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Ježek P. Physiological Fatty Acid-Stimulated Insulin Secretion and Redox Signaling Versus Lipotoxicity. Antioxid Redox Signal 2025; 42:566-622. [PMID: 39834189 DOI: 10.1089/ars.2024.0799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Significance: Type 2 diabetes as a world-wide epidemic is characterized by the insulin resistance concomitant to a gradual impairment of β-cell mass and function (prominently declining insulin secretion) with dysregulated fatty acids (FAs) and lipids, all involved in multiple pathological development. Recent Advances: Recently, redox signaling was recognized to be essential for insulin secretion stimulated with glucose (GSIS), branched-chain keto-acids, and FAs. FA-stimulated insulin secretion (FASIS) is a normal physiological event upon postprandial incoming chylomicrons. This contrasts with the frequent lipotoxicity observed in rodents. Critical Issues: Overfeeding causes FASIS to overlap with GSIS providing repeating hyperinsulinemia, initiates prediabetic states by lipotoxic effects and low-grade inflammation. In contrast the protective effects of lipid droplets in human β-cells counteract excessive lipids. Insulin by FASIS allows FATP1 recruitment into adipocyte plasma membranes when postprandial chylomicrons come late at already low glycemia. Future Directions: Impaired states of pancreatic β-cells and peripheral organs at prediabetes and type 2 diabetes should be revealed, including the inter-organ crosstalk by extracellular vesicles. Details of FA/lipid molecular physiology are yet to be uncovered, such as complex phenomena of FA uptake into cells, postabsorptive inactivity of G-protein-coupled receptor 40, carnitine carrier substrate specificity, the role of carnitine-O-acetyltransferase in β-cells, and lipid droplet interactions with mitochondria. Antioxid. Redox Signal. 42, 566-622.
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Affiliation(s)
- Petr Ježek
- Department of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
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Gao S, He J, Liu H, Fan L, Tian R. Neutrophils as mediators of the association between lipid accumulation product and kidney stones, but not for recurrent kidney stones in US adults. Urolithiasis 2025; 53:62. [PMID: 40163111 DOI: 10.1007/s00240-025-01735-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 03/15/2025] [Indexed: 04/02/2025]
Abstract
Kidney stones (KS) are prevalent and often recur, with obesity, metabolic disorders, and inflammation significantly impacting their pathophysiology. The traditional body mass index (BMI) has limitations, as it cannot effectively differentiate between fat and lean body mass or provide information about fat distribution. In contrast, the lipid accumulation product (LAP), which combines waist circumference and triglyceride levels, serves as a crucial indicator of visceral fat. This study examines the relationship between LAP and KS, including recurrent kidney stones (RKS), using data from the National Health and Nutrition Examination Survey (NHANES). It also investigates whether neutrophils mediate the connection between LAP and KS/RKS, comparing the predictive accuracy of LAP and BMI. Data from 2007 to 2014 covered 9910 KS participants and 880 RKS participants. Weighted logistic regression assessed the LAP-KS/RKS relationship, while mediation analysis explored the role of neutrophils. Receiver Operating Characteristic (ROC) curves evaluated the predictive capabilities of LAP and BMI. Results showed LAP was significantly associated with KS (OR = 1.629; 95% CI 1.296-2.047) and RKS (OR = 1.561; 95% CI 1.145-2.128). Neutrophils partially mediated the LAP-KS relationship (7.6%, p = 0.018), with no effect found for RKS. Moreover, LAP outperformed BMI in diagnostic accuracy. These findings suggest that LAP is an effective marker for assessing KS and RKS, aiding in the early identification of potential patients to reduce the incidence and recurrence of kidney stones.
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Affiliation(s)
- Shang Gao
- Department of Urology, General Hospital of Northern Theater Command, No. 83, Wenhua Road, Shenyang, 110016, Liaoning, China
- Department of Graduate School, China Medical University, Shenyang, China
| | - Jingteng He
- Department of Urology, General Hospital of Northern Theater Command, No. 83, Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Hongtao Liu
- Department of Urology, General Hospital of Northern Theater Command, No. 83, Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Lianhui Fan
- Department of Urology, General Hospital of Northern Theater Command, No. 83, Wenhua Road, Shenyang, 110016, Liaoning, China.
| | - Renli Tian
- Department of Urology, General Hospital of Northern Theater Command, No. 83, Wenhua Road, Shenyang, 110016, Liaoning, China.
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Tudorancea I, Șerban IL, Șerban DN, Costache-Enache II, Cătălin C, Naum AG, Iliescu R. Sympathetic nervous system inhibition enhances cardiac metabolism and improves hemodynamics and glucose-insulin dynamics in obese and lean rat models. Sci Rep 2025; 15:503. [PMID: 39747975 PMCID: PMC11697016 DOI: 10.1038/s41598-024-84218-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 12/20/2024] [Indexed: 01/04/2025] Open
Abstract
This study aimed to investigate the effects of chronic sympathoinhibition on glucose uptake by the myocardium and by the skeletal muscle in an animal model of obesity associated with leptin signaling deficiency. 6 obese Zucker rats (OZR) and 6 control Lean Zucker rats (LZR) were studied during basal conditions, chronic clonidine administration (30 days, 300 µg/kg), and washout recovery period. Glucose uptake in the myocardium and in the skeletal muscle was measured using positron emission tomography (PET) and 2-[18F] fluoro-2-deoxy-D-glucose ([18F]FDG). The standardized uptake value (SUV) corrected for blood glucose was used for the semi-quantitative analysis. Body weight, food and water intake, blood glucose concentration, blood pressure variability as an index of sympathetic activity and hemodynamic parameters such as mean arterial blood pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were analyzed. Myocardial glucose uptake was significantly lower during basal conditions in OZR versus LZR. In both OZR and LZR, chronic clonidine significantly reduced myocardial glucose uptake and hemodynamic variables (such as MAP, SBP, DBP, HR), and sympathetic activity (SA). [18F]FDG skeletal muscle uptake did not significantly differ in OZR versus LZR. Our findings indicate that cardiac glucose metabolism is reduced in obesity presumably in relation with the level of sympathetic activation.
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Affiliation(s)
- Ionuț Tudorancea
- Department of Physiology, "Grigore T. Popa" University of Medicine and Pharmacy, 16 University St., Iași, Romania
- Cardiology Clinic, "St. Spiridon" County Clinical Emergency Hospital, 1 Independenței Blvd, Iași, Romania
| | - Ionela Lăcrămioara Șerban
- Department of Physiology, "Grigore T. Popa" University of Medicine and Pharmacy, 16 University St., Iași, Romania
| | - Dragomir N Șerban
- Department of Physiology, "Grigore T. Popa" University of Medicine and Pharmacy, 16 University St., Iași, Romania
| | - Irina-Iuliana Costache-Enache
- Cardiology Clinic, "St. Spiridon" County Clinical Emergency Hospital, 1 Independenței Blvd, Iași, Romania
- Department of Internal Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 16 University St., Iași, Romania
| | - Caratașu Cătălin
- Advanced Research and Development Center for Experimental Medicine (CEMEX), "Grigore T. Popa" University of Medicine and Pharmacy, 16 University St., Iași, Romania
| | - Alexandru Grațian Naum
- Department of Biophysics, "Grigore T. Popa" University of Medicine and Pharmacy, 16 University St., Iași, Romania.
| | - Radu Iliescu
- Department of Pharmacology, "Grigore T. Popa" University of Medicine and Pharmacy, 16 University St., Iași, Romania
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Wu Y, Zhang Y, Zhao Y, Zhang X, Gu M, Huo W, Fu X, Li X, Guo B, Li J, Lu X, Hu F, Hu D, Zhang M. Elevated lipid accumulation product trajectory patterns are associated with increasing incident risk of type 2 diabetes mellitus in China. Prev Med 2025; 190:108186. [PMID: 39612991 DOI: 10.1016/j.ypmed.2024.108186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 11/21/2024] [Accepted: 11/23/2024] [Indexed: 12/01/2024]
Abstract
PURPOSE Our study aimed to identify the trajectory patterns of lipid accumulation product (LAP) and investigate their association with the incident risk of type 2 diabetes mellitus (T2DM) in China. METHODS This study included 37,316 eligible participants, with data collected between1998 and 2021. The LAP trajectory patterns were identified through latent mixture modeling. Logistic regression models were used to examine the association between different LAP trajectory patterns and the incident risk of T2DM. RESULTS Over an average period of 12.7 years, 3195 participants developed T2DM. Four LAP trajectory patterns were identified: low stable, moderate slow-increasing, high decreasing, and moderate fast-increasing. After adjusting for demographic and clinical confounders, the odds ratios (ORs) and 95 % confidence intervals (CIs) for T2DM were 1.67 (1.50, 1.86) for the moderate slow-increasing group, 1.63 (1.38, 1.94) for the high decreasing group, and 2.43 (2.07, 2.85) for the moderate fast-increasing group compared with the low stable group. Similar trajectory patterns were found in sex-specific populations as in the general population, while the elevated LAP trajectory pattern was more strongly associated with an increase in the incident risk of T2DM in females. CONCLUSION Individuals with moderate fast-increasing LAP trajectory patterns had a 2.4 times higher risk of developing T2DM compared to those with low stable LAP patterns. More attention should be paid to preventing T2DM in people with high levels of LAP, especially females, the elderly, drinkers, and people with a history of diabetes.
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Affiliation(s)
- Yuying Wu
- Department of Biostatistics and Epidemiology, School of Public Health, Shenzhen University Medical School, Shenzhen, Guangdong, PR China
| | - Yanyan Zhang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Yang Zhao
- Department of General Practice, Affiliated Luohu Hospital of Shenzhen University Medical School, Shenzhen, Guangdong, PR China
| | - Xing Zhang
- Department of Biostatistics and Epidemiology, School of Public Health, Shenzhen University Medical School, Shenzhen, Guangdong, PR China
| | - Minqi Gu
- Department of Biostatistics and Epidemiology, School of Public Health, Shenzhen University Medical School, Shenzhen, Guangdong, PR China
| | - Weifeng Huo
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Xueru Fu
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Xi Li
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Botang Guo
- Department of General Practice, Affiliated Luohu Hospital of Shenzhen University Medical School, Shenzhen, Guangdong, PR China
| | - Jianxin Li
- Key Laboratory of Cardiovascular Epidemiology, Chinese Academy of Medical Sciences, Department of Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Xiangfeng Lu
- Key Laboratory of Cardiovascular Epidemiology, Chinese Academy of Medical Sciences, Department of Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Fulan Hu
- Department of Biostatistics and Epidemiology, School of Public Health, Shenzhen University Medical School, Shenzhen, Guangdong, PR China
| | - Dongsheng Hu
- Department of Biostatistics and Epidemiology, School of Public Health, Shenzhen University Medical School, Shenzhen, Guangdong, PR China; Department of General Practice, Affiliated Luohu Hospital of Shenzhen University Medical School, Shenzhen, Guangdong, PR China
| | - Ming Zhang
- Department of Biostatistics and Epidemiology, School of Public Health, Shenzhen University Medical School, Shenzhen, Guangdong, PR China.
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Liu S, Fan B, Li X, Sun G. Global hotspots and trends in tea anti-obesity research: a bibliometric analysis from 2004 to 2024. Front Nutr 2024; 11:1496582. [PMID: 39606571 PMCID: PMC11598529 DOI: 10.3389/fnut.2024.1496582] [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: 09/14/2024] [Accepted: 10/28/2024] [Indexed: 11/29/2024] Open
Abstract
Background The prevalence of obesity and its related ailments is on the rise, posing a substantial challenge to public health. Tea, widely enjoyed for its flavors, has shown notable potential in mitigating obesity. Yet, there remains a lack of exhaustive bibliometric studies in this domain. Methods We retrieved and analyzed multidimensional data concerning tea and obesity studies from January 2004 to June 2024, using the Web of Science Core Collection database. This bibliometric investigation utilized tools such as Bibliometrix, CiteSpace, and VOSviewer to gather and analyze data concerning geographical distribution, leading institutions, prolific authors, impactful journals, citation patterns, and prevalent keywords. Results There has been a significant surge in publications relevant to this field within the last two decades. Notably, China, Hunan Agricultural University, and the journal Food and Function have emerged as leading contributors in terms of country, institution, and publication medium, respectively. Zhonghua Liu of Hunan Agricultural University has the distinction of most publications, whereas Joshua D. Lambert of The State University of New Jersey is the most cited author. Analyses of co-citations and frequently used keywords have identified critical focus areas within tea anti-obesity research. Current studies are primarily aimed at understanding the roles of tea components in regulating gut microbiota, boosting fat oxidation, and increasing metabolic rate. The research trajectory has progressed from preliminary mechanism studies and clinical trials to more sophisticated investigations into the mechanisms, particularly focusing on tea's regulatory effects on gut microbiota. Conclusion This study offers an intricate overview of the prevailing conditions, principal focus areas, and developmental trends in the research of tea's role against obesity. It delivers a comprehensive summary and discourse on the recent progress in this field, emphasizing the study's core findings and pivotal insights. Highlighting tea's efficacy in obesity prevention and treatment, this study also points out the critical need for continued research in this area.
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Affiliation(s)
- Shan Liu
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Boyan Fan
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Xiaoping Li
- The Center for Treatment of Pre-disease, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Guixiang Sun
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
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Spinedi E, Docena GH. Physiopathological Roles of White Adiposity and Gut Functions in Neuroinflammation. Int J Mol Sci 2024; 25:11741. [PMID: 39519291 PMCID: PMC11546880 DOI: 10.3390/ijms252111741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/23/2024] [Accepted: 10/08/2024] [Indexed: 11/16/2024] Open
Abstract
White adipose tissue (WAT) and the gut are involved in the development of neuroinflammation when an organism detects any kind of injury, thereby triggering metainflammation. In fact, the autonomous nervous system innervates both tissues, although the complex role played by the integrated sympathetic, parasympathetic, and enteric nervous system functions have not been fully elucidated. Our aims were to investigate the participation of inflamed WAT and the gut in neuroinflammation. Firstly, we conducted an analysis into how inflamed peripheral WAT plays a key role in the triggering of metainflammation. Indeed, this included the impact of the development of local insulin resistance and its metabolic consequences, a serious hypothalamic dysfunction that promotes neurodegeneration. Then, we analyzed the gut-brain axis dysfunction involved in neuroinflammation by examining cell interactions, soluble factors, the sensing of microbes, and the role of dysbiosis-related mechanisms (intestinal microbiota and mucosal barriers) affecting brain functions. Finally, we targeted the physiological crosstalk between cells of the brain-WAT-gut axis that restores normal tissue homeostasis after injury. We concluded the following: because any injury can result not only in overall insulin resistance and dysbiosis, which in turn can impact upon the brain, but that a high-risk of the development of neuroinflammation-induced neurodegenerative disorder can also be triggered. Thus, it is imperative to avoid early metainflammation by applying appropriate preventive (e.g., lifestyle and diet) or pharmacological treatments to cope with allostasis and thus promote health homeostasis.
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Affiliation(s)
- Eduardo Spinedi
- Centro de Endocrinología Experimental y Aplicada (CENEXA-UNLP-CONICET-CICPBA), University of La Plata Medical School, La Plata 1900, Argentina
| | - Guillermo Horacio Docena
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP-UNLP-CONICET-CICPBA), School of Sciences, University of La Plata, La Plata 1900, Argentina
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7
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Zhang Z, Yu Z, Liang D, Song K, Kong X, He M, Liao X, Huang Z, Kang A, Bai R, Ren Y. Roles of lipid droplets and related proteins in metabolic diseases. Lipids Health Dis 2024; 23:218. [PMID: 39030618 PMCID: PMC11264848 DOI: 10.1186/s12944-024-02212-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 07/11/2024] [Indexed: 07/21/2024] Open
Abstract
Lipid droplets (LDs), which are active organelles, derive from the monolayer membrane of the endoplasmic reticulum and encapsulate neutral lipids internally. LD-associated proteins like RAB, those in the PLIN family, and those in the CIDE family participate in LD formation and development, and they are active players in various diseases, organelles, and metabolic processes (i.e., obesity, non-alcoholic fatty liver disease, and autophagy). Our synthesis on existing research includes insights from the formation of LDs to their mechanisms of action, to provide an overview needed for advancing research into metabolic diseases and lipid metabolism.
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Affiliation(s)
- Zhongyang Zhang
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Zhenghang Yu
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Dianyuan Liang
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Ke Song
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Xiangxin Kong
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Ming He
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China
| | - Xinxin Liao
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Ziyan Huang
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Aijia Kang
- Institute of Hepatobiliary Pancreatic Intestinal Diseases, North Sichuan Medical College, Nanchong, 637000, China
| | - Rubing Bai
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China.
| | - Yixing Ren
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, South Maoyuan Road, Shunqing District, Nanchong, Sichuan Province, 637000, China.
- General Surgery, Chengdu XinHua Hospital Affiliated to North Sichuan Medical College, Chengdu, 610000, China.
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Rahman MA, Islam MM, Ripon MAR, Islam MM, Hossain MS. Regulatory Roles of MicroRNAs in the Pathogenesis of Metabolic Syndrome. Mol Biotechnol 2024; 66:1599-1620. [PMID: 37393414 DOI: 10.1007/s12033-023-00805-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 06/17/2023] [Indexed: 07/03/2023]
Abstract
Metabolic syndrome refers to a group of several disease conditions together with high glucose triglyceride levels, high blood pressure, lower high-density lipoprotein level, and large waist circumference. About 400 million people worldwide, one-third of the Euro-American population and 27% Chinese population over age 50 have it. microRNAs, an abundant novel class of endogenous small, non-coding RNAs in eukaryotic cells, act as negative controllers of gene expression by promoting either degradation/translational repression of target messenger RNA. More than 2000 microRNAs in the human genome have been identified and they are implicated in various biological & pathophysiological processes, including glucose homeostasis, inflammatory response, and angiogenesis. Destruction of microRNAs has a crucial role in the pathogenesis of obesity, cardiovascular disease, and diabetes. Recently the discovery of circulating microRNAs in human serum may help to promote metabolic crosstalk between organs and serves as a novel approach for the identification of various diseases, like Type 2 diabetes & atherosclerosis. In this review, we will discuss the most recent and up-to-date research on the pathophysiology and histopathology of metabolic syndrome besides their historical background and epidemiological highlight. As well as search the methodologies employed in this field of research and the potential role of microRNAs as novel biomarkers and therapeutic targets for metabolic syndrome in the human body. Furthermore, the significance of microRNAs in promising strategies, like stem cell therapy, which holds enormous promise for regenerative medicine in the treatment of metabolic disorders will also be discussed.
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Affiliation(s)
- Md Abdur Rahman
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Md Mahmodul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Md Abdur Rahman Ripon
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Md Monirul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Mohammad Salim Hossain
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh.
- Bangladesh Obesity Research Network (BORN), Noakhali, 3814, Bangladesh.
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Mann V, Sundaresan A, Shishodia S. Overnutrition and Lipotoxicity: Impaired Efferocytosis and Chronic Inflammation as Precursors to Multifaceted Disease Pathogenesis. BIOLOGY 2024; 13:241. [PMID: 38666853 PMCID: PMC11048223 DOI: 10.3390/biology13040241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/25/2024] [Accepted: 04/04/2024] [Indexed: 04/28/2024]
Abstract
Overnutrition, driven by the consumption of high-fat, high-sugar diets, has reached epidemic proportions and poses a significant global health challenge. Prolonged overnutrition leads to the deposition of excessive lipids in adipose and non-adipose tissues, a condition known as lipotoxicity. The intricate interplay between overnutrition-induced lipotoxicity and the immune system plays a pivotal role in the pathogenesis of various diseases. This review aims to elucidate the consequences of impaired efferocytosis, caused by lipotoxicity-poisoned macrophages, leading to chronic inflammation and the subsequent development of severe infectious diseases, autoimmunity, and cancer, as well as chronic pulmonary and cardiovascular diseases. Chronic overnutrition promotes adipose tissue expansion which induces cellular stress and inflammatory responses, contributing to insulin resistance, dyslipidemia, and metabolic syndrome. Moreover, sustained exposure to lipotoxicity impairs the efferocytic capacity of macrophages, compromising their ability to efficiently engulf and remove dead cells. The unresolved chronic inflammation perpetuates a pro-inflammatory microenvironment, exacerbating tissue damage and promoting the development of various diseases. The interaction between overnutrition, lipotoxicity, and impaired efferocytosis highlights a critical pathway through which chronic inflammation emerges, facilitating the development of severe infectious diseases, autoimmunity, cancer, and chronic pulmonary and cardiovascular diseases. Understanding these intricate connections sheds light on potential therapeutic avenues to mitigate the detrimental effects of overnutrition and lipotoxicity on immune function and tissue homeostasis, thereby paving the way for novel interventions aimed at reducing the burden of these multifaceted diseases on global health.
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Affiliation(s)
| | | | - Shishir Shishodia
- Department of Biology, Texas Southern University, Houston, TX 77004, USA; (V.M.); (A.S.)
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Ahn SH, Lee HS, Lee JH. Triglyceride-glucose-waist circumference index predicts the incidence of cardiovascular disease in Korean populations: competing risk analysis of an 18-year prospective study. Eur J Med Res 2024; 29:214. [PMID: 38566247 PMCID: PMC10985901 DOI: 10.1186/s40001-024-01820-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 03/29/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND The triglyceride and glucose-waist circumference (TyG-WC) index demonstrated a strong association with insulin resistance, especially in Asian population. However, evidence on the association between TyG-WC index and the occurrence of cardiovascular disease (CVD) is limited. This study aimed to verify association between the TyG-WC index and the occurrence of CVD by considering all-cause mortality as a competing risk. METHODS The study included 7482 participants divided into four groups based on the TyG-WC index quartiles. Kaplan-Meier curves illustrated cumulative incidence rates of CVD and all-cause mortality during the follow-up period. Log-rank tests determined group differences. The Cox proportional hazard spline curve demonstrates the dose-dependent relationship between the TyG-WC index and incident CVD. Modified Cox regression (Fine and Gray) estimated hazard ratios (HRs) with 95% CIs for incident CVD, treating death as a competing risk. Death event after incident CVD was excluded from the death count. RESULTS During the median 15.94 year of follow-up period, a total of 691 (9.24%) new-onset CVD cases and 562 (7.51%) all-cause mortality cases were confirmed. Cox proportional hazard spline curves suggested that TyG-WC index exhibited a dose-dependent positive correlation with incident CVD. The cumulative incidence rate of CVD was significantly higher in the groups with higher TyG-WC index quartiles in Kaplan-Meier curves. The adjusted HR (95% CI) for incident CVD in Q2-Q4, compared with Q1, was 1.47 (1.12-1.93), 1.91 (1.44-2.54) and 2.24 (1.63-3.07), respectively. There was no significant association between TyG-WC index and all-cause mortality. Specifically, angina and stroke were significantly associated with the TyG-WC index, in contrast to myocardial infarction and peripheral artery disease. CONCLUSIONS The TyG-WC index was positively associated with incident CVD even considering all-cause mortality as a competing risk. Therefore, TyG-WC index may be a valuable marker for predicting the occurrence of CVD.
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Affiliation(s)
- Sung Ho Ahn
- Department of Family Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Hye Sun Lee
- Biostatistics Collaboration Unit, Department of Research Affairs, Yonsei University College of Medicine, Seoul, 03277, Republic of Korea
| | - Jun-Hyuk Lee
- Department of Family Medicine, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, 01830, Republic of Korea.
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Huebbe P, Bilke S, Rueter J, Schloesser A, Campbel G, Glüer CC, Lucius R, Röcken C, Tholey A, Rimbach G. Human APOE4 Protects High-Fat and High-Sucrose Diet Fed Targeted Replacement Mice against Fatty Liver Disease Compared to APOE3. Aging Dis 2024; 15:259-281. [PMID: 37450924 PMCID: PMC10796091 DOI: 10.14336/ad.2023.0530] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 05/30/2023] [Indexed: 07/18/2023] Open
Abstract
Recent genome- and exome-wide association studies suggest that the human APOE ε4 allele protects against non-alcoholic fatty liver disease (NAFLD), while ε3 promotes hepatic steatosis and steatohepatitis. The present study aimed at examining the APOE genotype-dependent development of fatty liver disease and its underlying mechanisms in a targeted replacement mouse model. Male mice expressing the human APOE3 or APOE4 protein isoforms on a C57BL/6J background and unmodified C57BL/6J mice were chronically fed a high-fat and high-sucrose diet to induce obesity. After 7 months, body weight gain was more pronounced in human APOE than endogenous APOE expressing mice with elevated plasma biomarkers suggesting aggravated metabolic dysfunction. APOE3 mice exhibited the highest liver weights and, compared to APOE4, massive hepatic steatosis. An untargeted quantitative proteome analysis of the liver identified a high number of proteins differentially abundant in APOE3 versus APOE4 mice. The majority of the higher abundant proteins in APOE3 mice could be grouped to inflammation and damage-associated response, and lipid storage, amongst others. Results of the targeted qRT-PCR and Western blot analyses contribute to the overall finding that APOE3 as opposed to APOE4 promotes hepatic steatosis, inflammatory- and damage-associated response signaling and fibrosis in the liver of obese mice. Our experimental data substantiate the observation of an increased NAFLD-risk associated with the human APOEε3 allele, while APOEε4 appears protective. The underlying mechanisms of the protection possibly involve a higher capacity of nonectopic lipid deposition in subcutaneous adipose tissue and lower hepatic pathogen recognition in the APOE4 mice.
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Affiliation(s)
- Patricia Huebbe
- Institute of Human Nutrition and Food Science, Kiel University, D-24118 Kiel, Germany.
| | - Stephanie Bilke
- Institute of Experimental Medicine, Proteomics & Bioanalytics, Kiel University, D-24105 Kiel, Germany.
| | - Johanna Rueter
- Institute of Human Nutrition and Food Science, Kiel University, D-24118 Kiel, Germany.
| | - Anke Schloesser
- Institute of Human Nutrition and Food Science, Kiel University, D-24118 Kiel, Germany.
| | - Graeme Campbel
- Section Biomedical Imaging, Department of Radiology and Neuroradiology, Kiel University, D-24118 Kiel, Germany.
| | - Claus-C. Glüer
- Section Biomedical Imaging, Department of Radiology and Neuroradiology, Kiel University, D-24118 Kiel, Germany.
| | - Ralph Lucius
- Anatomical Institute, Kiel University, D-24118 Kiel, Germany.
| | - Christoph Röcken
- Department of Pathology, Kiel University and University Hospital Schleswig-Holstein, Campus Kiel, D-24105 Kiel, Germany.
| | - Andreas Tholey
- Institute of Experimental Medicine, Proteomics & Bioanalytics, Kiel University, D-24105 Kiel, Germany.
| | - Gerald Rimbach
- Institute of Human Nutrition and Food Science, Kiel University, D-24118 Kiel, Germany.
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12
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Engin AB. Mechanism of Obesity-Related Lipotoxicity and Clinical Perspective. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:131-166. [PMID: 39287851 DOI: 10.1007/978-3-031-63657-8_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The link between cellular exposure to fatty acid species and toxicity phenotypes remains poorly understood. However, structural characterization and functional profiling of human plasma free fatty acids (FFAs) analysis has revealed that FFAs are located either in the toxic cluster or in the cluster that is transcriptionally responsive to lipotoxic stress and creates genetic risk factors. Genome-wide short hairpin RNA screen has identified more than 350 genes modulating lipotoxicity. Hypertrophic adipocytes in obese adipose are both unable to expand further to store excess lipids in the diet and are resistant to the antilipolytic action of insulin. In addition to lipolysis, the inability of packaging the excess lipids into lipid droplets causes circulating fatty acids to reach toxic levels in non-adipose tissues. Deleterious effects of accumulated lipid in non-adipose tissues are known as lipotoxicity. Although triglycerides serve a storage function for long-chain non-esterified fatty acid and their products such as ceramide and diacylglycerols (DAGs), overloading of palmitic acid fraction of saturated fatty acids (SFAs) raises ceramide levels. The excess DAG and ceramide load create harmful effects on multiple organs and systems, inducing chronic inflammation in obesity. Thus, lipotoxic inflammation results in β cells death and pancreatic islets dysfunction. Endoplasmic reticulum stress stimuli induce lipolysis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and extracellular signal-regulated kinase (Erk) 1/2 signaling in adipocytes. However, palmitic acid-induced endoplasmic reticulum stress-c-Jun N-terminal kinase (JNK)-autophagy axis in hypertrophic adipocytes is a pro-survival mechanism against endoplasmic reticulum stress and cell death induced by SFAs. Endoplasmic reticulum-localized acyl-coenzyme A (CoA): glycerol-3-phosphate acyltransferase (GPAT) enzymes are mediators of lipotoxicity, and inhibiting these enzymes has therapeutic potential for lipotoxicity. Lipotoxicity increases the number of autophagosomes, which engulf palmitic acid, and thus suppress the autophagic turnover. Fatty acid desaturation promotes palmitate detoxification and storages into triglycerides. As therapeutic targets of glucolipotoxicity, in addition to caloric restriction and exercise, there are four different pharmacological approaches, which consist of metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, peroxisome proliferator-activated receptor-gamma (PPARγ) ligands thiazolidinediones, and chaperones are still used in clinical practice. Furthermore, induction of the brown fat-like phenotype with the mixture of eicosapentanoic acid and docosahexaenoic acid appears as a potential therapeutic application for treatment of lipotoxicity.
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
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13
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Cremades M, Talavera-Urquijo E, Beisani M, Pappa S, Jordà M, Tarascó J, Moreno P, Caballero A, Martínez-López E, Pellitero S, Balibrea JM. Transcriptional and epigenetic changes after dietary and surgical weight loss interventions in an animal model of obesity. Int J Obes (Lond) 2024; 48:103-110. [PMID: 37833561 DOI: 10.1038/s41366-023-01395-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 09/18/2023] [Accepted: 09/29/2023] [Indexed: 10/15/2023]
Abstract
BACKGROUND Identifying determinants that can predict response to weight loss interventions is imperative for optimizing therapeutic benefit. We aimed to identify changes in DNA methylation and mRNA expression of a subset of target genes following dietary and surgical interventions in high-fat-diet (HFD)-induced obese rats. METHODS Forty-two adult Wistar Han male rats were divided into two groups: control rats (n = 7) and obese rats (n = 28), fed a HFD for 10 weeks (t10). Obese rats were randomly subdivided into five intervention groups (seven animals per group): (i) HFD; (ii) very-low-calorie diet (VLCD); (iii) sham surgery, and (iv) sleeve gastrectomy (SG). At week sixteen (t16), animals were sacrificed and tissue samples were collected to analyze changes in DNA methylation and mRNA expression of the selected genes. RESULTS By type of intervention, the surgical procedures led to the greatest weight loss. Changes in methylation and/or expression of candidate genes occurred proportionally to the effectiveness of the weight loss interventions. Leptin expression, increased sixfold in the visceral fat of the obese rats, was partially normalized after all interventions. The expression of fatty acid synthase (FASN) and monocyte chemoattractant protein 1 (MCP-1) genes, which was reduced 0.5- and 0.15-fold, respectively, in the liver tissue of obese rats, were completely normalized after weight loss interventions, particularly after surgical interventions. The upregulation of FASN and MCP-1 gene expression was accompanied by a significant reduction in promoter methylation, up to 0.5-fold decrease in the case of the FASN (all intervention groups) and a 0.8-fold decrease in the case of the MCP-1 (SG group). CONCLUSIONS Changes in tissue expression of specific genes involved in the pathophysiological mechanisms of obesity can be significantly attenuated following weight loss interventions, particularly surgery. Some of these genes are regulated by epigenetic mechanisms.
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Affiliation(s)
- Manel Cremades
- Department of General and Digestive Surgery, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Eider Talavera-Urquijo
- Esophagogastric and Bariatric Surgery Unit, Department of General and Digestive Surgery, Donostia University Hospital, Donostia, Guipuzkoa, Spain
| | - Marc Beisani
- Bariatric and Upper Gastrointestinal Surgery Unit, Department of General and Digestive Surgery, Hospital del Mar, Barcelona, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
| | - Stella Pappa
- Germans Trias i Pujol Research Institute (IGTP), Badalona, Barcelona, Spain
| | - Mireia Jordà
- Germans Trias i Pujol Research Institute (IGTP), Badalona, Barcelona, Spain
| | - Jordi Tarascó
- Department of General and Digestive Surgery, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
- Endocrine-Metabolic and Bariatric Surgery Unit, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain
| | - Pau Moreno
- Department of General and Digestive Surgery, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
- Endocrine-Metabolic and Bariatric Surgery Unit, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain
| | - Albert Caballero
- Department of General and Digestive Surgery, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain
- Endocrine-Metabolic and Bariatric Surgery Unit, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain
| | - Eva Martínez-López
- Department of Endocrinology, Nutrition and Metabolism, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain
| | - Silvia Pellitero
- Universitat Autònoma de Barcelona, Barcelona, Spain
- Department of Endocrinology, Nutrition and Metabolism, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain
| | - José M Balibrea
- Department of General and Digestive Surgery, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain.
- Universitat Autònoma de Barcelona, Barcelona, Spain.
- Endocrine-Metabolic and Bariatric Surgery Unit, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain.
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14
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Miles LA, Bai H, Chakrabarty S, Baik N, Zhang Y, Parmer RJ, Samad F. Overexpression of Plg-R KT protects against adipose dysfunction and dysregulation of glucose homeostasis in diet-induced obese mice. Adipocyte 2023; 12:2252729. [PMID: 37642146 PMCID: PMC10481882 DOI: 10.1080/21623945.2023.2252729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/22/2023] [Accepted: 08/24/2023] [Indexed: 08/31/2023] Open
Abstract
The plasminogen receptor, Plg-RKT, is a unique cell surface receptor that is broadly expressed in cells and tissues throughout the body. Plg-RKT localizes plasminogen on cell surfaces and promotes its activation to the broad-spectrum serine protease, plasmin. In this study, we show that overexpression of Plg-RKT protects mice from high fat diet (HFD)-induced adipose and metabolic dysfunction. During the first 10 weeks on the HFD, the body weights of mice that overexpressed Plg-RKT (Plg-RKT-OEX) were lower than those of control mice (CagRosaPlgRKT). After 10 weeks on the HFD, CagRosaPlgRKT and Plg-RKT-OEX mice had similar body weights. However, Plg-RKT-OEX mice showed a more metabolically favourable body composition phenotype. Plg-RKT-OEX mice also showed improved glucose tolerance and increased insulin sensitivity. We found that the improved metabolic functions of Plg-RKT-OEX mice were mechanistically associated with increased energy expenditure and activity, decreased proinflammatory adipose macrophages and decreased inflammation, elevated brown fat thermogenesis, and higher expression of adipose PPARγ and adiponectin. These findings suggest that Plg-RKT signalling promotes healthy adipose function via multiple mechanisms to defend against obesity-associated adverse metabolic phenotypes.
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Affiliation(s)
- Lindsey A. Miles
- Department of Molecular Medicine, Scripps Research, La Jolla, CA, USA
| | - Hongdong Bai
- Department of Medicine, Veterans Administration San Diego Healthcare System, San Diego, CA, USA
| | - Sagarika Chakrabarty
- Department of Cell Biology, San Diego Biomedical Research Institute, San Diego, CA, USA
| | - Nagyung Baik
- Department of Molecular Medicine, Scripps Research, La Jolla, CA, USA
| | - Yuqing Zhang
- Department of Molecular Medicine, Scripps Research, La Jolla, CA, USA
| | - Robert J. Parmer
- Department of Medicine, Veterans Administration San Diego Healthcare System, San Diego, CA, USA
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Fahumiya Samad
- Department of Cell Biology, San Diego Biomedical Research Institute, San Diego, CA, USA
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15
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Gaebel R, Lang C, Vasudevan P, Lührs L, de Carvalho KAT, Abdelwahid E, David R. New Approaches in Heart Research: Prevention Instead of Cardiomyoplasty? Int J Mol Sci 2023; 24:ijms24109017. [PMID: 37240361 DOI: 10.3390/ijms24109017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/10/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
Cardiovascular diseases are the leading cause of death in industrialized nations. Due to the high number of patients and expensive treatments, according to the Federal Statistical Office (2017) in Germany, cardiovascular diseases account for around 15% of total health costs. Advanced coronary artery disease is mainly the result of chronic disorders such as high blood pressure, diabetes, and dyslipidemia. In the modern obesogenic environment, many people are at greater risk of being overweight or obese. The hemodynamic load on the heart is influenced by extreme obesity, which often leads to myocardial infarction (MI), cardiac arrhythmias, and heart failure. In addition, obesity leads to a chronic inflammatory state and negatively affects the wound-healing process. It has been known for many years that lifestyle interventions such as exercise, healthy nutrition, and smoking cessation drastically reduce cardiovascular risk and have a preventive effect against disorders in the healing process. However, little is known about the underlying mechanisms, and there is significantly less high-quality evidence compared to pharmacological intervention studies. Due to the immense potential of prevention in heart research, the cardiologic societies are calling for research work to be intensified, from basic understanding to clinical application. The topicality and high relevance of this research area are also evident from the fact that in March 2018, a one-week conference on this topic with contributions from top international scientists took place as part of the renowned "Keystone Symposia" ("New Insights into the Biology of Exercise"). Consistent with the link between obesity, exercise, and cardiovascular disease, this review attempts to draw lessons from stem-cell transplantation and preventive exercise. The application of state-of-the-art techniques for transcriptome analysis has opened new avenues for tailoring targeted interventions to very individual risk factors.
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Affiliation(s)
- Ralf Gaebel
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Cajetan Lang
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Praveen Vasudevan
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Larissa Lührs
- Advanced Therapy and Cellular Biotechnology in Regenerative Medicine Department, Pelé Pequeno Prίncipe Research Institute & Pequeno Prίncipe Faculties, Ave. Silva Jardim, P.O. Box 80240-020, Curitiba 1632, Brazil
| | - Katherine Athayde Teixeira de Carvalho
- Advanced Therapy and Cellular Biotechnology in Regenerative Medicine Department, Pelé Pequeno Prίncipe Research Institute & Pequeno Prίncipe Faculties, Ave. Silva Jardim, P.O. Box 80240-020, Curitiba 1632, Brazil
| | - Eltyeb Abdelwahid
- Feinberg School of Medicine, Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL 60611, USA
| | - Robert David
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
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16
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Natural Product Skatole Ameliorates Lipotoxicity-Induced Multiple Hepatic Damage under Hyperlipidemic Conditions in Hepatocytes. Nutrients 2023; 15:nu15061490. [PMID: 36986221 PMCID: PMC10052055 DOI: 10.3390/nu15061490] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/14/2023] [Accepted: 03/19/2023] [Indexed: 03/22/2023] Open
Abstract
Skatole (3-methylindole, 3MI) is a natural-origin compound derived from plants, insects, and microbial metabolites in human intestines. Skatole has an anti-lipid peroxidation effect and is a biomarker for several diseases. However, its effect on hepatocyte lipid metabolism and lipotoxicity has not been elucidated. Hepatic lipotoxicity is induced by excess saturated free fatty acids in hyperlipidemia, which directly damages the hepatocytes. Lipotoxicity is involved in several metabolic diseases and hepatocytes, particularly affecting nonalcoholic fatty liver disease (NAFLD) progression. NAFLD is caused by the accumulation of fat by excessive free fatty acids (FFAs) in the blood and is accompanied by hepatic damage, such as endoplasmic reticulum (ER) stress, abnormal glucose and insulin metabolism, oxidative stress, and lipoapoptosis with lipid accumulation. Hepatic lipotoxicity causes multiple hepatic damages in NAFLD and has a directly effect on the progression from NAFLD to nonalcoholic steatohepatitis (NASH). This study confirmed that the natural compound skatole improves various damages to hepatocytes caused by lipotoxicity in hyperlipidemic conditions. To induce lipotoxicity, we exposed HepG2, SNU-449, and Huh7 cells to palmitic acid, a saturated fatty acid, and confirmed the protective effect of skatole. Skatole inhibited fat accumulation in the hepatocytes, reduced ER and oxidative stress, and recovered insulin resistance and glucose uptake. Importantly, skatole reduced lipoapoptosis by regulating caspase activity. In conclusion, skatole ameliorated multiple types of hepatocyte damage induced by lipotoxicity in the presence of excess free fatty acids.
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17
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Shi M, Yang S, Huang X, Wang S, Li W, Yun J, Lu C, Yang Y, Cai C, Gao P, Guo X, Li B, Cao G. Caveolae-associated protein 3 promotes adipogenic differentiation of porcine preadipocytes by promoting extracellular signal-regulated kinase phosphorylation. Anim Sci J 2023; 94:e13822. [PMID: 36922373 DOI: 10.1111/asj.13822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 02/03/2023] [Accepted: 02/16/2023] [Indexed: 03/18/2023]
Abstract
Fat deposition is one of the key factors affecting the economic development of pig husbandry. The aim of this study was to investigate the expression characteristics of caveolae-associated protein 3 (CAVIN3) and to elucidate its effect and mechanism on adipogenic differentiation of porcine preadipocytes. Cell transfection, quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot, and oil red O staining were used to detect the effect of CAVIN3 on the differentiation of porcine preadipocytes. The results showed that CAVIN3 was expressed in various tissues, with higher expression in adipose tissue, differentially expressed during cell adipogenic differentiation, and mainly distributed in the cytoplasm. Functional studies showed that, after CAVIN3 interference in preadipocytes, the expression of adipogenic factors and the content of lipid droplets were significantly decreased (p < 0.05). The results were reversed after CAVIN3 was overexpressed. The mechanism research showed that LY3214996 inhibited the extracellular signal-regulated kinase (ERK) phosphorylation and further inhibited lipogenic factors expression. Overexpression of CAVIN3 attenuates the inhibitory effect of LY3214996 on ERK phosphorylation and attenuates its inhibitory effect on adipogenic differentiation. Therefore, this study demonstrated that CAVIN3 promotes the differentiation of porcine preadipocytes by promoting ERK phosphorylation. The present study can lay a theoretical foundation for further studying the molecular mechanism of porcine fat deposition.
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Affiliation(s)
- Mingyue Shi
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Shuai Yang
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Xiaoyu Huang
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Shouyuan Wang
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Wenxia Li
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Jiale Yun
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Chang Lu
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Yang Yang
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Chunbo Cai
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Pengfei Gao
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Xiaohong Guo
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Bugao Li
- College of Animal Science, Shanxi Agricultural University, Taigu, China
| | - Guoqing Cao
- College of Animal Science, Shanxi Agricultural University, Taigu, China
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18
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Therapeutic Potential of VEGF-B in Coronary Heart Disease and Heart Failure: Dream or Vision? Cells 2022; 11:cells11244134. [PMID: 36552897 PMCID: PMC9776740 DOI: 10.3390/cells11244134] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 12/23/2022] Open
Abstract
Coronary heart disease (CHD) is the leading cause of death around the world. Based on the roles of vascular endothelial growth factor (VEGF) family members to regulate blood and lymphatic vessels and metabolic functions, several therapeutic approaches have been attempted during the last decade. However proangiogenic therapies based on classical VEGF-A have been disappointing. Therefore, it has become important to focus on other VEGFs such as VEGF-B, which is a novel member of the VEGF family. Recent studies have shown the very promising potential of the VEGF-B to treat CHD and heart failure. The aim of this review article is to present the role of VEGF-B in endothelial biology and as a potential therapeutic agent for CHD and heart failure. In addition, key differences between the VEGF-A and VEGF-B effects on endothelial functions are demonstrated.
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19
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O'Donovan SD, Erdős B, Jacobs DM, Wanders AJ, Thomas EL, Bell JD, Rundle M, Frost G, Arts ICW, Afman LA, van Riel NAW. Quantifying the contribution of triglycerides to metabolic resilience through the mixed meal model. iScience 2022; 25:105206. [PMID: 36281448 DOI: 10.1016/j.isci.2022.105206] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 09/01/2022] [Accepted: 09/22/2022] [Indexed: 11/26/2022] Open
Abstract
Despite the pivotal role played by elevated circulating triglyceride levels in the pathophysiology of cardio-metabolic diseases many of the indices used to quantify metabolic health focus on deviations in glucose and insulin alone. We present the Mixed Meal Model, a computational model describing the systemic interplay between triglycerides, free fatty acids, glucose, and insulin. We show that the Mixed Meal Model can capture deviations in the post-meal excursions of plasma glucose, insulin, and triglyceride that are indicative of features of metabolic resilience; quantifying insulin resistance and liver fat; validated by comparison to gold-standard measures. We also demonstrate that the Mixed Meal Model is generalizable, applying it to meals with diverse macro-nutrient compositions. In this way, by coupling triglycerides to the glucose-insulin system the Mixed Meal Model provides a more holistic assessment of metabolic resilience from meal response data, quantifying pre-clinical metabolic deteriorations that drive disease development in overweight and obesity.
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Affiliation(s)
- Shauna D O'Donovan
- Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands.,Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.,Eindhoven Artifical Intelligence Systems Institute (EAISI), Eindhoven University of Technology, Eindhoven, the Netherlands
| | - Balázs Erdős
- Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, the Netherlands
| | - Doris M Jacobs
- Unilever Global Food Innovation Centre, Bronland 14, 6708WH Wageningen, the Netherlands
| | - Anne J Wanders
- Unilever Global Food Innovation Centre, Bronland 14, 6708WH Wageningen, the Netherlands
| | - E Louise Thomas
- Research Center for Optimal Health, School of Life Sciences, University of Westminster, London, UK
| | - Jimmy D Bell
- Research Center for Optimal Health, School of Life Sciences, University of Westminster, London, UK
| | - Milena Rundle
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, UK
| | - Gary Frost
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, UK
| | - Ilja C W Arts
- Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, the Netherlands
| | - Lydia A Afman
- Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands
| | - Natal A W van Riel
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.,Eindhoven Artifical Intelligence Systems Institute (EAISI), Eindhoven University of Technology, Eindhoven, the Netherlands
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20
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Ding M, Li H, Zheng L. Drosophila exercise, an emerging model bridging the fields of exercise and aging in human. Front Cell Dev Biol 2022; 10:966531. [PMID: 36158212 PMCID: PMC9507000 DOI: 10.3389/fcell.2022.966531] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 08/22/2022] [Indexed: 11/29/2022] Open
Abstract
Exercise is one of the most effective treatments for the diseases of aging. In recent years, a growing number of researchers have used Drosophila melanogaster to study the broad benefits of regular exercise in aging individuals. With the widespread use of Drosophila exercise models and the upgrading of the Drosophila exercise apparatus, we should carefully examine the differential contribution of regular exercise in the aging process to facilitate more detailed quantitative measurements and assessment of the exercise phenotype. In this paper, we review some of the resources available for Drosophila exercise models. The focus is on the impact of regular exercise or exercise adaptation in the aging process in Drosophila and highlights the great potential and current challenges faced by this model in the field of anti-aging research.
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21
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Yan K, Mei Z, Zhao J, Prodhan MAI, Obal D, Katragadda K, Doelling B, Hoetker D, Posa DK, He L, Yin X, Shah J, Pan J, Rai S, Lorkiewicz PK, Zhang X, Liu S, Bhatnagar A, Baba SP. Integrated Multilayer Omics Reveals the Genomic, Proteomic, and Metabolic Influences of Histidyl Dipeptides on the Heart. J Am Heart Assoc 2022; 11:e023868. [PMID: 35730646 PMCID: PMC9333374 DOI: 10.1161/jaha.121.023868] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Background Histidyl dipeptides such as carnosine are present in a micromolar to millimolar range in mammalian hearts. These dipeptides facilitate glycolysis by proton buffering. They form conjugates with reactive aldehydes, such as acrolein, and attenuate myocardial ischemia–reperfusion injury. Although these dipeptides exhibit multifunctional properties, a composite understanding of their role in the myocardium is lacking. Methods and Results To identify histidyl dipeptide–mediated responses in the heart, we used an integrated triomics approach, which involved genome‐wide RNA sequencing, global proteomics, and unbiased metabolomics to identify the effects of cardiospecific transgenic overexpression of the carnosine synthesizing enzyme, carnosine synthase (Carns), in mice. Our result showed that higher myocardial levels of histidyl dipeptides were associated with extensive changes in the levels of several microRNAs, which target the expression of contractile proteins, β‐fatty acid oxidation, and citric acid cycle (TCA) enzymes. Global proteomic analysis showed enrichment in the expression of contractile proteins, enzymes of β‐fatty acid oxidation, and the TCA in the Carns transgenic heart. Under aerobic conditions, the Carns transgenic hearts had lower levels of short‐ and long‐chain fatty acids as well as the TCA intermediate—succinic acid; whereas, under ischemic conditions, the accumulation of fatty acids and TCA intermediates was significantly attenuated. Integration of multiple data sets suggested that β‐fatty acid oxidation and TCA pathways exhibit correlative changes in the Carns transgenic hearts at all 3 levels. Conclusions Taken together, these findings reveal a central role of histidyl dipeptides in coordinated regulation of myocardial structure, function, and energetics.
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Affiliation(s)
- Keqiang Yan
- Beijing Institute of Genomics Chinese Academy of Sciences, Beishan Industrial Zone Shenzhen China
| | - Zhanlong Mei
- Beijing Institute of Genomics Chinese Academy of Sciences, Beishan Industrial Zone Shenzhen China
| | - Jingjing Zhao
- Diabetes and Obesity Center University of Louisville KY.,Christina Lee Brown Envirome Institute University of Louisville KY USA
| | | | - Detlef Obal
- Department of Anesthesiology and Perioperative and Pain Medicine Stanford University Palo Alto CA
| | - Kartik Katragadda
- Diabetes and Obesity Center University of Louisville KY.,Christina Lee Brown Envirome Institute University of Louisville KY USA
| | - Benjamin Doelling
- Diabetes and Obesity Center University of Louisville KY.,Christina Lee Brown Envirome Institute University of Louisville KY USA
| | - David Hoetker
- Diabetes and Obesity Center University of Louisville KY.,Christina Lee Brown Envirome Institute University of Louisville KY USA
| | - Dheeraj Kumar Posa
- Diabetes and Obesity Center University of Louisville KY.,Christina Lee Brown Envirome Institute University of Louisville KY USA
| | - Liqing He
- Department of Chemistry University of Louisville KY
| | - Xinmin Yin
- Department of Chemistry University of Louisville KY
| | - Jasmit Shah
- Department of Medicine, Medical college The Aga Khan University Nairobi Kenya
| | - Jianmin Pan
- Biostatistics Shared Facility University of Louisville Health, Brown Cancer Center Louisville KY
| | - Shesh Rai
- Biostatistics Shared Facility University of Louisville Health, Brown Cancer Center Louisville KY
| | - Pawel Konrad Lorkiewicz
- Diabetes and Obesity Center University of Louisville KY.,Christina Lee Brown Envirome Institute University of Louisville KY USA
| | - Xiang Zhang
- Department of Chemistry University of Louisville KY
| | - Siqi Liu
- Beijing Institute of Genomics Chinese Academy of Sciences, Beishan Industrial Zone Shenzhen China
| | - Aruni Bhatnagar
- Diabetes and Obesity Center University of Louisville KY.,Christina Lee Brown Envirome Institute University of Louisville KY USA
| | - Shahid P Baba
- Diabetes and Obesity Center University of Louisville KY.,Christina Lee Brown Envirome Institute University of Louisville KY USA
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22
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Wang Y, Zhao H, Yang L, Zhang H, Yu X, Fei W, Zhen Y, Gao Z, Chen S, Ren L. Quantitative proteomics analysis based on tandem mass tag labeling coupled with labeling coupled with liquid chromatography-tandem mass spectrometry discovers the effect of silibinin on non-alcoholic fatty liver disease in mice. Bioengineered 2022; 13:6750-6766. [PMID: 35246007 PMCID: PMC9208462 DOI: 10.1080/21655979.2022.2045837] [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] [Indexed: 11/14/2022] Open
Abstract
In recent years, the beneficial effects of silibinin (SIL) on nonalcoholic fatty liver disease (NAFLD) have attracted widespread attention. We tried to study the intervention effect of SIL on NAFLD, and explore the potential mechanisms and targets of SIL on NAFLD improvement. Thirty-three male C57BL6/J mice were divided into three groups, and, respectively, fed a normal diet (ND), a high-fat diet (HFD) or a HFD given SIL treatment (HFD+SIL). Biochemical indexes and histopathological changes of mice in each group were detected. In addition, quantitative proteomics analysis based on tandem mass tag (TMT) labeling coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis was performed on protein changes in the livers. SIL could reduce the weight of mice, reduce liver lipid deposition, and improve glucose metabolism. Through comparison among the three experimental groups, a total of 30 overlapping proteins were found. These identified proteins were closely linked to liver lipid metabolism and energy homeostasis. Moreover, some drug targets were found, namely perilipin-2, phosphatidate phosphatase LPIN1, farnesyl pyrophosphate synthase, and glutathione S-transferase A1. In conclusions, high-fat diet increases the expressions of proteins implicated in lipid synthesis and transport in the liver, which can result in disorders of liver lipid metabolism. SIL can decrease liver lipid deposition and increase insulin sensitivity by regulating the expressions of these proteins. It not only improves the disorder of lipid metabolism in vivo, but also improves the disorder of glucose metabolism.
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Affiliation(s)
- Yichao Wang
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Hang Zhao
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Liying Yang
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - He Zhang
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Xian Yu
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Wenjie Fei
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yunfeng Zhen
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Zhe Gao
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Shuchun Chen
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Luping Ren
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
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23
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Roh JH, Lee H, Yun-Jeong B, Park CS, Kim HJ, Yoon SY. A nationwide survey of the association between nonalcoholic fatty liver disease and the incidence of asthma in Korean adults. PLoS One 2022; 17:e0262715. [PMID: 35061826 PMCID: PMC8782316 DOI: 10.1371/journal.pone.0262715] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 01/01/2022] [Indexed: 01/21/2023] Open
Abstract
Background Asthma and nonalcoholic fatty liver disease (NAFLD) are chronic diseases known to be associated with metabolic abnormalities. We aimed to clarify the association between NAFLD and asthma incidence in a large population-based cohort. Methods and findings We selected 160,603 individuals without comorbidities from the National Health Insurance Service-National Sample cohort between 2009 and 2014. NAFLD was defined using a surrogate marker, fatty liver index (FLI). During a median of 5.08 years’ follow-up, 16,377 subjects (10.2%) were newly diagnosed with asthma and categorized into three groups according to FLI. The cumulative incidence of asthma was higher in subjects with higher vs. lower FLIs (FLI < 30, 10.1%; 30 ≤ FLI < 60, 10.8%; FLI ≥ 60, 10.5%). Higher FLI was associated with an increased incidence of asthma (Hazard ratios (HR)highest vs. lowest FLI, 1.25; 95% CI, 1.15–1.36). The results using another definition of NAFLD, as measured by the hepatic steatosis index (HSI), were similar to the primary results. This association was more pronounced in women than in men (HR 1.46; 95% CI, 1.13–1.64 vs. HR 1.07; 95% CI, 0.94–1.20). Conclusions This study demonstrated that NAFLD, as measured by FLI and HSI, may influence the incidence rates of asthma in adults, especially in women.
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Affiliation(s)
- Jae-Hyung Roh
- Department of Cardiology in Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Sejong Hospital, Sejong, Korea
| | - Hanbyul Lee
- Department of Statistics, Kyungpook National University, Daegu, Korea
| | - Bae Yun-Jeong
- Health Innovation Bigdata Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea
| | - Chan Sun Park
- Department of Internal medicine, Inje University, Haeundae Paik Hospital, Busan, Korea
| | - Hyo-Jung Kim
- Division of Pulmonology, Department of Internal Medicine, INJE Haeundae Paik Hospital, Busan, Korea
| | - Sun-Young Yoon
- Department of Allergy and Pulmonology in Internal Medicine, Chungnam National University, Chungnam National University Sejong Hospital, Sejong, Korea
- * E-mail:
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24
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Liu XX, Zhang LZ, Zhang HH, Lai LF, Wang YQ, Sun J, Xu NG, Li ZX. Low-frequency electroacupuncture improves disordered hepatic energy metabolism in insulin-resistant Zucker diabetic fatty rats via the AMPK/mTORC1/p70S6K signaling pathway. Acupunct Med 2022; 40:360-368. [PMID: 35034504 DOI: 10.1177/09645284211070301] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Disordered hepatic energy metabolism is found in obese rats with insulin resistance (IR). There are insufficient experimental studies of electroacupuncture (EA) for IR and type 2 diabetes mellitus (T2DM). The aim of this study was to probe the effect of EA on disordered hepatic energy metabolism and the adenosine monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase, 70-kDa (p70S6K) signaling pathway. METHODS Zucker Diabetic Fatty (ZDF) rats were randomly divided into three groups: EA group receiving EA treatment; Pi group receiving pioglitazone gavage; and ZF group remaining untreated (n = 8 per group). Inbred non-insulin-resistant Zucker lean rats formed an (untreated) healthy control group (ZL, n = 8). Fasting plasma glucose (FPG), fasting insulin (FINS), C-peptide, C-reactive protein (CRP) and homeostatic model assessment of insulin resistance (HOMA-IR) indices were measured. Hematoxylin-eosin (H&E) staining was used to investigate the liver morphologically. The mitochondrial structure of hepatocytes was observed by transmission electron microscopy (TEM). Western blotting was adopted to determine protein expression of insulin receptor substrate 1 (IRS-1), mTOR, mTORC1, AMPK, tuberous sclerosis 2 (TSC2) and p70S6K, and their phosphorylation. RT-PCR was used to quantify IRS-1, mTOR, mTORC1, AMPK and p70S6K mRNA levels. RESULTS Compared with the ZF group, FPG, FINS, C-peptide, CRP and HOMA-IR levels were significantly reduced in the EA group (p < 0.05, p < 0.01). Evaluation of histopathology showed improvement in liver appearances following EA. Phosphorylation levels of AMPK, mTOR and TSC2 decreased, and IRS-1 and p70S6K increased, in hepatocytes of the ZF group, while these negative effects appeared to be alleviated by EA. CONCLUSIONS EA can effectively ameliorate IR and regulate energy metabolism in the ZDF rat model. AMPK/mTORC1/p70S6K and related molecules may represent a potential mechanism of action underlying these effects.
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Affiliation(s)
- Xiao-Xiao Liu
- Fourth Affiliated Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China.,South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Li-Zhi Zhang
- South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hai-Hua Zhang
- Department of Tuina, Fourth Affiliated Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Lan-Feng Lai
- South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi-Qiao Wang
- South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jian Sun
- Traditional Therapy Department of Fangchun, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Neng-Gui Xu
- South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhi-Xing Li
- Department of Soft Tissue Traumatology, Fourth Affiliated Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
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25
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Aloe vera in diabetic dyslipidemia: Improving blood glucose and lipoprotein levels in pre-clinical and clinical studies. J Ayurveda Integr Med 2022; 13:100675. [PMID: 36481618 PMCID: PMC9732414 DOI: 10.1016/j.jaim.2022.100675] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 10/05/2022] [Accepted: 11/08/2022] [Indexed: 12/12/2022] Open
Abstract
Dyslipidemia is a common feature of type 2 diabetes mellitus and is characterised by elevated triglyceride, decreased HDL cholesterol, and increased small dense LDL cholesterol levels. The underlying causes appears to be associated with insulin resistance, increased free fatty acid reflux, and low-grade inflammation, resulting in increased hepatic lipogenesis, and altered lipoprotein metabolism. Improved glycaemic control has been shown to have a positive effect on lipoprotein levels in diabetics. This can be achieved through medications/therapeutics and life style changes. Several classes of pharmacologic agents are currently in use to treat dyslipidemia. However, they may have dangerous long-term side effects, including an increased risk of liver dysfunction, weight gain, and cardiovascular diseases. Therefore, stronger alternatives with fewer side effects are required to reduce the diabetes associated complications. Many secondary plant metabolites have been shown to improve glucose homeostasis and lower lipid levels. Aloe vera and its constituents have long been used in a traditional medicine system for a diverse range of biological activities, including hypoglycaemic, antioxidant, anticarcinogenic, anti-inflammatory, and wound healing effects through various mechanisms and they have been covered well in literature. However, studies on the potential role of Aloe vera in the treatment of diabetic dyslipidemia are scanty. Therefore, in this systematic review, we focussed on the potential effect of Aloe vera and its active components in alleviating diabetic dyslipidemia, as well as their mechanism of action in pre-clinical and clinical studies.
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26
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Tippetts TS, Holland WL, Summers SA. Cholesterol - the devil you know; ceramide - the devil you don't. Trends Pharmacol Sci 2021; 42:1082-1095. [PMID: 34750017 PMCID: PMC8595778 DOI: 10.1016/j.tips.2021.10.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/29/2021] [Accepted: 10/01/2021] [Indexed: 01/20/2023]
Abstract
Ectopic lipids play a key role in numerous pathologies, including heart disease, stroke, and diabetes. Of all the lipids studied, perhaps the most well understood is cholesterol, a widely used clinical biomarker of cardiovascular disease and a target of pharmacological interventions (e.g., statins). Thousands of studies have interrogated the regulation and action of this disease-causing sterol. As a growing body of literature indicates, a new class of lipid-based therapies may be on the horizon. Ceramides are cholesterol-independent biomarkers of heart disease and diabetes in humans. Studies in rodents suggest that they are causative agents of disease, as lowering ceramides through genetic or pharmacological interventions prevents cardiovascular disease and diabetes. Herein, we discuss the evidence supporting the potential of therapeutics targeting ceramides to treat cardiometabolic disease, contrasting it with the robust datasets that drove the creation of cholesterol-lowering pharmaceuticals.
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Affiliation(s)
| | | | - Scott A. Summers
- Correspondence should be addressed to: Scott A. Summers, Department of Nutrition and Integrative Physiology, University of Utah College of Health, 15N, 2030 East, Rm 3110, Salt Lake City Utah 84112, , Tel: 801-585-9359
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27
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Wei X, Zhao Z, Zhong R, Tan X. A comprehensive review of herbacetin: From chemistry to pharmacological activities. JOURNAL OF ETHNOPHARMACOLOGY 2021; 279:114356. [PMID: 34166735 DOI: 10.1016/j.jep.2021.114356] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 06/09/2021] [Accepted: 06/19/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Herbacetin is an active constituent of traditional Chinese medicines such as Ephedra sinica Stapf (MaHuang) and Sedum roseum (L.). Scop. (Hong JingTian). MaHuang was used to treat cough, asthma, fever, and edema for more than 5000 years, while Hong JingTian was used to treat depression, fatigue, cancers, and cardiovascular disease. Recent studies indicate that herbacetin and its glycosides play a critical role in the pharmacological activities of these herbs. However, currently, no comprehensive review on herbacetin has been published yet. AIM OF THE STUDY This review aimed to summarize information on the chemistry, natural sources, and pharmacokinetic features of herbacetin, with an emphasis on its pharmacological activities and possible mechanisms of action. MATERIALS AND METHODS A literature search was performed on the Web of Science, PubMed, and China Knowledge Resource Integrated databases (CNKI) using the search term "herbacetin" ("all fields") from 1935 to 2020. Information was also obtained from classic books of Chinese herbal medicine, Chinese pharmacopeia, and the database "The Plant List" (www.theplantlist.org). Studies have been analyzed and summarized in this review if they dealt with chemistry, taxonomy, pharmacokinetic, and pharmacological activity. RESULTS Herbacetin is distributed in various plants and can be extracted or synthesized. It showed diverse pharmacological activities including antioxidant, antiviral, anti-inflammatory, anticancer, antidiabetic, and anticholinesterase. It is thought to have great potential in cancer treatment, especially colon and skin cancers. However, the bioavailability of herbacetin is low and the toxicity of herbacetin has not been studied. Thus, more studies are required to solve these problems. CONCLUSIONS Herbacetin shows promising pharmacological activities against multiple diseases. Future research should focus on improving bioavailability, further studying its pharmacological mechanism, evaluating its toxicity and optimal dose, and performing the clinical assessment. We hope that the present review will serve as a guideline for future research on herbacetin.
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Affiliation(s)
- Xiaohan Wei
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China; Guangzhou Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, 510515, China; Guangdong Provincial Engineering Laboratory of Chinese Medicine Preparation, Technology, Guangzhou, 510515, China
| | - Zhejun Zhao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Rongheng Zhong
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Xiaomei Tan
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China; Guangzhou Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, 510515, China; Guangdong Provincial Engineering Laboratory of Chinese Medicine Preparation, Technology, Guangzhou, 510515, China.
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28
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Morgunova GV, Shilovsky GA, Khokhlov AN. Effect of Caloric Restriction on Aging: Fixing the Problems of Nutrient Sensing in Postmitotic Cells? BIOCHEMISTRY. BIOKHIMIIA 2021; 86:1352-1367. [PMID: 34903158 DOI: 10.1134/s0006297921100151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The review discusses the role of metabolic disorders (in particular, insulin resistance) in the development of age-related diseases and normal aging with special emphasis on the changes in postmitotic cells of higher organisms. Caloric restriction helps to prevent such metabolic disorders, which could probably explain its ability to prolong the lifespan of laboratory animals. Maintaining metabolic homeostasis is especially important for the highly differentiated long-lived body cells, whose lifespan is comparable to the lifespan of the organism itself. Normal functioning of these cells can be ensured only upon correct functioning of the cytoplasm clean-up system and availability of all required nutrients and energy sources. One of the central problems in gerontology is the age-related disruption of glucose metabolism leading to obesity, diabetes, metabolic syndrome, and other related pathologies. Along with the adipose tissue, skeletal muscles are the main consumers of insulin; hence the physical activity of muscles, which supports their energy metabolism, delays the onset of insulin resistance. Insulin resistance disrupts the metabolism of cardiomyocytes, so that they fail to utilize the nutrients to perform their functions even being surrounded by a nutrient-rich environment, which contributes to the development of age-related cardiovascular diseases. Metabolic pathologies also alter the nutrient sensitivity of neurons, thus disrupting the action of insulin in the central nervous system. In addition, there is evidence that neurons can develop insulin resistance as well. It has been suggested that affecting nutritional sensors (e.g., AMPK) in postmitotic cells might improve the state of the entire multicellular organism, slow down its aging, and increase the lifespan.
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Affiliation(s)
- Galina V Morgunova
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia.
| | - Gregory A Shilovsky
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
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Abstract
PURPOSE OF REVIEW This review outlines recent research in the application of low carbohydrate diets (LCD) for insulin resistance (IR) and metabolic syndrome (MetS). RECENT FINDINGS Studies included in this review explore how a LCD can be used in the management of patients with IR and MetS. LCDs have been shown to result in Type 2 Diabetes Mellitus (T2DM) remission, improve lipid profiles and dramatically reduce intrahepatic fat. SUMMARY The field of nutritional science is notoriously complex. The LCD has a simple narrative, which can easily and safely be applied in clinical practice. Current guidelines recognise and encourage the use of LCD as a valid option for patients with T2DM and obesity. Structured, evidence-based education should be available for all clinicians to increase confidence and ensure consistency and quality control. Further real-world evidence into the application and scalability of a LCD are required. The use of digital health solutions and improved health technology should see significant advances in this field, with dietary habit being driven by patient-derived health data in response to food, and not population-based food guidelines. The narrative around MetS and IR needs to change from progression to remission, with a LCD being a valid option for this.
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30
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Chang GR, Hou PH, Wang CM, Lin JW, Lin WL, Lin TC, Liao HJ, Chan CH, Wang YC. Imipramine Accelerates Nonalcoholic Fatty Liver Disease, Renal Impairment, Diabetic Retinopathy, Insulin Resistance, and Urinary Chromium Loss in Obese Mice. Vet Sci 2021; 8:189. [PMID: 34564583 PMCID: PMC8473438 DOI: 10.3390/vetsci8090189] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/23/2021] [Accepted: 09/07/2021] [Indexed: 12/12/2022] Open
Abstract
Imipramine is a tricyclic antidepressant that has been approved for treating depression and anxiety in patients and animals and that has relatively mild side effects. However, the mechanisms of imipramine-associated disruption to metabolism and negative hepatic, renal, and retinal effects are not well defined. In this study, we evaluated C57BL6/J mice subjected to a high-fat diet (HFD) to study imipramine's influences on obesity, fatty liver scores, glucose homeostasis, hepatic damage, distribution of chromium, and retinal/renal impairments. Obese mice receiving imipramine treatment had higher body, epididymal fat pad, and liver weights; higher serum triglyceride, aspartate and alanine aminotransferase, creatinine, blood urea nitrogen, renal antioxidant enzyme, and hepatic triglyceride levels; higher daily food efficiency; and higher expression levels of a marker of fatty acid regulation in the liver compared with the controls also fed an HFD. Furthermore, the obese mice that received imipramine treatment exhibited insulin resistance, worse glucose intolerance, decreased glucose transporter 4 expression and Akt phosphorylation levels, and increased chromium loss through urine. In addition, the treatment group exhibited considerably greater liver damage and higher fatty liver scores, paralleling the increases in patatin-like phospholipid domain containing protein 3 and the mRNA levels of sterol regulatory element-binding protein 1 and fatty acid-binding protein 4. Retinal injury worsened in imipramine-treated mice; decreases in retinal cell layer organization and retinal thickness and increases in nuclear factor κB and inducible nitric oxide synthase levels were observed. We conclude that administration of imipramine may result in the exacerbation of nonalcoholic fatty liver disease, diabetes, diabetic retinopathy, and kidney injury.
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Affiliation(s)
- Geng-Ruei Chang
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan; (G.-R.C.); (C.-M.W.); (T.-C.L.); (H.-J.L.)
| | - Po-Hsun Hou
- Department of Psychiatry, Taichung Veterans General Hospital, 4 Section, 1650 Taiwan Boulevard, Taichung 40705, Taiwan;
- Faculty of Medicine, National Yang-Ming University, 2 Section, 155 Linong Street, Beitou District, Taipei 11221, Taiwan
- College of Medicine, National Chung Hsing University, 145 Xingda Road, South District, Taichung 40227, Taiwan
| | - Chao-Min Wang
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan; (G.-R.C.); (C.-M.W.); (T.-C.L.); (H.-J.L.)
| | - Jen-Wei Lin
- Bachelor Degree Program in Animal Healthcare, Hungkuang University, 6 Section, 1018 Taiwan Boulevard, Shalu District, Taichung 433304, Taiwan; (J.-W.L.); (W.-L.L.)
| | - Wei-Li Lin
- Bachelor Degree Program in Animal Healthcare, Hungkuang University, 6 Section, 1018 Taiwan Boulevard, Shalu District, Taichung 433304, Taiwan; (J.-W.L.); (W.-L.L.)
- General Education Center, Chaoyang University of Technology, 168 Jifeng Eastern Road, Taichung 413310, Taiwan
| | - Tzu-Chun Lin
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan; (G.-R.C.); (C.-M.W.); (T.-C.L.); (H.-J.L.)
| | - Huei-Jyuan Liao
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan; (G.-R.C.); (C.-M.W.); (T.-C.L.); (H.-J.L.)
| | - Chee-Hong Chan
- Division of Nephrology, Chang Bing Show Chwan Memorial Hospital, 6 Lugong Road, Lukang Township, Changhua 50544, Taiwan
| | - Yu-Chen Wang
- Division of Cardiology, Asia University Hospital, 222 Fuxin Road, Wufeng District, Taichung 41354, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Asia University, 500 Lioufeng Road, Wufeng District, Taichung 41354, Taiwan
- Division of Cardiovascular Medicine, China Medical University Hospital, 2 Yude Road, North District, Taichung 404332, Taiwan
- College of Medicine, China Medical University, 91 Hsueh-Shih Road, North District, Taichung 404333, Taiwan
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Chung HR, Moon JH, Lim JS, Lee YA, Shin CH, Hong JS, Kwak SH, Choi SH, Jang HC. Maternal Hyperglycemia during Pregnancy Increases Adiposity of Offspring. Diabetes Metab J 2021; 45:730-738. [PMID: 33618504 PMCID: PMC8497931 DOI: 10.4093/dmj.2020.0154] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 08/04/2020] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND The effect of intrauterine hyperglycemia on fat mass and regional fat proportion of the offspring of mothers with gestational diabetes mellitus (OGDM) remains to be determined. METHODS The body composition of OGDM (n=25) and offspring of normoglycemic mothers (n=49) was compared using dualenergy X-ray absorptiometry at age 5 years. The relationship between maternal glucose concentration during a 100 g oral glucose tolerance test (OGTT) and regional fat mass or proportion was analyzed after adjusting for maternal prepregnancy body mass index (BMI). RESULTS BMI was comparable between OGDM and control (median, 16.0 kg/m2 vs. 16.1 kg/m2 ). Total, truncal, and leg fat mass were higher in OGDM compared with control (3,769 g vs. 2,245 g, P=0.004; 1,289 g vs. 870 g, P=0.017; 1,638 g vs. 961 g, P=0.002, respectively), whereas total lean mass was lower in OGDM (15,688 g vs. 16,941 g, P=0.001). Among OGDM, total and truncal fat mass were correlated with fasting and 3-hour glucose concentrations of maternal 100 g OGTT during pregnancy (total fat mass, r=0.49, P=0.018 [fasting], r=0.473, P=0.023 [3-hour]; truncal fat mass, r=0.571, P=0.004 [fasting], r=0.558, P=0.006 [3-hour]), but there was no correlation between OGDM leg fat mass and maternal OGTT during pregnancy. Regional fat indices were not correlated with concurrent maternal 75 g OGTT values. CONCLUSION Intrauterine hyperglycemia is associated with increased fat mass, especially truncal fat, in OGDM aged 5 years.
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Affiliation(s)
- Hye Rim Chung
- Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Joon Ho Moon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jung Sub Lim
- Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Korea
| | - Young Ah Lee
- Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Korea
| | - Choong Ho Shin
- Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Korea
| | - Joon-Seok Hong
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Soo Heon Kwak
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Sung Hee Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hak Chul Jang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Corresponding author: Hak Chul Jang https://orcid.org/0000-0002-4188-6536 Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea E-mail:
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Šimják P, Anderlová K, Cinkajzlová A, Pařízek A, Kršek M, Haluzík M. The possible role of endocrine dysfunction of adipose tissue in gestational diabetes mellitus. MINERVA ENDOCRINOL 2021; 45:228-242. [PMID: 33000620 DOI: 10.23736/s0391-1977.20.03192-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Gestational diabetes mellitus (GDM) is diabetes that is first diagnosed in the second or third trimester of pregnancy in patients who did not have a history of diabetes before pregnancy. Consequences of GDM include increased risk of macrosomia and birth complications in the infant and an increased risk of maternal type 2 diabetes mellitus (T2DM) after pregnancy. There is also a longer-term risk of obesity, T2DM, and cardiovascular diseases in the child. GDM is the result of impaired glucose tolerance due to pancreatic β-cell dysfunction on a background of insulin resistance that physiologically increases during pregnancy. The strongest clinical predictors of GDM are overweight and obesity. The fact that women with GDM are more likely to be overweight or obese suggests that adipose tissue dysfunction may be involved in the pathogenesis of GDM, similarly to T2DM. Adipose tissue is not only involved in energy storage but also functions as an active endocrine organ secreting adipokines (specific hormones and cytokines) with the ability to alter insulin sensitivity. Recent evidence points to a crucial role of numerous adipokines produced by fat in the development of GDM. The following text summarizes the current knowledge about a possible role of selected adipokines in the development of GDM.
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Affiliation(s)
- Patrik Šimják
- Department of Gynecology and Obstetrics, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Kateřina Anderlová
- Department of Gynecology and Obstetrics, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.,Third Department of Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Anna Cinkajzlová
- Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Antonín Pařízek
- Department of Gynecology and Obstetrics, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Michal Kršek
- Third Department of Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Martin Haluzík
- Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic -
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Hypolipidemic Effects and Preliminary Mechanism of Chrysanthemum Flavonoids, Its Main Components Luteolin and Luteoloside in Hyperlipidemia Rats. Antioxidants (Basel) 2021; 10:antiox10081309. [PMID: 34439559 PMCID: PMC8389196 DOI: 10.3390/antiox10081309] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 07/25/2021] [Accepted: 08/12/2021] [Indexed: 12/24/2022] Open
Abstract
This study aimed to investigate the key constituents and preliminary mechanism for the hypolipidemic activity of chrysanthemum flavonoids. Hyperlipidemia (HPL) rats were divided into five groups: the model control group (MC); Chrysanthemum flavone intervention group (CF); luteolin intervention group; luteoloside intervention group and simvastatin intervention group. The body weight, organ coefficient, serum lipids, antioxidant activity, and lipid metabolism enzymes were detected. Hematoxylin and eosin (H&E) staining was used to observe the liver and adipose tissue. Chrysanthemum flavonoids, luteolin, and luteoloside can reduce the weight and levels of total cholesterol (TC), triglycerides (TG), and LDL-C, and increase the level of HDL-C in the blood and reduce liver steatosis. Indicators of liver function (AST, ALT, and ALP) improved. The antioxidant activity (GSH-Px, CAT, SOD) and enzymes associated with lipid catabolism (FAβO, CYP7A1, and HL) increased, while lipid peroxidation products (MDA) and enzymes associated with lipid synthesis (FAS, HMG-CoA, and DGAT) decreased. Chrysanthemum flavonoids had a better effect on the antioxidant level and lipid metabolism-related enzyme activity. There was no significant difference in the effects of the chrysanthemum flavonoids, luteolin, and Luteoloside on improving blood lipids and hepatic steatosis—mechanisms that may be related to antioxidant levels and regulating enzymes involved in the metabolism of fatty acids, cholesterol, and triglycerides in the liver. However, chrysanthemum flavonoids had a stronger antioxidant and lipid metabolism regulation ability, and the long-term effects may be better.
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Renzini A, Riera CS, Minic I, D’Ercole C, Lozanoska-Ochser B, Cedola A, Gigli G, Moresi V, Madaro L. Metabolic Remodeling in Skeletal Muscle Atrophy as a Therapeutic Target. Metabolites 2021; 11:517. [PMID: 34436458 PMCID: PMC8398298 DOI: 10.3390/metabo11080517] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/03/2021] [Accepted: 08/04/2021] [Indexed: 02/07/2023] Open
Abstract
Skeletal muscle is a highly responsive tissue, able to remodel its size and metabolism in response to external demand. Muscle fibers can vary from fast glycolytic to slow oxidative, and their frequency in a specific muscle is tightly regulated by fiber maturation, innervation, or external causes. Atrophic conditions, including aging, amyotrophic lateral sclerosis, and cancer-induced cachexia, differ in the causative factors and molecular signaling leading to muscle wasting; nevertheless, all of these conditions are characterized by metabolic remodeling, which contributes to the pathological progression of muscle atrophy. Here, we discuss how changes in muscle metabolism can be used as a therapeutic target and review the evidence in support of nutritional interventions and/or physical exercise as tools for counteracting muscle wasting in atrophic conditions.
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Affiliation(s)
- Alessandra Renzini
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, 00185 Rome, Italy; (A.R.); (C.S.R.); (I.M.); (C.D.); (B.L.-O.); (L.M.)
| | - Carles Sánchez Riera
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, 00185 Rome, Italy; (A.R.); (C.S.R.); (I.M.); (C.D.); (B.L.-O.); (L.M.)
| | - Isidora Minic
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, 00185 Rome, Italy; (A.R.); (C.S.R.); (I.M.); (C.D.); (B.L.-O.); (L.M.)
| | - Chiara D’Ercole
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, 00185 Rome, Italy; (A.R.); (C.S.R.); (I.M.); (C.D.); (B.L.-O.); (L.M.)
| | - Biliana Lozanoska-Ochser
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, 00185 Rome, Italy; (A.R.); (C.S.R.); (I.M.); (C.D.); (B.L.-O.); (L.M.)
| | - Alessia Cedola
- Institute of Nanotechnology, c/o Dipartimento di Fisica, National Research Council (CNR-NANOTEC), Sapienza University of Rome, 00185 Rome, Italy;
| | - Giuseppe Gigli
- Institute of Nanotechnology, c/o Campus Ecotekne, National Research Council (CNR-NANOTEC), Monteroni, 73100 Lecce, Italy;
| | - Viviana Moresi
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, 00185 Rome, Italy; (A.R.); (C.S.R.); (I.M.); (C.D.); (B.L.-O.); (L.M.)
- Institute of Nanotechnology, c/o Dipartimento di Fisica, National Research Council (CNR-NANOTEC), Sapienza University of Rome, 00185 Rome, Italy;
| | - Luca Madaro
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, 00185 Rome, Italy; (A.R.); (C.S.R.); (I.M.); (C.D.); (B.L.-O.); (L.M.)
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Martin S, Cule M, Basty N, Tyrrell J, Beaumont RN, Wood AR, Frayling TM, Sorokin E, Whitcher B, Liu Y, Bell JD, Thomas EL, Yaghootkar H. Genetic Evidence for Different Adiposity Phenotypes and Their Opposing Influences on Ectopic Fat and Risk of Cardiometabolic Disease. Diabetes 2021; 70:1843-1856. [PMID: 33980691 DOI: 10.2337/db21-0129] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 05/06/2021] [Indexed: 11/13/2022]
Abstract
To understand the causal role of adiposity and ectopic fat in type 2 diabetes and cardiometabolic diseases, we aimed to identify two clusters of adiposity genetic variants: one with "adverse" metabolic effects (UFA) and the other with, paradoxically, "favorable" metabolic effects (FA). We performed a multivariate genome-wide association study using body fat percentage and metabolic biomarkers from UK Biobank and identified 38 UFA and 36 FA variants. Adiposity-increasing alleles were associated with an adverse metabolic profile, higher risk of disease, higher CRP, and higher fat in subcutaneous and visceral adipose tissue, liver, and pancreas for UFA and a favorable metabolic profile, lower risk of disease, higher CRP and higher subcutaneous adipose tissue but lower liver fat for FA. We detected no sexual dimorphism. The Mendelian randomization studies provided evidence for a risk-increasing effect of UFA and protective effect of FA for type 2 diabetes, heart disease, hypertension, stroke, nonalcoholic fatty liver disease, and polycystic ovary syndrome. FA is distinct from UFA by its association with lower liver fat and protection from cardiometabolic diseases; it was not associated with visceral or pancreatic fat. Understanding the difference in FA and UFA may lead to new insights in preventing, predicting, and treating cardiometabolic diseases.
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Affiliation(s)
- Susan Martin
- Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Royal Devon & Exeter Hospital, Exeter, U.K
| | | | - Nicolas Basty
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, U.K
| | - Jessica Tyrrell
- Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Royal Devon & Exeter Hospital, Exeter, U.K
| | - Robin N Beaumont
- Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Royal Devon & Exeter Hospital, Exeter, U.K
| | - Andrew R Wood
- Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Royal Devon & Exeter Hospital, Exeter, U.K
| | - Timothy M Frayling
- Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Royal Devon & Exeter Hospital, Exeter, U.K
| | | | - Brandon Whitcher
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, U.K
| | - Yi Liu
- Calico Life Sciences LLC, South San Francisco, CA
| | - Jimmy D Bell
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, U.K
| | - E Louise Thomas
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, U.K
| | - Hanieh Yaghootkar
- Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Royal Devon & Exeter Hospital, Exeter, U.K.
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, U.K
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Asano T, Tsujii M, Iino T, Odake K, Sudo A. Pathological features of reinnervated skeletal muscles after crush injury of the sciatic nerve in ob/ob mice. Muscle Nerve 2021; 64:365-373. [PMID: 34212392 DOI: 10.1002/mus.27365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 06/21/2021] [Accepted: 06/27/2021] [Indexed: 11/11/2022]
Abstract
INTRODUCTION/AIMS Obesity is a factor contributing to suboptimal improvement of motor function in peripheral nerve disorders. In this study we aimed to evaluate the skeletal muscles during denervation and reinnervation after nerve crush injury in leptin-deficient (ob/ob) mice. METHODS Experiments were performed on the skeletal muscles of the hindlimbs in 20 male ob/ob mice and controls. Characteristics of the gastrocnemius muscles were evaluated by histological analysis, immunohistological analysis, and Sircol-collagen assay after measurement of body weight and wet weight of the skeletal muscles, and by walking track analysis. The sciatic nerve was denervated by crushing with smooth forceps and reinnervation was evaluated. RESULTS Gastrocnemius wet weight was significantly lower in the ob/ob mice than in the control mice. A smaller cross-sectional area of type II fibers and increase of type I fiber grouping of the skeletal muscles was demonstrated in the ob/ob mice. After nerve injury, motor function recovery was equal between the groups but the cross-sectional area of type II fibers was significantly smaller in the ob/ob mice than in control mice at 4 weeks. The denervated muscles showed an increase in collagen deposition in the interstitial space; predominant in the ob/ob mice after nerve injury. DISCUSSION The results of this study suggest that fibrosis in the skeletal muscle of obese patients after nerve injury is prominent, which may impair improvement of muscle function after treatment of peripheral nerve disorders.
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Affiliation(s)
- Takahiro Asano
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Masaya Tsujii
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Takahiro Iino
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Kazuya Odake
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Akihiro Sudo
- Department of Orthopaedic Surgery, Graduate School of Medicine, Mie University, Tsu, Japan
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Chang GR, Liu HY, Yang WC, Wang CM, Wu CF, Lin JW, Lin WL, Wang YC, Lin TC, Liao HJ, Hou PH, Chan CH, Lin CF. Clozapine Worsens Glucose Intolerance, Nonalcoholic Fatty Liver Disease, Kidney Damage, and Retinal Injury and Increases Renal Reactive Oxygen Species Production and Chromium Loss in Obese Mice. Int J Mol Sci 2021; 22:ijms22136680. [PMID: 34206460 PMCID: PMC8268139 DOI: 10.3390/ijms22136680] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/09/2021] [Accepted: 06/18/2021] [Indexed: 12/18/2022] Open
Abstract
Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozapine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine’s adverse metabolic effects—such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy—was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver damage, fatty liver scores, glucose homeostasis, renal impairment, and retinopathy in mice fed a high fat diet (HFD). We discovered that obese mice treated with clozapine gained more weight and had greater kidney, liver, and retroperitoneal and epididymal fat pad masses; higher daily food efficiency; higher serum or hepatic triglyceride, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels; and higher hepatic lipid regulation marker expression than did the HFD-fed control mice. Furthermore, the clozapine group mice exhibited insulin resistance, poorer insulin sensitivity, greater glucose intolerance, and less Akt phosphorylation; their GLUT4 expression was lower, they had renal damage, more reactive oxygen species, and IL-1 expression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased iNOS and NF-κB expression; a net negative chromium balance occurred because more chromium was excreted through urine, and this influenced chromium mobilization, which did not help overcome the hyperglycemia. Our clozapine group had considerably higher fatty liver scores, which was supported by the findings of lowered adiponectin protein levels and increased FASN protein, PNPLA3 protein, FABP4 mRNA, and SREBP1 mRNA levels. We conclude that clozapine can worsen nonalcoholic fatty liver disease, diabetes, and kidney and retinal injury. Therefore, long-term administration of clozapine warrants higher attention.
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Affiliation(s)
- Geng-Ruei Chang
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan; (G.-R.C.); (C.-M.W.); (C.-F.W.); (T.-C.L.); (H.-J.L.)
| | - Hsien-Yueh Liu
- Bachelor Degree Program in Animal Healthcare, Hungkuang University, 6 Section, 1018 Taiwan Boulevard, Shalu District, Taichung 433304, Taiwan; (H.-Y.L.); (J.-W.L.); (W.-L.L.)
| | - Wei-Cheng Yang
- School of Veterinary Medicine, National Taiwan University, 4 Section, 1 Roosevelt Road, Taipei 100046, Taiwan;
| | - Chao-Min Wang
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan; (G.-R.C.); (C.-M.W.); (C.-F.W.); (T.-C.L.); (H.-J.L.)
| | - Ching-Fen Wu
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan; (G.-R.C.); (C.-M.W.); (C.-F.W.); (T.-C.L.); (H.-J.L.)
| | - Jen-Wei Lin
- Bachelor Degree Program in Animal Healthcare, Hungkuang University, 6 Section, 1018 Taiwan Boulevard, Shalu District, Taichung 433304, Taiwan; (H.-Y.L.); (J.-W.L.); (W.-L.L.)
| | - Wei-Li Lin
- Bachelor Degree Program in Animal Healthcare, Hungkuang University, 6 Section, 1018 Taiwan Boulevard, Shalu District, Taichung 433304, Taiwan; (H.-Y.L.); (J.-W.L.); (W.-L.L.)
- General Education Center, Chaoyang University of Technology, 168 Jifeng Eastern Road, Taichung 413310, Taiwan
| | - Yu-Chen Wang
- Division of Cardiology, Asia University Hospital, 222 Fuxin Road, Wufeng District, Taichung 413505, Taiwan;
- Department of Medical Laboratory Science and Biotechnology, Asia University, 500 Lioufeng Road, Wufeng District, Taichung 413305, Taiwan
- Division of Cardiovascular Medicine, China Medical University Hospital, 2 Yude Road, North District, Taichung 404332, Taiwan
- College of Medicine, China Medical University, 91 Hsueh-Shih Road, North District, Taichung 404333, Taiwan
| | - Tzu-Chun Lin
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan; (G.-R.C.); (C.-M.W.); (C.-F.W.); (T.-C.L.); (H.-J.L.)
| | - Huei-Jyuan Liao
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan; (G.-R.C.); (C.-M.W.); (C.-F.W.); (T.-C.L.); (H.-J.L.)
| | - Po-Hsun Hou
- Department of Psychiatry, Taichung Veterans General Hospital, 4 Section, 1650 Taiwan Boulevard, Taichung 407219, Taiwan
- Faculty of Medicine, National Yang Ming Chiao Tung University, 2 Section, 155 Linong Street, Beitou District, Taipei 112304, Taiwan
- Correspondence: (P.-H.H.); (C.-H.C.); (C.-F.L.); Tel.: +886-4-23592525 (P.-H.H.); +886-975-617071 (C.-H.C.); +886-8-7703202 (C.-F.L.)
| | - Chee-Hong Chan
- Division of Nephrology, Chang Bing Show Chwan Memorial Hospital, 6 Lugong Road, Lukang Township, Changhua 505029, Taiwan
- Correspondence: (P.-H.H.); (C.-H.C.); (C.-F.L.); Tel.: +886-4-23592525 (P.-H.H.); +886-975-617071 (C.-H.C.); +886-8-7703202 (C.-F.L.)
| | - Chuen-Fu Lin
- Department of Veterinary Medicine, College of Veterinary Medicine, National Pingtung University of Science and Technology, 1 Shuefu Road, Neipu, Pingtung 912301, Taiwan
- Correspondence: (P.-H.H.); (C.-H.C.); (C.-F.L.); Tel.: +886-4-23592525 (P.-H.H.); +886-975-617071 (C.-H.C.); +886-8-7703202 (C.-F.L.)
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Barrientos C, Pérez A, Vázquez J. Ameliorative Effects of Oral Glucosamine on Insulin Resistance and Pancreatic Tissue Damage in Experimental Wistar rats on a High-fat Diet. Comp Med 2021; 71:215-221. [PMID: 34082859 DOI: 10.30802/aalas-cm-21-000009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hyperlipidemia due to a high-fat diet (HFD) is a risk factor for inducing insulin resistance (IR) and adverse effects on pancreatic β-cells in obesity and type 2 diabetes mellitus. This relationship may be due to activation of the hexosaminebiosynthesis pathway. Administration of exogenous glucosamine (GlcN) can increase the end product of this pathway (uridine-5'-diphosphate-N-acetyl-glucosamine), which can mediate IR and protein glycosylation. The objective of this study was to evaluate the effects of oral GlcN and HFD on IR and pancreatic histologic damage in a 22 wk study of 4 groups of male Wistar rats: control group with normal chow diet, HFD group (24%. g/g lard), GlcN group (500 mg/kg-1 per day of glucosamine hydrochloride in drinking water) and HFD plus oral GlcN. Metabolic variables related to IR that were measured included triglycerides (TG), free fatty acids (FFAs) and malondialdehyde (MDA). Histopathologic evaluation of the pancreas was also performed. The results showed IR in the HFD group, which had increased pancreatic nuclear pyknosis and vacuolization, with fatty infiltration and structural alteration of the islets of Langerhans. TG, FFAs and MDA were higher in serum and pancreatic tissue as compared with the control group. The GlcN group did not develop IR and had only mild nuclear pyknosis with no significant change in the pancreatic content of TG, FFAs and MDA. However, the combined administration of GlcN and HFD attenuated IR and improved TG, FFAs and MDA levels in serum and pancreatic tissue and the pancreatic histopathologic changes, with no significant differences as compared with the control group. These findings suggest that the oral GlcN at a dose of 500 mg/kg-1 is protective against IR and the pancreatic histologic damage caused by HFD.
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Affiliation(s)
- Cornelio Barrientos
- Department of Physiology, Higher School of Medicine, National Polytechnic Institute. Mexico City, Mexico;,
| | - Angélica Pérez
- Department of Physiology, Higher School of Medicine, National Polytechnic Institute. Mexico City, Mexico
| | - Jorge Vázquez
- Graduate Department. Higher School of Nursing and Obstetrics, National Polytechnic Institute, Mexico City, Mexico
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ANGPTL3 Variants Associate with Lower Levels of Irisin and C-Peptide in a Cohort of Arab Individuals. Genes (Basel) 2021; 12:genes12050755. [PMID: 34067751 PMCID: PMC8170900 DOI: 10.3390/genes12050755] [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: 04/10/2021] [Revised: 05/11/2021] [Accepted: 05/12/2021] [Indexed: 11/16/2022] Open
Abstract
ANGPTL3 is an important regulator of lipid metabolism. Its inhibition in people with hypercholesteremia reduces plasma lipid levels dramatically. Genome-wide association studies have associated ANGPTL3 variants with lipid traits. Irisin, an exercise-modulated protein, has been associated with lipid metabolism. Intracellular accumulation of lipids impairs insulin action and contributes to metabolic disorders. In this study, we evaluate the impact of ANGPTL3 variants on levels of irisin and markers associated with lipid metabolism and insulin resistance. ANGPTL3 rs1748197 and rs12130333 variants were genotyped in a cohort of 278 Arab individuals from Kuwait. Levels of irisin and other metabolic markers were measured by ELISA. Significance of association signals was assessed using Bonferroni-corrected p-values and empirical p-values. The study variants were significantly associated with low levels of c-peptide and irisin. Levels of c-peptide and irisin were mediated by interaction between carrier genotypes (GA + AA) at rs1748197 and measures of IL13 and TG, respectively. While levels of c-peptide and IL13 were directly correlated in individuals with the reference genotype, they were inversely correlated in individuals with the carrier genotype. Irisin correlated positively with TG and was strong in individuals with carrier genotypes. These observations illustrate ANGPTL3 as a potential link connecting lipid metabolism, insulin resistance and cardioprotection.
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Gulnaz A, Nadeem J, Han JH, Lew LC, Son JD, Park YH, Rather IA, Hor YY. Lactobacillus Sps in Reducing the Risk of Diabetes in High-Fat Diet-Induced Diabetic Mice by Modulating the Gut Microbiome and Inhibiting Key Digestive Enzymes Associated with Diabetes. BIOLOGY 2021; 10:biology10040348. [PMID: 33924088 PMCID: PMC8074288 DOI: 10.3390/biology10040348] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/08/2021] [Accepted: 04/17/2021] [Indexed: 12/31/2022]
Abstract
Simple Summary Type 2 diabetes (T2D) is increasingly spreading across the globe. The disease is linked to a disruption of gut microbiome. Probiotics are essential gut microbiota modulators proven to restore microbiota changes, thereby conferring health to its host. This study aimed to use probiotics (lactobacilli) and their metabolites as natural anti-diabetic therapy through the modulation of gut microbiota and inhibit diabetes-causing enzymes. Lactobacillus-treated high-fat diet mice showed lower blood glucose levels and body weight. Interestingly, our study also proved that the lactobacilli altered gut microbiota composition by suppressing opportunistic bacteria that are highly associated with metabolic diseases. Our findings substantiate the use of probiotics as natural anti-diabetic therapeutics. Abstract Obesity caused by a high-fat diet (HFD) affects gut microbiota linked to the risk of type-2 diabetes (T2D). This study evaluates live cells and ethanolic extract (SEL) of Lactobacillus sakei Probio65 and Lactobacillus plantarum Probio-093 as natural anti-diabetic compounds. In-vitro anti-diabetic effects were determined based on the inhibition of α-glucosidase and α-amylase enzymes. The SEL of Probio65 and Probio-093 significantly retarded α-glucosidase and α-amylase enzymes (p < 0.05). Live Probio65 and Probio-093 inhibited α-glucosidase and α-amylase, respectively (p < 0.05). In mice fed with a 45% kcal high-fat diet (HFD), the SEL and live cells of both strains reduced body weight significantly compared to HFD control (p < 0.05). Probio-093 also improved blood glucose level compared to control (p < 0.05). The gut microbiota modulatory effects of lactobacilli on HFD-induced diabetic mice were analyzed with qPCR method. The SEL and live cells of both strains reduced phyla Deferribacteres compared to HFD control (p < 0.05). The SEL and live cells of Probio-093 promoted more Actinobacteria (phyla), Bifidobacterium, and Prevotella (genus) compared to control (p < 0.05). Both strains exerted metabolic-modulatory effects, with strain Probio-093 showing more prominent alteration in gut microbiota, substantiating the role of probiotics in gut microbiome modulations and anti-diabetic effect. Both lactobacilli are potential candidates to lessen obesity-linked T2D.
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Affiliation(s)
- Aneela Gulnaz
- Department of Biotechnology, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk 38541, Korea; (A.G.); (J.N.); (J.-H.H.); (Y.-H.P.)
| | - Jawad Nadeem
- Department of Biotechnology, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk 38541, Korea; (A.G.); (J.N.); (J.-H.H.); (Y.-H.P.)
| | - Jong-Hun Han
- Department of Biotechnology, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk 38541, Korea; (A.G.); (J.N.); (J.-H.H.); (Y.-H.P.)
| | - Lee-Ching Lew
- Probionic Corp. Jeonbuk Institute for Food-Bioindustry, 111-18, Wonjangdong-gil, Deokjin-gu, Jeonju-si, Jeollabuk-do 38541, Korea;
| | - Jae-Dong Son
- Department of Veterinary Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju-si, Gyeongsangnam-do 52828, Korea;
| | - Yong-Ha Park
- Department of Biotechnology, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk 38541, Korea; (A.G.); (J.N.); (J.-H.H.); (Y.-H.P.)
- Probionic Corp. Jeonbuk Institute for Food-Bioindustry, 111-18, Wonjangdong-gil, Deokjin-gu, Jeonju-si, Jeollabuk-do 38541, Korea;
| | - Irfan A. Rather
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Correspondence: or (I.A.R.); (Y.-Y.H.)
| | - Yan-Yan Hor
- Department of Biotechnology, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk 38541, Korea; (A.G.); (J.N.); (J.-H.H.); (Y.-H.P.)
- Correspondence: or (I.A.R.); (Y.-Y.H.)
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Tomé-Carneiro J, Crespo MC, López de Las Hazas MC, Visioli F, Dávalos A. Olive oil consumption and its repercussions on lipid metabolism. Nutr Rev 2021; 78:952-968. [PMID: 32299100 DOI: 10.1093/nutrit/nuaa014] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Consumption of highly processed foods, such as those high in trans fats and free sugars, coupled with sedentarism and chronic stress increases the risk of obesity and cardiometabolic disorders, while adherence to a Mediterranean diet is inversely associated with the prevalence of such diseases. Olive oil is the main source of fat in the Mediterranean diet. Data accumulated thus far show consumption of extra virgin, (poly)phenol-rich olive oil to be associated with specific health benefits. Of note, recommendations for consumption based on health claims refer to the phenolic content of extra virgin olive oil as beneficial. However, even though foods rich in monounsaturated fatty acids, such as olive oil, are healthier than foods rich in saturated and trans fats, their inordinate use can lead to adverse effects on health. The aim of this review was to summarize the data on olive oil consumption worldwide and to critically examine the literature on the potential adverse effects of olive oil and its main components, particularly any effects on lipid metabolism. As demonstrated by substantial evidence, extra virgin olive oil is healthful and should be preferentially used within the context of a balanced diet, but excessive consumption may lead to adverse consequences.
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Affiliation(s)
- João Tomé-Carneiro
- Laboratory of Functional Foods, Madrid Institute for Advanced Studies (IMDEA)-Food, Campus of International Excellence UAM + CSIC, Madrid, Spain
| | - María Carmen Crespo
- Laboratory of Functional Foods, Madrid Institute for Advanced Studies (IMDEA)-Food, Campus of International Excellence UAM + CSIC, Madrid, Spain
| | - María Carmen López de Las Hazas
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, Campus of International Excellence UAM + CSIC, Madrid, Spain
| | - Francesco Visioli
- Laboratory of Functional Foods, Madrid Institute for Advanced Studies (IMDEA)-Food, Campus of International Excellence UAM + CSIC, Madrid, Spain.,Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Alberto Dávalos
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies (IMDEA)-Food, Campus of International Excellence UAM + CSIC, Madrid, Spain
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42
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Scapaticci S, D’Adamo E, Mohn A, Chiarelli F, Giannini C. Non-Alcoholic Fatty Liver Disease in Obese Youth With Insulin Resistance and Type 2 Diabetes. Front Endocrinol (Lausanne) 2021; 12:639548. [PMID: 33889132 PMCID: PMC8056131 DOI: 10.3389/fendo.2021.639548] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
Currently, Non-Alcoholic Fatty Liver Disease (NAFLD) is the most prevalent form of chronic liver disease in children and adolescents worldwide. Simultaneously to the epidemic spreading of childhood obesity, the rate of affected young has dramatically increased in the last decades with an estimated prevalence of NAFLD of 3%-10% in pediatric subjects in the world. The continuous improvement in NAFLD knowledge has significantly defined several risk factors associated to the natural history of this complex liver alteration. Among them, Insulin Resistance (IR) is certainly one of the main features. As well, not surprisingly, abnormal glucose tolerance (prediabetes and diabetes) is highly prevalent among children/adolescents with biopsy-proven NAFLD. In addition, other factors such as genetic, ethnicity, gender, age, puberty and lifestyle might affect the development and progression of hepatic alterations. However, available data are still lacking to confirm whether IR is a risk factor or a consequence of hepatic steatosis. There is also evidence that NAFLD is the hepatic manifestation of Metabolic Syndrome (MetS). In fact, NAFLD often coexist with central obesity, impaired glucose tolerance, dyslipidemia, and hypertension, which represent the main features of MetS. In this Review, main aspects of the natural history and risk factors of the disease are summarized in children and adolescents. In addition, the most relevant scientific evidence about the association between NAFLD and metabolic dysregulation, focusing on clinical, pathogenetic, and histological implication will be provided with some focuses on the main treatment options.
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Affiliation(s)
| | | | | | | | - Cosimo Giannini
- Department of Pediatrics, University of Chieti, Chieti, Italy
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43
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Yeap BB, Dedic D, Budgeon CA, Murray K, Knuiman MW, Hunter M, Zhu K, Cooke BR, Lim EM, Mulrennan S, Walsh JP, Green DJ. U-shaped association of vigorous physical activity with risk of metabolic syndrome in men with low lean mass, and no interaction of physical activity and serum 25-hydroxyvitamin D with metabolic syndrome risk. Intern Med J 2021; 50:460-469. [PMID: 31161619 DOI: 10.1111/imj.14379] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 05/16/2019] [Accepted: 05/29/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND There is uncertainty over how lean mass, physical activity (PA) and 25-hydroxyvitamin D (25-OH-D) status interact on metabolic syndrome (MetS) risk in adults. AIMS To test the hypothesis that these factors additively influence MetS risk. METHODS Four thousand eight hundred and fifty-eight adults (54.6% female) mean ± SD age 58.0 ± 5.8 years, body mass index 28.1 ± 4.8 kg/m2 , resident in Busselton, Western Australia. PA assessed by questionnaire (all/total and vigorous), lean mass using dual energy X-ray absorptiometry (% total body mass), serum 25-OH-D via immunoassay, analysed using multivariable logistic regression. RESULTS In men, lower total PA was associated with MetS (no vs >24 h/week odds ratio (OR) = 3.1; ≤8 vs >24 h/week OR = 1.8, both P < 0.001), as was lower lean mass (low vs high OR = 20.4; medium vs high OR = 7.4, both P < 0.001). Men with low lean mass exhibited a U-shaped relationship of vigorous PA with MetS risk (covariate-adjusted: 0 vs 4-8 h/week OR = 2.1, P = 0.037; >12 vs 4-8 h/week OR = 4.3, P = 0.002; interaction P = 0.039). In women, low PA (0 vs >24 h/week OR = 2.1, P = 0.003) and lean mass (low vs high OR = 13.1; medium vs high OR = 7.2, both P < 0.001) were associated with MetS risk. Low 25-OH-D status was associated with MetS in men (low vs high OR = 4.1; medium vs high OR = 2.3, both P < 0.001) and women (OR = 3.5 and 2.1 respectively, both P < 0.001) with no PA interaction. CONCLUSIONS Men and women with high lean mass have low risk of MetS regardless of PA. Low lean mass identifies men who may benefit most from increasing PA, with an optimal level associated with lowest risk. 25-OH-D and PA do not interact on MetS risk.
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Affiliation(s)
- Bu B Yeap
- Medical School, University of Western Australia, Perth, Western Australia, Australia.,Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia, Australia
| | - Deila Dedic
- Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia, Australia
| | - Charley A Budgeon
- School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia
| | - Kevin Murray
- School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia
| | - Matthew W Knuiman
- School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia
| | - Michael Hunter
- School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia.,Busselton Population Medical Research Institute, Busselton, Western Australia, Australia
| | - Kun Zhu
- Medical School, University of Western Australia, Perth, Western Australia, Australia.,Department of Endocrinology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - Brian R Cooke
- Department of Clinical Biochemistry, PathWest Laboratory Medicine, Fiona Stanley Hospital and Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - Ee M Lim
- Department of Endocrinology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.,Department of Clinical Biochemistry, PathWest Laboratory Medicine, Fiona Stanley Hospital and Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - Siobhain Mulrennan
- Medical School, University of Western Australia, Perth, Western Australia, Australia.,Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - John P Walsh
- Medical School, University of Western Australia, Perth, Western Australia, Australia.,Department of Endocrinology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - Daniel J Green
- School of Exercise and Sport Science, University of Western Australia, Perth, Western Australia, Australia
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44
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Čolak E, Pap D. The role of oxidative stress in the development of obesity and obesity-related metabolic disorders. J Med Biochem 2021; 40:1-9. [PMID: 33584134 PMCID: PMC7857849 DOI: 10.5937/jomb0-24652] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 01/30/2020] [Indexed: 12/21/2022] Open
Abstract
Obesity is a serious medical condition, defined as excessive accumulation of fat. Abdominal fat is recognized as the major risk for obesity related diseases such as: hypertension, dyslipidemia, type 2 diabetes mellitus, coronary heart disease, stroke, non-alcoholic fatty liver disease etc. Fat accumulation is also related to pro-oxidant and pro-inflammatory states. Recently published articles suggest that oxidative stress may be a link between obesity and related complications. Adiposity leads to increased oxidative stress via several multiple biochemical processes such as superoxide generation through the action of NADPH oxidase, glyceraldehyde auto-oxidation, oxidative phosphorylation, protein kinase C (PKC) activation, and polyol and hexosamine pathways. On the other hand, oxidative stress plays a causative role in the development of obesity, by stimulating the deposition of adipose tissue, including preadipocyte proliferation, adipocyte differentiation and growth. Exercise-induced weight loss can improve the redox state by modulating both oxidative stress and antioxidant promoters, which reduce endothelial dysfunction and inflammation.
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Affiliation(s)
- Emina Čolak
- Clinical Center of Serbia, Institute of Medical Biochemistry, Department for Scientific Research and Education, Belgrade
| | - Dragana Pap
- Students Health Protection Institute, Department of Laboratory Diagnostics, Novi Sad
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45
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Han JC, Weiss R. Obesity, Metabolic Syndrome and Disorders of Energy Balance. SPERLING PEDIATRIC ENDOCRINOLOGY 2021:939-1003. [DOI: 10.1016/b978-0-323-62520-3.00024-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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46
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Zhang L, Zhang Z, Wang B, Yuan Y, Sun L, Gao H, Fu L. Relative Children's Lipid Accumulation Product Is a Novel Indicator for Metabolic Syndrome. Front Endocrinol (Lausanne) 2021; 12:645825. [PMID: 34093432 PMCID: PMC8173219 DOI: 10.3389/fendo.2021.645825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 02/22/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND The children's lipid accumulation product (CLAP) is associated with MS in Chinese children and adolescents. The aim of this study was to develop a more effective indicator, the relative children's lipid accumulation product (RCLAP) was evaluated for correlation with MS and the density of lipid accumulation. METHODS A stratified cluster sampling method was used to recruit 683 students aged 8-15 years in this study. The presence of MS was defined according to the NCEP-ATP III criteria. The participants' guardians signed informed consent before the medical examination. This study was approved by the Medical Ethics Committee of the Bengbu Medical College [(2015) No.003] and was conducted in accordance with the Declaration of Helsinki. RESULTS The overall prevalence of MS was 4.8% (male 6.6%, female 2.8%). After adjusting for sedentary activity time, relative children's lipid accumulation product per height (RCLAP-H) and relative children's lipid accumulation product per sitting height (RCLAP-SH) significantly increased the risk of MS in girls [OR (95% CI): 96.13 (11.11-831.97) and 96.13 (11.11-831.97), respectively]. After adjusting for ages and moderate-to-vigorous physical activity time, RCLAP-H, and RCLAP-SH significantly increased the risk of MS in boys [OR (95% CI): 171.75 (33.60-878.00) and 133.18 (27.65-641.39), respectively]. The AUCs of RCLAP-H and RCLAP-SH for predicting MS were 0.950, 0.948 in girls, and 0.952, 0.952 in boys, which were higher than BMI, WHtR, Tg/HDL-C, CLAP, and CLAP combining height, sitting height. CONCLUSIONS The RCLAP-H and RCLAP-SH were more effective indicators for predicting MS than BMI, WHtR, Tg/HDL-C, and CLAP in children and adolescents.
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Affiliation(s)
| | | | | | | | | | | | - Lianguo Fu
- *Correspondence: Lianguo Fu, ; Huaiquan Gao,
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47
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Winters SJ, Scoggins CR, Appiah D, Ghooray DT. The hepatic lipidome and HNF4α and SHBG expression in human liver. Endocr Connect 2020; 9:1009-1018. [PMID: 33064664 PMCID: PMC7576643 DOI: 10.1530/ec-20-0401] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 09/16/2020] [Indexed: 01/14/2023]
Abstract
Low plasma levels of sex hormone-binding globulin (SHBG) are a marker for obesity, insulin resistance, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. The transcription factor HNF4α is a major determinant of hepatic SHBG expression and thereby serum SHBG levels, and mediates in part the association of low SHBG with hyperinsulinemia and hepatic steatosis. We analyzed the lipidome in human liver specimens from a cohort of patients who underwent hepatic resection as a treatment for cancer, providing insight into hepatic lipids in those without extreme obesity or the clinical diagnosis of NAFLD or non-alcoholic steatohepatitis. Both steatosis and high HOMA-IR were associated with higher levels of saturated and unsaturated FA, other than arachidonic, with the most dramatic rise in 18:1 oleate, consistent with increased stearoyl-CoA desaturase activity. Individuals with low HOMA-IR had low levels of total hepatic fatty acids, while both low and high fatty acid levels characterized the high HOMA-IR group. Both insulin resistance and high levels of hepatic fat were associated with low expression levels of HNF4α and thereby SHBG, but the expression of these genes was also low in the absence of these determinants, implying additional regulatory mechanisms that remain to be determined. The relationship of all FA studied to HNFα and SHBG mRNAs was inverse, and similar to that for total triglyceride concentrations, irrespective of chain length and saturation vs unsaturation.
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Affiliation(s)
- Stephen J Winters
- Division of Endocrinology, Metabolism and Diabetes, University of Louisville, Louisville, Kentucky, USA
- Correspondence should be addressed to S J Winters:
| | - Charles R Scoggins
- Division of Surgical Oncology, University of Louisville, Louisville, Kentucky, USA
| | - Duke Appiah
- Department of Public Health, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Dushan T Ghooray
- Division of Endocrinology, Metabolism and Diabetes, University of Louisville, Louisville, Kentucky, USA
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48
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Huang DQ, Yeo YH, Tan E, Takahashi H, Yasuda S, Saruwatari J, Tanaka K, Oniki K, Kam LY, Muthiah MD, Hyogo H, Ono M, Barnett SD, Li J, Zou B, Fung J, Lee TY, Wong VWS, Yuen MF, Dan YY, Lim SG, Cheung R, Toyoda H, Eguchi Y, Nguyen MH. ALT Levels for Asians With Metabolic Diseases: A Meta-analysis of 86 Studies With Individual Patient Data Validation. Hepatol Commun 2020; 4:1624-1636. [PMID: 33163833 PMCID: PMC7603525 DOI: 10.1002/hep4.1593] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 07/06/2020] [Accepted: 07/27/2020] [Indexed: 12/14/2022] Open
Abstract
The current alanine aminotransferase (ALT) upper limit of normal was defined using selected healthy Caucasian blood donors. Given the global rise in obesity and different body habitus in Asians, we aimed to perform a systematic review and meta-analysis combined with bootstrap modeling and individual patient data validation to estimate the ALT upper threshold for Asians, including the overweight and diabetics. We included studies from PubMed, Embase, and Cochrane database searches that identified individuals without known liver diseases (i.e., viral hepatitis, alcohol, and ultrasound-detected nonalcoholic fatty liver disease). The mean ALT (U/L) was estimated using a random-effects mixed model and upper threshold (95th-percentile value, U/L) via a bootstrap model with 10,000 resamples. We screened 4,995 studies and identified 86 studies that reported ALT values for 526,641 individuals without excessive alcohol intake or known liver diseases, yielding a mean ALT of 19 and ALT upper threshold of 32. The ALT upper threshold was 37 in males versus 31 in females, 39 in overweight versus 28 in normal-weight individuals, and 36 for diabetics versus 33 for nondiabetics. We validated our study level data with individual patient level data in 6,058 individuals from five study centers in Japan. Consistent with our study-level data, we found that the ALT upper threshold in our individual patient data analysis was indeed higher in overweight versus normal-weight individuals (39 vs. 32) and in diabetics versus nondiabetics (42 vs. 33). Conclusion: We provide validated reference ranges for ALT upper threshold derived from Asians without known liver disease, including individuals with ultrasound-detected nonalcoholic fatty liver disease who are normal weight, overweight, nondiabetic, and diabetic, to inform practice.
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Affiliation(s)
- Daniel Q Huang
- Division of Gastroenterology and Hepatology Department of Medicine National University Hospital Singapore Singapore.,Department of Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
| | - Yee Hui Yeo
- Division of Gastroenterology and Hepatology Stanford University Medical Center Palo Alto CA USA
| | - Eunice Tan
- Division of Gastroenterology and Hepatology Department of Medicine National University Hospital Singapore Singapore
| | | | - Satoshi Yasuda
- Department of Gastroenterology Ogaki Municipal Hospital Ogaki Japan
| | - Junji Saruwatari
- Division of Pharmacology and Therapeutics Graduate School of Pharmaceutical Sciences Kumamoto University Kumamoto Japan
| | | | - Kentaro Oniki
- Division of Pharmacology and Therapeutics Graduate School of Pharmaceutical Sciences Kumamoto University Kumamoto Japan
| | - Leslie Y Kam
- Division of Gastroenterology and Hepatology Stanford University Medical Center Palo Alto CA USA
| | - Mark D Muthiah
- Division of Gastroenterology and Hepatology Department of Medicine National University Hospital Singapore Singapore.,Department of Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
| | - Hideyuki Hyogo
- Department of Gastroenterology and Hepatology JA Hiroshima General Hospital Hiroshima Japan
| | - Masafumi Ono
- Department of Internal Medicine Tokyo Women's Medical University Medical Center East Tokyo Japan
| | - Scott D Barnett
- Division of Gastroenterology and Hepatology Stanford University Medical Center Palo Alto CA USA
| | - Jie Li
- Department of Infectious Disease Shandong Provincial Hospital Affiliated to Shandong University Shandong China
| | - Biyao Zou
- Division of Gastroenterology and Hepatology Stanford University Medical Center Palo Alto CA USA
| | - James Fung
- Department of Medicine Queen Mary Hospital The University of Hong Kong Hong Kong Hong Kong
| | - Teng-Yu Lee
- Division of Gastroenterology Department of Internal Medicine Taichung Veterans General Hospital Taichung Taiwan.,Department of Medicine Chung Shan Medical University Taichung Taiwan
| | - Vincent Wai-Sun Wong
- Institute of Digestive Disease Faculty of Medicine Chinese University of Hong Kong Hong Kong Hong Kong
| | - Man-Fung Yuen
- Department of Medicine Queen Mary Hospital The University of Hong Kong Hong Kong Hong Kong
| | - Yock Young Dan
- Division of Gastroenterology and Hepatology Department of Medicine National University Hospital Singapore Singapore.,Department of Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
| | - Seng Gee Lim
- Division of Gastroenterology and Hepatology Department of Medicine National University Hospital Singapore Singapore.,Department of Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
| | - Ramsey Cheung
- Division of Gastroenterology and Hepatology Stanford University Medical Center Palo Alto CA USA
| | - Hidenori Toyoda
- Department of Gastroenterology Ogaki Municipal Hospital Ogaki Japan
| | | | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology Stanford University Medical Center Palo Alto CA USA
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49
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Park PJ, Kim ST. Caveolae-Associated Protein 3 (Cavin-3) Influences Adipogenesis via TACE-Mediated Pref-1 Shedding. Int J Mol Sci 2020; 21:ijms21145000. [PMID: 32679831 PMCID: PMC7404391 DOI: 10.3390/ijms21145000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 07/06/2020] [Accepted: 07/13/2020] [Indexed: 12/16/2022] Open
Abstract
Abnormal adipogenesis regulation is accompanied by a variety of metabolic dysfunctions and disorders. Caveolae play an important role in the regulation of fat production, modulated by caveolae-associated proteins (Cavin-1 to 4). Here, we investigated the role of Cavin-3 in lipogenesis and adipocyte differentiation, as the regulatory functions and roles of Cavin-3 in adipocytes are unknown. A Cavin-3 knockdown/overexpression stable cell line was established, and adipogenesis-related gene and protein expression changes were investigated by real-time quantitative PCR and Western blot analysis, respectively. Additionally, confocal immune-fluorescence microscopy was used to verify the intracellular position of the relevant factors. The results showed that Cavin-3 mRNA and protein expression were elevated, along with physiological factors such as lipid droplet formation, during adipogenesis. Cavin-3 silencing resulted in retarded adipocyte differentiation, and its overexpression accelerated this process. Furthermore, Cavin-3 knockdown resulted in decreased expression of adipogenesis-related genes, such as PPAR-γ, FAS, aP2, and Adipoq, whereas preadipocyte factor-1 (Pref-1) was markedly increased during adipocyte maturation. Overall, Cavin-3 influences caveolar stability and modulates the tumor necrosis factor-alpha-converting enzyme (TACE)-mediated Pref-1 shedding process in both mouse and human adipocytes. The Cavin-3-dependent shedding mechanism appears to be an important process in adipocyte maturation, providing a potential therapeutic target for obesity-related disorders.
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Affiliation(s)
- Phil June Park
- Bioscience Laboratory, AMOREPACIFIC R&D Center, 1920 Yonggu-daero, Giheung-gu, Yongin-si, Gyeonggi-do 17074, Korea
- Correspondence: (P.J.P.); (S.T.K.); Tel.: +82-31-280-5639 (P.J.P.); +82-55-320-4038 (S.T.K.)
| | - Sung Tae Kim
- Department of Pharmaceutical Engineering, Inje University, 197 Inje-ro, Gimhae-si, Gyeongsangnam-do 50834, Korea
- Correspondence: (P.J.P.); (S.T.K.); Tel.: +82-31-280-5639 (P.J.P.); +82-55-320-4038 (S.T.K.)
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50
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Michael OS, Dibia CL, Adeyanju OA, Olaniyi KS, Areola ED, Olatunji LA. Estrogen-progestin oral contraceptive and nicotine exposure synergistically confers cardio-renoprotection in female Wistar rats. Biomed Pharmacother 2020; 129:110387. [PMID: 32540646 DOI: 10.1016/j.biopha.2020.110387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 06/04/2020] [Accepted: 06/07/2020] [Indexed: 10/24/2022] Open
Abstract
Approximately fifty percent of premenopausal women who smoke cigarettes or on nicotine replacement therapy are also on hormonal contraceptives, especially oral estrogen-progestin. Oral estrogen-progestin therapy has been reported to promote insulin resistance (IR) which causes lipid influx into non-adipose tissue and impairs Na+/K+ -ATPase activity, especially in the heart and kidney. However, the effects of nicotine on excess lipid and altered Na+/K+ -ATPase activity associated with the use of estrogen-progestin therapy have not been fully elucidated. This study therefore aimed at investigating the effect of nicotine on cardiac and renal lipid influx and Na+/K+ -ATPase activity during estrogen-progestin therapy. Twenty-four female Wistar rats grouped into 4 (n = 6/group) received (p.o.) vehicle, nicotine (1.0 mg/kg) with or without estrogen-progestin steroids (1.0 μg ethinyl estradiol and 5.0 μg levonorgestrel) and estrogen-progestin only daily for 6 weeks. Data showed that estrogen-progestin treatment or nicotine exposure caused IR, hyperinsulinemia, increased cardiac and renal uric acid, malondialdehyde, triglyceride, glycogen synthase kinase-3, plasminogen activator inhibitor-1, reduced bilirubin and circulating estradiol. Estrogen-progestin treatment led to decreased cardiac Na+/K+-ATPase activity while nicotine did not alter Na+/K+-ATPase activity but increased plasma and tissue cotinine. Renal Na+/K+-ATPase activity was not altered by the treatments. However, all these alterations were reversed following combined administration of oral estrogen-progestin therapy and nicotine. The present study therefore demonstrates that oral estrogen-progestin therapy and nicotine exposure synergistically prevents IR-linked cardio-renotoxicity with corresponding improvement in cardiac and renal lipid accumulation, oxidative stress, inflammation and Na+/K+-ATPase activity.
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Affiliation(s)
- O S Michael
- Cardiometabolic Research Unit, Department of Physiology, College of Health Sciences, Bowen University, Iwo, Nigeria; HOPE Cardiometabolic Research Team, Department of Physiology, University of Ilorin, Ilorin, Nigeria.
| | - C L Dibia
- HOPE Cardiometabolic Research Team, Department of Physiology, University of Ilorin, Ilorin, Nigeria; Department of Physiology, Nnamdi Azikiwe University, Awka, Anambra State, Nigeria
| | - O A Adeyanju
- HOPE Cardiometabolic Research Team, Department of Physiology, University of Ilorin, Ilorin, Nigeria; Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, 360101, Nigeria
| | - K S Olaniyi
- HOPE Cardiometabolic Research Team, Department of Physiology, University of Ilorin, Ilorin, Nigeria; Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, 360101, Nigeria
| | - E D Areola
- HOPE Cardiometabolic Research Team, Department of Physiology, University of Ilorin, Ilorin, Nigeria
| | - L A Olatunji
- HOPE Cardiometabolic Research Team, Department of Physiology, University of Ilorin, Ilorin, Nigeria
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