6%, and 23.8% to 25.0% of these effects. The association of WC and the number of abnormal MetS components with the serum RBP4 level was enhanced by higher HOMA-IR (β for interaction, 0.13 and 0.01 for HOMA1-IR, and 0.32 and 0.02 for HOMA2-IR, respectively). CONCLUSIONS HOMA-IR is associated with the circulating RBP4 level and cardiometabolic risk factors in adolescents. Pediatric HOMA-IR may have mediating and modifying effects on the positive correlations between RBP4 and the clustering of MetS components.
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Affiliation(s)
- Wei-Ting Lin
- Department of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Global Community Health and Behavioral Sciences, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana
| | - Pei-Chen Lin
- Research Center of Cijin Cohort Study, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chun-Ying Lee
- Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Ling Chen
- Department of Nuclear Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Te-Fu Chan
- Department of Obstetrics and Gynecology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Sharon Tsai
- Department of Laboratory Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan
| | - Hsiao-Ling Huang
- Department of Oral Hygiene, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Pei-Wen Wu
- Department of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Ting Chin
- Department of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hui-Yi Lin
- Biostatistics Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Chien-Hung Lee
- Department of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan.,Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
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23
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Chen X, Shen T, Li Q, Chen X, Li Y, Li D, Chen G, Ling W, Chen YM. Retinol Binding Protein-4 Levels and Non-alcoholic Fatty Liver Disease: A community-based cross-sectional study. Sci Rep 2017; 7:45100. [PMID: 28332619 PMCID: PMC5362806 DOI: 10.1038/srep45100] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 02/16/2017] [Indexed: 12/21/2022] Open
Abstract
Previous reports on the association between retinol binding protein 4 (RBP4) and nonalcoholic fatty liver disease (NAFLD) were controversial. This study aimed to investigate the association between the serum RBP4 levels and occurrence of NAFLD in Chinese population. In total, 2938 participants aged 40–75 years were involved in this community-based cross-sectional study. General information, lifestyle factors, serum levels of RBP4 and the presence of NAFLD were determined. Patients with NAFLD had significantly higher concentrations of RBP4 (37.9 ± 6.8 μg/ml) than did non-NAFLD controls (35.0 ± 6.7 μg/ml) (P < 0.001). The odds ratios (ORs) of NAFLD for the highest (vs. lowest) quartile of RBP4 were 1.884 (95% CI: 1.391, 2.551) for females (P < 0.001), and 2.107 (95% CI: 1.357, 3.273) for male participants (P < 0.01) after adjusting for related factors. The serum RBP4 levels were positively associated with the prevalence of NAFLD in middle-aged and elderly Chinese people, and Homeostatic model assessment-insulin resistance (HOMA-IR), trunk fat, the waist-to-hip ratio (WHR), systolic blood pressure (SBP), fasting insulin, high density lipoprotein cholesterol (HDL-C) and triglycerides (TG) might be implicated in the pathogenesis of RBP4 in NAFLD.
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Affiliation(s)
- Xuechen Chen
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China
| | - Tianran Shen
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China
| | - Qing Li
- Department of Epidemiology, School of Public Health, Guilin Medical University, Guilin, P. R. China
| | - Xu Chen
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China
| | - Yanping Li
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China
| | - Dan Li
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China
| | - Gengdong Chen
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China
| | - Wenhua Ling
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China
| | - Yu-Ming Chen
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.,Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China
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24
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Booth A, Magnuson A, Fouts J, Foster MT. Adipose tissue: an endocrine organ playing a role in metabolic regulation. Horm Mol Biol Clin Investig 2017; 26:25-42. [PMID: 26910750 DOI: 10.1515/hmbci-2015-0073] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 01/01/2016] [Indexed: 12/14/2022]
Abstract
Adipose tissue is a complex endocrine organ with an intricate role in whole body homeostasis. Beyond storing energy, adipose tissue is fundamental in numerous processes including, but not limited to, metabolism, food intake and immune cell function. Adipokines and cytokines are the signaling factors from adipose tissue. These factors play a role in maintaining health, but are also candidates for pathologies associated with obesity. Indeed excessive adiposity causes dysregulation of these factors which negatively affect health and contribute to numerous obesity-induced co-morbidities. In particular, adipokines are fundamental in regulation of glucose homeostasis and insulin signaling, thus aberrant production of these adipose derived hormones correlates with the development and progression of type 2 diabetes. Therefore, elucidation of adipose regulation is crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. In the present review, we summarize current data on the relation between adipokines and adipose depot derived cytokines in the maintenance of glucose homeostasis. Specifically, physiological and molecular functions of several adipokines are defined with particular focus on interactions within the insulin-signaling pathway and subsequent regulation of glucose uptake in both standard and obesity-induced dysregulated conditions. This same relation will be discussed for cytokines and inflammation as well.
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25
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Oh KJ, Lee DS, Kim WK, Han BS, Lee SC, Bae KH. Metabolic Adaptation in Obesity and Type II Diabetes: Myokines, Adipokines and Hepatokines. Int J Mol Sci 2016; 18:ijms18010008. [PMID: 28025491 PMCID: PMC5297643 DOI: 10.3390/ijms18010008] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/24/2016] [Accepted: 12/12/2016] [Indexed: 12/21/2022] Open
Abstract
Obesity and type II diabetes are characterized by insulin resistance in peripheral tissues. A high caloric intake combined with a sedentary lifestyle is the leading cause of these conditions. Whole-body insulin resistance and its improvement are the result of the combined actions of each insulin-sensitive organ. Among the fundamental molecular mechanisms by which each organ is able to communicate and engage in cross-talk are cytokines or peptides which stem from secretory organs. Recently, it was reported that several cytokines or peptides are secreted from muscle (myokines), adipose tissue (adipokines) and liver (hepatokines) in response to certain nutrition and/or physical activity conditions. Cytokines exert autocrine, paracrine or endocrine effects for the maintenance of energy homeostasis. The present review is focused on the relationship and cross-talk amongst muscle, adipose tissue and the liver as secretory organs in metabolic diseases.
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Affiliation(s)
- Kyoung-Jin Oh
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea.
| | - Da Som Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
| | - Won Kon Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea.
| | - Baek Soo Han
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea.
| | - Sang Chul Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea.
| | - Kwang-Hee Bae
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea.
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Abstract
Testosterone is a key hormone in the pathology of metabolic diseases such as obesity. Low testosterone levels are associated with increased fat mass (particularly central adiposity) and reduced lean mass in males. These morphological features are linked to metabolic dysfunction, and testosterone deficiency is associated with energy imbalance, impaired glucose control, reduced insulin sensitivity and dyslipidaemia. A bidirectional relationship between testosterone and obesity underpins this association indicated by the hypogonadal-obesity cycle and evidence weight loss can lead to increased testosterone levels. Androgenic effects on enzymatic pathways of fatty acid metabolism, glucose control and energy utilization are apparent and often tissue specific with differential effects noted in different regional fat depots, muscle and liver to potentially explain the mechanisms of testosterone action. Testosterone replacement therapy demonstrates beneficial effects on measures of obesity that are partially explained by both direct metabolic actions on adipose and muscle and also potentially by increasing motivation, vigour and energy allowing obese individuals to engage in more active lifestyles. The degree of these beneficial effects may be dependent on the treatment modality with longer term administration often achieving greater improvements. Testosterone replacement may therefore potentially be an effective adjunctive treatment for weight management in obese men with concomitant hypogonadism.
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Affiliation(s)
- D M Kelly
- Department of Human Metabolism, Medical School, The University of Sheffield, Sheffield, UK
| | - T H Jones
- Department of Human Metabolism, Medical School, The University of Sheffield, Sheffield, UK.,Centre for Diabetes and Endocrinology, Barnsley Hospital NHS Foundation Trust, Barnsley, UK
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Huang QT, Huang Q, Luo W, Li F, Hang LL, Yu YH, Zhong M. Circulating retinol-binding protein 4 levels in gestational diabetes mellitus: a meta-analysis of observational studies. Gynecol Endocrinol 2015; 31:337-44. [PMID: 25703255 DOI: 10.3109/09513590.2015.1005594] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Retinol-binding protein 4 (RBP4) is a novel adipocyte-derived cytokine playing an important role in the regulation of energy metabolism and insulin sensitivity. Although the association between RBP4 and metabolic dysfunction is well established, studies on the relationship between circulating RBP4 levels and the risk of gestational diabetes mellitus (GDM) have yielded inconclusive results. We performed a meta-analysis to investigate whether women with GDM had higher circulating RBP4 levels than the normglycemic pregnant women. PubMed, Web of Science and EMBASE were searched up to 1 August 2014. A total of 14 studies comprised of 884 women with GDM and 1251 normglycemic pregnant women were included. The overall results suggested that maternal circulating RBP4 levels were significantly higher in GDM than their normal controls (SMD: 0.49 μg/ml, 95% CI: 0.23-0.75 μg/ml, p < 0.001, random effect model). However, stratified results indicated that this significant difference only existed in the second/third trimester and was limited to Asian populations. Furthermore, subgroup analysis according to matched maternal age and BMI still demonstrated that GDM had higher circulating RBP4 levels than the normal controls. Our findings suggested that Asian women with GDM had increased circulating RBP4 levels in their second/third trimester.
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Affiliation(s)
- Qi-Tao Huang
- Division of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University , Guangzhou , P.R. China and
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Li F, Xia K, Sheikh SA, Cheng J, Li C, Yang T. Involvement of RBP4 in hyperinsulinism-induced vascular smooth muscle cell proliferation. Endocrine 2015; 48:472-82. [PMID: 24888764 DOI: 10.1007/s12020-014-0304-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 05/14/2014] [Indexed: 12/20/2022]
Abstract
Retinol-binding protein 4 (RBP4) is a newly discovered adipocytokine related to insulin resistance (IR). Hyperinsulinemia and IR are the major risk factors for cardiovascular diseases (CVD). The role of RBP4 in CVD has not yet been determined. The present study was designed to analyze the correlation of RBP4 and CVD risk factors and to evaluate the role of RBP4 in proliferation of vascular smooth muscle cells during hyperinsulinemia and the underlying mechanisms. Plasma RBP4 concentration, IR-related indexes, and cardiovascular risk factors were measured from blood samples of hyperinsulinemic rats (HIns) and control SD rats (Cons). The vascular morphology and the expression of ERK1/2, p-ERK1/2 in arterial tissues of rats were assessed. Different concentrations of RBP4 (1, 4 μg/ml) were used as intervention factor during insulin-induced aortic smooth muscle cells (RASMCs) proliferation. The expression of cell growth signaling pathways was assessed to identify the active pathway during this proliferation. Specifically, ERK1/2 inhibitor PD98059 and JAK2 inhibitor AG490 were used to detect it. RBP4 expression was higher in HIns compared with Cons (p < 0.01). Plasma RBP4 concentrations were positively correlated with TG (r = 0.490), hsCRP (r = 0.565), media thickness (r = 0.890), and p-ERK1/2 protein (r = 0.746) (p < 0.05 each). In cultured RASMCs, RBP4 enhanced insulin-induced proliferation of cells and expression of p-ERK1/2 and p-JAK2. Blockade of ERK1/2 signaling pathway inhibited RBP4-induced proliferation of RASMCs, while suppressing JAK2 remains unchanged. These results suggest that plasma RBP4 concentrations were associated with CVD. In addition, RBP4 increases the proliferation of VSMCs induced by hyperinsulinism via activation of MAPK signaling pathway.
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Affiliation(s)
- Fei Li
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha, 410008, China
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Ansar H, Mirzaei K, Malek A, Najmafshar A, Hossein-nezhad A. Possible resting metabolic rate modification by the circulating RBP4 in obese subjects. Diabetes Metab Syndr 2015; 9:19-23. [PMID: 25450816 DOI: 10.1016/j.dsx.2014.09.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
AIM Adipose tissue derived retinol-binding protein 4 (RBP-4), known as one of the most important adipokins, has a link with insulin resistance and metabolic syndrome in obesity. The purpose of this study was to investigate the possible correlation between fasting serum RBP4 and resting metabolic rate (RMR) as a predictor of weight gain, body composition and insulin resistance in obese and non-obese subjects. MATERIALS AND METHODS In this case-control study, 73 obese and 90 non-obese participants were assessed following an overnight fasting for RMR by means of indirect calorimetry. Body composition was measured using body composition analyzer. Serum RBP4 levels were quantified by ELISA method. RESULTS Circulating RBP4 level correlated positively with log insulin (r=0.278, p=0.04) in obese subjects. There were no significant correlation between RBP4 and body composition in obese subjects except fat free mass (r=0.42, p=0.001). We found reduced RMR/kg in higher RBP4 concentration, moreover, a negative correlation was found between RBP4 and RMR/kg (r=-0.35, p=0.01) in obese group. Based on ROC analysis and RMR/kg cut-off value (=20 kcal/24 h/kg) for predicting the risk of obesity, 83.3% of participants with RMR/kg<20 kcal/24 h/kg had high RBP4 concentration, however in subjects with RMR/kg≥20 kcal/24 h/kg this percentage was 16.7 (p=0.01). CONCLUSION Our findings demonstrated that RBP4 concentration had relation with RMR which was different among obese and non-obese groups. These results may suggest the possible role of RBP4 in alteration of metabolic rate through insulin or other metabolic effects.
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Affiliation(s)
- Hasti Ansar
- School of Nutritional Science and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Khadijeh Mirzaei
- School of Nutritional Science and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Anita Malek
- Department of Pathology and Laboratory Medicine, Boston Medical Center, Boston, MA, USA
| | | | - Arash Hossein-nezhad
- Tehran University of Medical Science, Tehran, Iran; Department of Medicine, Section of Endocrinology, Nutrition and Diabetes, Vitamin D, Skin and Bone, Research Laboratory, Boston University Medical Center, Boston, MA, USA.
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Andrade-Oliveira V, Câmara NOS, Moraes-Vieira PM. Adipokines as drug targets in diabetes and underlying disturbances. J Diabetes Res 2015; 2015:681612. [PMID: 25918733 PMCID: PMC4397001 DOI: 10.1155/2015/681612] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2014] [Accepted: 03/19/2015] [Indexed: 12/14/2022] Open
Abstract
Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormonal and inflammatory regulation. White adipose tissue is recognized as a multifactorial organ that secretes several adipose-derived factors that have been collectively termed "adipokines." Adipokines are pleiotropic molecules that gather factors such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidin, RBP4, and inflammatory cytokines, including TNF and IL-1β, among others. Multiple roles in metabolic and inflammatory responses have been assigned to these molecules. Several adipokines contribute to the self-styled "low-grade inflammatory state" of obese and insulin-resistant subjects, inducing the accumulation of metabolic anomalies within these individuals, including autoimmune and inflammatory diseases. Thus, adipokines are an interesting drug target to treat autoimmune diseases, obesity, insulin resistance, and adipose tissue inflammation. The aim of this review is to present an overview of the roles of adipokines in different immune and nonimmune cells, which will contribute to diabetes as well as to adipose tissue inflammation and insulin resistance development. We describe how adipokines regulate inflammation in these diseases and their therapeutic implications. We also survey current attempts to exploit adipokines for clinical applications, which hold potential as novel approaches to drug development in several immune-mediated diseases.
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Affiliation(s)
- Vinícius Andrade-Oliveira
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, SP, Brazil
| | - Niels O. S. Câmara
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, SP, Brazil
- Laboratory of Clinical and Experimental Immunology, Nephrology Division, Federal University of São Paulo, SP, Brazil
| | - Pedro M. Moraes-Vieira
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, MA, USA
- *Pedro M. Moraes-Vieira:
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Nyman E, Rajan MR, Fagerholm S, Brännmark C, Cedersund G, Strålfors P. A single mechanism can explain network-wide insulin resistance in adipocytes from obese patients with type 2 diabetes. J Biol Chem 2014; 289:33215-30. [PMID: 25320095 DOI: 10.1074/jbc.m114.608927] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The response to insulin is impaired in type 2 diabetes. Much information is available about insulin signaling, but understanding of the cellular mechanisms causing impaired signaling and insulin resistance is hampered by fragmented data, mainly obtained from different cell lines and animals. We have collected quantitative and systems-wide dynamic data on insulin signaling in primary adipocytes and compared cells isolated from healthy and diabetic individuals. Mathematical modeling and experimental verification identified mechanisms of insulin control of the MAPKs ERK1/2. We found that in human adipocytes, insulin stimulates phosphorylation of the ribosomal protein S6 and hence protein synthesis about equally via ERK1/2 and mTORC1. Using mathematical modeling, we examined the signaling network as a whole and show that a single mechanism can explain the insulin resistance of type 2 diabetes throughout the network, involving signaling both through IRS1, PKB, and mTOR and via ERK1/2 to the nuclear transcription factor Elk1. The most important part of the insulin resistance mechanism is an attenuated feedback from the protein kinase mTORC1 to IRS1, which spreads signal attenuation to all parts of the insulin signaling network. Experimental inhibition of mTORC1 using rapamycin in adipocytes from non-diabetic individuals induced and thus confirmed the predicted network-wide insulin resistance.
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Affiliation(s)
- Elin Nyman
- From the Department of Clinical and Experimental Medicine and
| | | | - Siri Fagerholm
- From the Department of Clinical and Experimental Medicine and
| | | | - Gunnar Cedersund
- From the Department of Clinical and Experimental Medicine and the Department of Biomedical Engineering, Linköping University, SE58185 Linköping, Sweden
| | - Peter Strålfors
- From the Department of Clinical and Experimental Medicine and
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Gursoy AY, Aynaoglu G, Caglar GS, Soylemez F. Early second trimester retinol-binding protein-4 values in cases with or without gestational diabetes mellitus risk factors: a cross-sectional study. J Obstet Gynaecol Res 2014; 41:55-61. [PMID: 25227411 DOI: 10.1111/jog.12499] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Accepted: 05/07/2014] [Indexed: 01/15/2023]
Abstract
AIM Retinol-binding protein-4 (RBP-4) has been correlated with different degrees of insulin resistance including gestational diabetes mellitus (GDM). Presence of risk factors for GDM is an indication for early screening. We studied RBP-4 values in the early second trimester of pregnancy in pregnant subjects with or without GDM risk factors and compared the results by routine GDM screening methodology. METHODS Seventy-nine patients with at least one GDM risk factor and 46 patients without any GDM risk factors were enrolled in the cross-sectional study as risk and control groups, respectively. In the early second trimester, RBP-4 values were measured, in addition to fasting plasma glucose and 50-g glucose challenge test in all subjects. RESULTS The RBP-4 values in 16-18th weeks of pregnancy were not significantly different between risk and control groups (95.3 ± 20.1 vs 103.1 ± 24.4 μg/mL, respectively; P = 0.055) although fasting plasma glucose levels and 50-g glucose challenge test results were higher in the risk group than the control group (75.3 vs 69.3 mg/dL and 112.4 vs 97.5 mg/dL, respectively; P < 0.05). CONCLUSION Presence of GDM risk factors does not have an impact on early second trimester RBP-4 values in pregnant subjects.
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Affiliation(s)
- Asli Yarci Gursoy
- Faculty of Medicine, Department of Obstetrics and Gynecology, Ufuk University, Ankara, Turkey
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Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci 2014; 15:6184-223. [PMID: 24733068 PMCID: PMC4013623 DOI: 10.3390/ijms15046184] [Citation(s) in RCA: 1296] [Impact Index Per Article: 117.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 03/27/2014] [Accepted: 04/01/2014] [Indexed: 02/06/2023] Open
Abstract
Accumulating evidence indicates that obesity is closely associated with an increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease. Obesity results from an imbalance between food intake and energy expenditure, which leads to an excessive accumulation of adipose tissue. Adipose tissue is now recognized not only as a main site of storage of excess energy derived from food intake but also as an endocrine organ. The expansion of adipose tissue produces a number of bioactive substances, known as adipocytokines or adipokines, which trigger chronic low-grade inflammation and interact with a range of processes in many different organs. Although the precise mechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excess adipose tissue and adipose tissue dysfunction can contribute to the development of obesity-related metabolic diseases. In this review, we focus on the role of several adipokines associated with obesity and the potential impact on obesity-related metabolic diseases. Multiple lines evidence provides valuable insights into the roles of adipokines in the development of obesity and its metabolic complications. Further research is still required to fully understand the mechanisms underlying the metabolic actions of a few newly identified adipokines.
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Affiliation(s)
- Un Ju Jung
- Center for Food and Nutritional Genomics Research, Kyungpook National University, 1370 Sankyuk Dong Puk-ku, Daegu 702-701, Korea.
| | - Myung-Sook Choi
- Center for Food and Nutritional Genomics Research, Kyungpook National University, 1370 Sankyuk Dong Puk-ku, Daegu 702-701, Korea.
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Li F, Xia K, Sheikh MSA, Cheng J, Li C, Yang T. Retinol binding protein 4 promotes hyperinsulinism‑induced proliferation of rat aortic smooth muscle cells. Mol Med Rep 2014; 9:1634-40. [PMID: 24604418 PMCID: PMC4020478 DOI: 10.3892/mmr.2014.2028] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Accepted: 02/20/2014] [Indexed: 01/15/2023] Open
Abstract
Recent studies have suggested that retinol binding protein 4 (RBP4), an adipocytokine related to insulin resistance (IR), may play an important role in the development of atherosclerosis and cardiovascular diseases (CVD). Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) is one of the most common causes of atherosclerosis. Hyperinsulinism promotes proliferation of VSMCs through the MAPK pathway. However, whether RBP4 is involved in insulin-induced proliferation of VSMCs leading to atherosclerosis remains unclear. In the present study, we evaluated the role of RBP4 and the potential relevance of signaling pathways in this process. Different concentrations of RBP4 (1 and 4 μg/ml) were added to rat aortic smooth muscle cells (RASMCs) during insulin-induced proliferation. The levels of cell growth signaling pathway proteins ERK1/2, p-ERK1/2, JAK2, p-JAK2, STAT3 and p-STAT3 were assessed by western blotting in order to identify the pathway(s) that are activated during insulin-induced proliferation. The specific inhibitors of ERK1/2 (PD98059) and JAK2 (AG490) were used to confirm our findings. Insulin induced proliferation of RASMCs in a concentration- and time-dependent manner, and increased the expression of ERK1/2, p-ERK1/2, JAK2, p-JAK2, STAT3 and p-STAT3 in a time-dependent manner. RBP4 enhanced insulin-induced proliferation of RASMCs and expression of p-ERK1/2 and p-JAK2. RBP4-induced proliferation of RASMCs was reduced by the ERK1/2 inhibitor, while it was unaffected by the JAK2 inhibitor. These results suggest that RBP4 mediates VSMC proliferation induced by insulin via activation of the MAPK pathway, and highlight RBP4 as a modulator of atherosclerosis in hyperinsulinemia, therby enhancing our understanding on a number of unexpected aspects of CVD.
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Affiliation(s)
- Fei Li
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Ke Xia
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Md Sayed Ali Sheikh
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Jinfang Cheng
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Chuanchang Li
- Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Tianlun Yang
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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Cheng J, Li Y, Wu G, Zheng J, Lu H, Shi X, Yang G. Ectopic expression of RBP4 impairs the insulin pathway and inguinal fat deposition in mice. J Physiol Biochem 2014; 70:479-86. [PMID: 24590924 DOI: 10.1007/s13105-014-0326-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Accepted: 02/18/2014] [Indexed: 01/15/2023]
Abstract
A large body of evidence has linked retinol-binding protein 4 (RBP4) to systemic insulin resistance, but little is known about its function in fat deposition. This study aimed to confirm the involvement of RBP4 in inguinal fat deposition and insulin by intraperitoneal injection of adenovirus-mediated RBP4 to mice. Intraperitoneal injection of adenoviral vectors was validated as an efficient gene manipulation tool for over-expressing recombinant proteins in vivo. Ectopic expression of RBP4 decelerated inguinal fat deposition by decreasing the size of adipocytes. Moreover, the introduction of exogenous RBP4 blunted the response of inguinal adipocytes to insulin signals. These findings suggest that RBP4 impaired in vivo adipogenesis, partly through the repression of the insulin pathway.
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Affiliation(s)
- Jia Cheng
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
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Östh M, Öst A, Kjolhede P, Strålfors P. The concentration of β-carotene in human adipocytes, but not the whole-body adipocyte stores, is reduced in obesity. PLoS One 2014; 9:e85610. [PMID: 24416432 PMCID: PMC3885716 DOI: 10.1371/journal.pone.0085610] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 12/06/2013] [Indexed: 01/15/2023] Open
Abstract
We have examined the concentration of β-carotene in the fat of isolated abdominal subcutaneous adipocytes obtained from lean (BMI<23 kg/m2), non-obese with higher BMI (23≤BMI<28 kg/m2), obese (BMI≥28 kg/m2), and from a group of obese subjects with type 2 diabetes. The concentration of β-carotene was 50% lower in the adipocytes from the obese and obese/diabetic groups compared with the lean and non-obese groups. Interestingly, the total amount of β-carotene in the adipocyte stores of each subject was constant among all groups. Triacylglycerol constituted 92±1% (by weight) of the adipocyte lipids in the lean group and this was increased to 99±2% in the obese group with diabetes (p<0.05). The concentration of cholesteryl esters was in all cases <0.1 g per 100 g of total lipids, demonstrating that mature human adipocytes have negligible stores of cholesteryl ester. Our findings demonstrate that adipocyte concentrations of β-carotene are reduced in obese subjects. The lower concentrations in adipocytes from subjects with type 2 diabetes apparently reflect subjectś obesity. Our finding that whole-body stores of β-carotene in adipocytes are constant raises new questions regarding what function it serves, as well as the mechanisms for maintaining constant levels in the face of varied adipose tissue mass among individuals over a period of time.
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Affiliation(s)
- Martin Östh
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Anita Öst
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Preben Kjolhede
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Peter Strålfors
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
- * E-mail:
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Fang P, Shi M, Yu M, Guo L, Bo P, Zhang Z. Endogenous peptides as risk markers to assess the development of insulin resistance. Peptides 2014; 51:9-14. [PMID: 24184593 DOI: 10.1016/j.peptides.2013.10.025] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Revised: 10/19/2013] [Accepted: 10/21/2013] [Indexed: 01/15/2023]
Abstract
Insulin resistance, the reciprocal of insulin sensitivity, is known to be a characteristic of type 2 diabetes mellitus, and is regarded as an important mechanism in the pathogenesis. The hallmark of insulin resistance is a gradual break-down of insulin-regulative glucose uptake by muscle and adipose tissues in subjects. Insulin resistance is increasingly estimated in various disease conditions to examine and assess their etiology, pathogenesis and consequences. Although our understanding of insulin resistance has tremendously been improved in recent years, certain aspects of its estimation and etiology still remain elusive to clinicians and researchers. There are numerous factors involved in pathogenesis and mechanisms of insulin resistance. Recent studies have provided compelling clues about some peptides and proteins, including galanin, galanin-like peptide, ghrelin, adiponectin, retinol binding protein 4 (RBP4) and CRP, which may be used to simplify and to improve the determination of insulin resistance. And alterations of these peptide levels may be recognized as risk markers of developing insulin resistance and type 2 diabetes mellitus. This review examines the updated information for these peptides, highlighting the relations between these peptide levels and insulin resistance. The plasma high ghrelin, RBP4 and CRP as well as low galanin, GALP and adiponectin levels may be taken as the markers of deteriorating insulin resistance. An increase in the knowledge of these marker proteins and peptides will help us correctly diagnose and alleviate insulin resistance in clinic and study.
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Affiliation(s)
- Penghua Fang
- Research Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China; Department of Physiology, Nanjing University of Chinese Medicine Hanlin College, Taizhou, Jiangsu 225300, China
| | - Mingyi Shi
- Research Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China
| | - Mei Yu
- Taizhou Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Taizhou, Jiangsu 225300, China
| | - Lili Guo
- Research Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China
| | - Ping Bo
- Research Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China
| | - Zhenwen Zhang
- Research Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China; Department of Endocrinology, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China.
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Paragh G, Seres I, Harangi M, Fülöp P. Dynamic interplay between metabolic syndrome and immunity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 824:171-90. [PMID: 25039000 DOI: 10.1007/978-3-319-07320-0_13] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Obesity and its co-morbidities as metabolic syndrome, type 2 diabetes mellitus and cardiovascular diseases are major health problems worldwide. Several reports indicated that nutrient excess and metabolic syndrome are linked with altered immune response. Indeed, metabolic syndrome is characterized by insulin resistance and chronic low-grade inflammation, which conditions are the consequences of the complex interaction between adipocytes and immune cells. Enlarged white adipose tissue is infiltrated by immune cells and secretes various bioactive substances, like adipokines, cytokines and other inflammatory mediators. Due to its special architecture in which metabolic and immune cells are in intimate proximity, metabolic and immunologic pathways are closely integrated in adipose tissue. With the contribution of altered gut microbiota, adipokines and cytokines modulate insulin signaling and immune response leading to adipose tissue inflammation and systemic insulin resistance. In this chapter, we focus on the cellular and molecular mechanisms that lead to impaired insulin sensitivity and chronic low-grade inflammation in obesity. We also detail the potential role of adipokines and immune cells in this deleterious process, and the concerns of vaccination in metabolic syndrome. Finally, we address the links between obesity and gut microbiota as an emerging new field of interest, and scratch the surface of potential therapeutic opportunities.
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Affiliation(s)
- György Paragh
- Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, H-4032, Hungary,
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Jufvas A, Sjödin S, Lundqvist K, Amin R, Vener AV, Strålfors P. Global differences in specific histone H3 methylation are associated with overweight and type 2 diabetes. Clin Epigenetics 2013; 5:15. [PMID: 24004477 PMCID: PMC3766271 DOI: 10.1186/1868-7083-5-15] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 07/12/2013] [Indexed: 01/15/2023] Open
Abstract
Background Epidemiological evidence indicates yet unknown epigenetic mechanisms underlying a propensity for overweight and type 2 diabetes. We analyzed the extent of methylation at lysine 4 and lysine 9 of histone H3 in primary human adipocytes from 43 subjects using modification-specific antibodies. Results The level of lysine 9 dimethylation was stable, while adipocytes from type 2 diabetic and non-diabetic overweight subjects exhibited about 40% lower levels of lysine 4 dimethylation compared with cells from normal-weight subjects. In contrast, trimethylation at lysine 4 was 40% higher in adipocytes from overweight diabetic subjects compared with normal-weight and overweight non-diabetic subjects. There was no association between level of modification and age of subjects. Conclusions The findings define genome-wide molecular modifications of histones in adipocytes that are directly associated with overweight and diabetes, and thus suggest a molecular basis for existing epidemiological evidence of epigenetic inheritance.
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Affiliation(s)
- Asa Jufvas
- Department of Clinical and Experimental Medicine, Linköping University, Linköping SE58185, Sweden.
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Vestergaard ET, Krag MB, Poulsen MM, Pedersen SB, Moller N, Jorgensen JOL, Jessen N. Ghrelin- and GH-induced insulin resistance: no association with retinol-binding protein-4. Endocr Connect 2013; 2:96-103. [PMID: 23781325 PMCID: PMC3682232 DOI: 10.1530/ec-13-0019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2013] [Accepted: 05/07/2013] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Supraphysiological levels of ghrelin and GH induce insulin resistance. Serum levels of retinol-binding protein-4 (RBP4) correlate inversely with insulin sensitivity in patients with type 2 diabetes. We aimed to determine whether ghrelin and GH affect RBP4 levels in human subjects. MATERIALS AND METHODS To study GH-independent effects of ghrelin, seven hypopituitary men undergoing replacement therapy with GH and hydrocortisone were given ghrelin (5 pmol/kg per min) and saline infusions for 300 min in a randomized, double-blind, placebo-controlled, crossover design. Circulating RBP4 levels were measured at baseline and during a hyperinsulinemic-euglycemic clamp on both study days. To study the direct effects of GH, nine healthy men were treated with GH (2 mg at 2200 h) and placebo for 8 days in a randomized, double-blind, placebo-controlled, crossover study. Serum RBP4 levels were measured before and after treatment, and insulin sensitivity was measured by the hyperinsulinemic-euglycemic clamp technique. RESULTS Ghrelin acutely decreased peripheral insulin sensitivity. Serum RBP4 concentrations decreased in response to insulin infusion during the saline experiment (mg/l): 43.2±4.3 (baseline) vs 40.4±4.2 (clamp), P<0.001, but this effect was abrogated during ghrelin infusion (mg/l): 42.4±4.5 (baseline) vs 42.9±4.7 (clamp), P=0.73. In healthy subjects, serum RBP4 levels were not affected by GH administration (mg/l): 41.7±4.1 (GH) vs 43.8±4.6 (saline), P=0.09, although GH induced insulin resistance. CONCLUSIONS i) Serum RBP4 concentrations decrease in response to hyperinsulinemia, ii) ghrelin abrogates the inhibitory effect of insulin on circulating RBP4 concentrations, and iii) ghrelin as well as GH acutely induces insulin resistance in skeletal muscle without significant changes in circulating RBP4 levels.
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Affiliation(s)
- Esben Thyssen Vestergaard
- Medical Research LaboratoriesInstitute of Clinical Medicine, Aarhus UniversityNorrebrogade 44DK-8000, Aarhus CDenmark
- Department of Endocrinology and DiabetesAarhus University HospitalNorrebrogade 44DK-8000, Aarhus CDenmark
- Department of PediatricsRegional Hospital West JutlandGl. Landevej 61DK-7400, HerningDenmark
- Correspondence should be addressed to E T Vestergaard
| | - Morten B Krag
- Department of Endocrinology and DiabetesAarhus University HospitalNorrebrogade 44DK-8000, Aarhus CDenmark
| | - Morten M Poulsen
- Department of Endocrinology and DiabetesAarhus University HospitalTage-Hansens Gade 2DK-8000, Aarhus CDenmark
| | - Steen B Pedersen
- Department of Endocrinology and DiabetesAarhus University HospitalTage-Hansens Gade 2DK-8000, Aarhus CDenmark
| | - Niels Moller
- Medical Research LaboratoriesInstitute of Clinical Medicine, Aarhus UniversityNorrebrogade 44DK-8000, Aarhus CDenmark
- Department of Endocrinology and DiabetesAarhus University HospitalNorrebrogade 44DK-8000, Aarhus CDenmark
| | - Jens Otto Lunde Jorgensen
- Medical Research LaboratoriesInstitute of Clinical Medicine, Aarhus UniversityNorrebrogade 44DK-8000, Aarhus CDenmark
- Department of Endocrinology and DiabetesAarhus University HospitalNorrebrogade 44DK-8000, Aarhus CDenmark
| | - Niels Jessen
- Medical Research LaboratoriesInstitute of Clinical Medicine, Aarhus UniversityNorrebrogade 44DK-8000, Aarhus CDenmark
- Department of Endocrinology and DiabetesAarhus University HospitalNorrebrogade 44DK-8000, Aarhus CDenmark
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Abstract
Testosterone is a hormone that plays a key role in carbohydrate, fat and protein metabolism. It has been known for some time that testosterone has a major influence on body fat composition and muscle mass in the male. Testosterone deficiency is associated with an increased fat mass (in particular central adiposity), reduced insulin sensitivity, impaired glucose tolerance, elevated triglycerides and cholesterol and low HDL-cholesterol. All these factors are found in the metabolic syndrome (MetS) and type 2 diabetes, contributing to cardiovascular risk. Clinical trials demonstrate that testosterone replacement therapy improves the insulin resistance found in these conditions as well as glycaemic control and also reduces body fat mass, in particular truncal adiposity, cholesterol and triglycerides. The mechanisms by which testosterone acts on pathways to control metabolism are not fully clear. There is, however, an increasing body of evidence from animal, cell and clinical studies that testosterone at the molecular level controls the expression of important regulatory proteins involved in glycolysis, glycogen synthesis and lipid and cholesterol metabolism. The effects of testosterone differ in the major tissues involved in insulin action, which include liver, muscle and fat, suggesting a complex regulatory influence on metabolism. The cumulative effects of testosterone on these biochemical pathways would account for the overall benefit on insulin sensitivity observed in clinical trials. This review discusses the current knowledge of the metabolic actions of testosterone and how testosterone deficiency contributes to the clinical disease states of obesity, MetS and type 2 diabetes and the role of testosterone replacement.
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Affiliation(s)
- Daniel M Kelly
- Department of Human Metabolism, Medical School, The University of Sheffield, Sheffield S10 2RX, UK
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Molfino A, Heymsfield SB, Zhu F, Kotanko P, Levin NW, Dwyer T, Kaysen GA. Prealbumin is associated with visceral fat mass in patients receiving hemodialysis. J Ren Nutr 2013; 23:406-10. [PMID: 23623396 DOI: 10.1053/j.jrn.2013.02.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 01/27/2013] [Accepted: 02/12/2013] [Indexed: 01/15/2023] Open
Abstract
OBJECTIVE Albumin and prealbumin are associated with nutritional status and inflammatory status. Each has a residual effect on mortality outcomes when included in regression models that include the other. Prealbumin is increased in the obese mouse model as a consequence of stabilization of prealbumin by retinol binding protein 4 (RBP4) secreted by adipocytes. We carried out this study to establish the contribution of adiposity to prealbumin levels in prevalent patients receiving dialysis and the relationship of prealbumin to RBP4. DESIGN AND METHODS We determined whether prealbumin was associated with adiposity in patients receiving hemodialysis (HD), controlling for the effects of inflammation and nutrition. We evaluated body composition in 48 prevalent patients receiving HD by magnetic resonance imaging (MRI), measuring total skeletal muscle mass (SM), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and serum albumin, prealbumin, RBP4, and interleukin-6 (IL-6) levels. We used normalized protein catabolic rate (nPCR) to report nutrition and separately analyzed the determinants of albumin and then of prealbumin by multiple stepwise regression. RESULTS Thirty-two patients were women, 16 patients were diabetic, and median age and body mass index were 54.5 and 27.3 kg/m(2), respectively. Median total adipose tissue (TAT) was 24.3 kg and VAT was 3.25 kg. Prealbumin was positively associated with VAT, nPCR, and RBP4 and was negatively associated with IL-6; r(2) for the model was 0.64. By contrast, albumin was positively associated with nPCR and negatively associated with IL-6 but not with any measure of adiposity (r(2) for the model = 0.2). CONCLUSIONS Prealbumin, like albumin, is associated with markers of nutrition (nPCR) and inflammation, but unlike albumin, prealbumin levels are positively associated with visceral adiposity.
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Affiliation(s)
- Alessio Molfino
- Department of Internal Medicine, Division of Nephrology, University of California, Davis, Davis, California; Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy
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Cheng J, Song ZY, Pu L, Yang H, Zheng JM, Zhang ZY, Shi XE, Yang GS. Retinol binding protein 4 affects the adipogenesis of porcine preadipocytes through insulin signaling pathways. Biochem Cell Biol 2013; 91:236-43. [PMID: 23859018 DOI: 10.1139/bcb-2012-0112] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Retinol binding protein 4 (RBP4), a novel cytokine, is mainly secreted by hepatocytes and adipocytes. RBP4 reportedly induces insulin resistance and RBP4 secretion is increased in the adipocytes of animals or humans with type 2 diabetes, obesity, and metabolic syndrome, but its role in preadipocyte differentiation remains unclear. In this study, we investigated the effect of RBP4 on the differentiation of porcine preadipocytes into adipocytes. The results suggest that RBP4 significantly suppresses the differentiation of porcine preadipocytes into adipocytes, including those treated with the hormone cocktail methylisobutylxanthine-dexamethasone-insulin. RBP4 also weakened the activity of normal threonine 308, the phosphorylation of serine/threonine kinase AKT, and downstream insulin signaling, including the mammalian target of rapamycin (mTOR) and β-catenin. Moreover, the activation of insulin signaling mediated by knockdown RBP4 in porcine preadipocytes was recovered in the suppression of LY294002. RBP4 also had a suppressive effect on the differentiation of porcine preadipocytes by decreasing the activation of insulin signaling pathways.
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Affiliation(s)
- Jia Cheng
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, PR China
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Brännmark C, Nyman E, Fagerholm S, Bergenholm L, Ekstrand EM, Cedersund G, Strålfors P. Insulin signaling in type 2 diabetes: experimental and modeling analyses reveal mechanisms of insulin resistance in human adipocytes. J Biol Chem 2013; 288:9867-9880. [PMID: 23400783 DOI: 10.1074/jbc.m112.432062] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Type 2 diabetes originates in an expanding adipose tissue that for unknown reasons becomes insulin resistant. Insulin resistance reflects impairments in insulin signaling, but mechanisms involved are unclear because current research is fragmented. We report a systems level mechanistic understanding of insulin resistance, using systems wide and internally consistent data from human adipocytes. Based on quantitative steady-state and dynamic time course data on signaling intermediaries, normally and in diabetes, we developed a dynamic mathematical model of insulin signaling. The model structure and parameters are identical in the normal and diabetic states of the model, except for three parameters that change in diabetes: (i) reduced concentration of insulin receptor, (ii) reduced concentration of insulin-regulated glucose transporter GLUT4, and (iii) changed feedback from mammalian target of rapamycin in complex with raptor (mTORC1). Modeling reveals that at the core of insulin resistance in human adipocytes is attenuation of a positive feedback from mTORC1 to the insulin receptor substrate-1, which explains reduced sensitivity and signal strength throughout the signaling network. Model simulations with inhibition of mTORC1 are comparable with experimental data on inhibition of mTORC1 using rapamycin in human adipocytes. We demonstrate the potential of the model for identification of drug targets, e.g. increasing the feedback restores insulin signaling, both at the cellular level and, using a multilevel model, at the whole body level. Our findings suggest that insulin resistance in an expanded adipose tissue results from cell growth restriction to prevent cell necrosis.
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Affiliation(s)
- Cecilia Brännmark
- Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden
| | - Elin Nyman
- Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden
| | - Siri Fagerholm
- Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden
| | - Linnéa Bergenholm
- Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden
| | - Eva-Maria Ekstrand
- Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden
| | - Gunnar Cedersund
- Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden; Department of Biomedical Engineering, Linköping University, SE58185 Linköping, Sweden
| | - Peter Strålfors
- Department of Clinical and Experimental Medicine, Linköping University, SE58185 Linköping, Sweden.
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Abetew DF, Qiu C, Fida NG, Dishi M, Hevner K, Williams MA, Enquobahrie DA. Association of retinol binding protein 4 with risk of gestational diabetes. Diabetes Res Clin Pract 2013; 99:48-53. [PMID: 23153527 PMCID: PMC3544538 DOI: 10.1016/j.diabres.2012.10.023] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Revised: 09/24/2012] [Accepted: 10/22/2012] [Indexed: 02/08/2023]
Abstract
AIM We investigated association of maternal retinol binding protein 4 (RBP4) with risk of gestational diabetes (GDM). METHODS GDM cases (N=173) and controls (N=187) were selected from among participants of a cohort study of risk factors of pregnancy complications. Early pregnancy (16 weeks on average) serum RBP4 concentration was measured using an ELISA-based immunoassay. Logistic regression was used to estimate unadjusted and adjusted odds ratios (ORs/aORs) and 95% confidence intervals (95%CI). RESULTS Mean serum RBP4 was significantly higher among GDM cases compared with controls (47.1 vs. 41.1 μg/ml, respectively; p-value <0.05). Participants in the highest quartile for serum RBP4 had a 1.89-fold higher risk of GDM compared with participants in the lowest quartile (95%CI: 1.05-3.43). However, this relationship did not reach statistical significance after adjustment for confounders (aOR: 1.54; 95%CI: 0.82-2.90). Women who were ≥35 years old and who had high RBP4 (≥38.3 μg/ml, the median) had a 2.31-fold higher risk of GDM compared with women who were <35 years old and had low RBP4 (<38.3 μg/ml) (aOR: 2.31; 95%CI: 1.26-4.23; p-value for interaction=0.021). CONCLUSION Overall, there is modest evidence of a positive association of early pregnancy elevated RBP4 concentration with increased GDM risk, particularly among women with advanced age.
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Affiliation(s)
- Dejene F Abetew
- Center for Perinatal Studies, Swedish Medical Center, Seattle, WA, United States.
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Zhou Y, Rui L. Lipocalin 13 regulation of glucose and lipid metabolism in obesity. VITAMINS AND HORMONES 2013; 91:369-83. [PMID: 23374724 DOI: 10.1016/b978-0-12-407766-9.00015-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Lipocalin (LCN) family members are small secreted proteins that bind to small hydrophobic molecules via their characteristic central β-barrels. A couple of LCN family members, including major urinary protein 1, retinol-binding protein 4, LCN2, and LCN13, have been reported to regulate insulin sensitivity and nutrient metabolism. LCN13 is expressed by multiple tissues, including the liver, pancreas, epididymis, and skeletal muscle, and is secreted into the bloodstream in mice. Obesity is associated with a downregulation of LCN13 expression and lower levels of circulating LCN13. LCN13 therapies overcome LCN13 deficiency in mice with either genetic or dietary obesity, leading to an improvement in hyperglycemia, hyperinsulinemia, insulin resistance, glucose intolerance, and hepatic steatosis. In hepatocytes, LCN13 directly suppresses hepatic gluconeogenesis and lipogenesis but increases fatty acid β oxidation. LCN13 also enhances insulin sensitivity in adipocytes. The potential mechanisms of the antidiabetes and antisteatosis actions of LCN13 are discussed.
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Affiliation(s)
- Yingjiang Zhou
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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Ding J, Sackmann-Sala L, Kopchick JJ. Mouse models of growth hormone action and aging: a proteomic perspective. Proteomics 2012; 13:674-85. [PMID: 23019135 DOI: 10.1002/pmic.201200271] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2012] [Revised: 07/19/2012] [Accepted: 07/27/2012] [Indexed: 12/12/2022]
Abstract
Growth hormone (GH) is a protein secreted by the anterior pituitary and circulates throughout the body to exert important actions on growth and metabolism. GH stimulates the secretion of insulin-like growth factor-I (IGF-I) that mediates some of the growth promoting actions of GH. The GH/IGF-I axis has recently been recognized as important in terms of longevity in organisms ranging from Caenorhabditis elegans to mice. For example, GH transgenic mice possess short lifespans while GH receptor null (GHR-/-) mice have extended longevity. Thus, the actions of GH (or IGF-I) or lack thereof impact the aging process. In this review, we summarize the proteomic analyses of plasma and white adipose tissue in these two mouse models of GH action, i.e. GH transgenic and GHR-/- mice. At the protein level, we wanted to establish novel plasma biomarkers of GH action as a function of age and to determine differences in adipose tissue depots. We have shown that these proteomic approaches have not only confirmed several known physiological actions of GH, but also resulted in novel protein biomarkers and targets that may be indicative of the aging process and/or new functions of GH. These results may generate new directions for GH and/or aging research.
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Affiliation(s)
- Juan Ding
- Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
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Alapatt P, Guo F, Komanetsky SM, Wang S, Cai J, Sargsyan A, Rodríguez Díaz E, Bacon BT, Aryal P, Graham TE. Liver retinol transporter and receptor for serum retinol-binding protein (RBP4). J Biol Chem 2012; 288:1250-65. [PMID: 23105095 DOI: 10.1074/jbc.m112.369132] [Citation(s) in RCA: 108] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Vitamin A (retinol) is absorbed in the small intestine, stored in liver, and secreted into circulation bound to serum retinol-binding protein (RBP4). Circulating retinol may be taken up by extrahepatic tissues or recycled back to liver multiple times before it is finally metabolized or degraded. Liver exhibits high affinity binding sites for RBP4, but specific receptors have not been identified. The only known high affinity receptor for RBP4, Stra6, is not expressed in the liver. Here we report discovery of RBP4 receptor-2 (RBPR2), a novel retinol transporter expressed primarily in liver and intestine and induced in adipose tissue of obese mice. RBPR2 is structurally related to Stra6 and highly conserved in vertebrates, including humans. Expression of RBPR2 in cultured cells confers high affinity RBP4 binding and retinol transport, and RBPR2 knockdown reduces RBP4 binding/retinol transport. RBPR2 expression is suppressed by retinol and retinoic acid and correlates inversely with liver retinol stores in vivo. We conclude that RBPR2 is a novel retinol transporter that potentially regulates retinol homeostasis in liver and other tissues. In addition, expression of RBPR2 in liver and fat suggests a possible role in mediating established metabolic actions of RBP4 in those tissues.
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Affiliation(s)
- Philomena Alapatt
- Molecular Medicine Program and Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City, Utah 84112, USA
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Kaess BM, Enserro DM, McManus DD, Xanthakis V, Chen MH, Sullivan LM, Ingram C, O'Donnell CJ, Keaney JF, Vasan RS, Glazer NL. Cardiometabolic correlates and heritability of fetuin-A, retinol-binding protein 4, and fatty-acid binding protein 4 in the Framingham Heart Study. J Clin Endocrinol Metab 2012; 97:E1943-7. [PMID: 22855337 PMCID: PMC3674297 DOI: 10.1210/jc.2012-1458] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
CONTEXT Fetuin-A, retinol-binding protein 4 (RBP4), and fatty-acid binding protein 4 (FABP4) are novel biomarkers that may link adiposity to insulin resistance and the metabolic syndrome (MetSyn). OBJECTIVE The aim of this study was to investigate the correlates of these three adiposity biomarkers in a large community-based sample. DESIGN, SETTING, PARTICIPANTS, AND OUTCOMES: Serum concentrations of fetuin-A, RBP4, and FABP4 were assayed in 3658 participants of the Third Generation Framingham Heart Study cohort (mean age 40 yr, 54% women). We used multivariable regression to cross-sectionally relate biomarkers to insulin resistance, cardiovascular risk factors, and the MetSyn. The genetic contribution to inter-individual variation in biomarker levels was assessed using variance-components analysis. RESULTS All three biomarkers exhibited sexual dimorphisms (levels higher in women for fetuin-A and FABP4 but greater in men for RBP4) and were associated positively with insulin resistance assessed using the homeostasis model, with high-sensitivity C-reactive protein, and with prevalent MetSyn (P<0.01 for all). The biomarkers showed distinct patterns of association with metabolic risk factors. RBP4 levels were correlated with body mass index only in unadjusted but not in adjusted models. None of the biomarkers were associated with prevalent diabetes in multivariable models. Circulating fetuin-A, RBP4, and FABP4 levels showed modest heritability, ranging from 15-44% (all P<0.0001). CONCLUSIONS In our large young- to middle-aged community-based sample, we observed that circulating levels of fetuin-A, RBP4, and FABP4 are associated with insulin resistance and with distinct components of MetSyn consistent with the multifactorial pathogenesis of metabolic dysregulation.
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Affiliation(s)
- Bernhard M Kaess
- National Heart, Blood, and Lung Institute's Framingham Heart Study, Framingham, MA 01702, USA
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Harwood HJ. The adipocyte as an endocrine organ in the regulation of metabolic homeostasis. Neuropharmacology 2012; 63:57-75. [DOI: 10.1016/j.neuropharm.2011.12.010] [Citation(s) in RCA: 185] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Revised: 11/28/2011] [Accepted: 12/09/2011] [Indexed: 02/06/2023]
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