|
1
|
Chen LJ, Herder C, Xie R, Brenner H, Schöttker B. Comparison of the metabolic profiles and their cardiovascular event risks of metformin users versus insulin users. A cohort study of people with type 2 diabetes from the UK Biobank. Diabetes Res Clin Pract 2025; 222:112108. [PMID: 40122179 DOI: 10.1016/j.diabres.2025.112108] [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: 01/09/2025] [Revised: 03/12/2025] [Accepted: 03/15/2025] [Indexed: 03/25/2025]
Abstract
AIM The aims of this study were to compare the metabolic profiles of type 2 diabetes mellitus patients with metformin and insulin monotherapy, to assess the associations of metabolites with major adverse cardiovascular events (MACE) distinctly for metformin-only and insulin-only users, and to test for effect modification by the glucose-lowering treatment. METHODS We included 3,058 metformin-only and 558 insulin-only users from the UK Biobank. Mean concentrations of 249 metabolites of metformin and insulin users were compared with Cohen's d, their associations with MACE were assessed with Cox regression and interaction terms were tested. RESULTS Mean VLDL size, HDL size, and concentrations of large and very large HDL molecules differed between insulin-only and metformin-only users. Overall, 75 metabolomic biomarkers were significantly associated with MACE in insulin-only users and 57 in metformin-only users. Significant interaction terms were observed between treatment group and albumin (protective in metformin users only) and 86 lipids/fatty acids, which were all statistically significantly associated with MACE among insulin users only. CONCLUSION Metformin and insulin users have different metabolic profiles and a consistent pattern emerged that the metabolic profile of metformin users is favorable compared to the one of insulin users due to a lower associated MACE risk.
Collapse
Affiliation(s)
- Li-Ju Chen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christian Herder
- Institute for Clinical Diabetology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Ruijie Xie
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ben Schöttker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| |
Collapse
|
|
2
|
Yuenyong I, Potue P, Maneesai P, Khamseekaew J, Manimmanakorn A, Iampanichakul M, Pakdeechote P. Tangeretin Unravels Metabolic Dysfunction-Associated Fatty Liver Disease in Rats by Enhancing the IRS/Akt Pathway. Life (Basel) 2025; 15:491. [PMID: 40141836 PMCID: PMC11944169 DOI: 10.3390/life15030491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/10/2025] [Accepted: 03/17/2025] [Indexed: 03/28/2025] Open
Abstract
Excessive high-fat diet (HFD) intake can precipitate metabolic dysfunction-associated fatty liver disease (MAFLD). Tangeretin is a citrus flavonoid possessing many biological properties. We examined the impact of tangeretin on MAFLD and its underlying mechanism. Rats were given HFD plus 15% fructose solution for four months to produce metabolic syndrome. Metabolic syndrome rats were administered 100 mg/kg of metformin or 25 mg/kg of tangeretin for the last four weeks. HFD-induced increased body weight, liver weight, adipose tissue weight, fasting blood glucose, serum insulin, total triglyceride, total cholesterol, and free fatty acids and reduced adiponectin and high-density lipoprotein cholesterol levels in metabolic syndrome, which were alleviated by tangeretin (p < 0.05). Tangeretin stabilized alanine transaminase activity, liver catalase, and inflammatory and oxidative stress markers in HFD rats compared to untreated HFD rats (p < 0.05). Tangeretin reduced hepatic steatosis induced by HFD. Downregulation of hepatic insulin receptor substrate-1 (IRS-1) and protein kinase B (Akt) protein expression in metabolic syndrome rats was recovered by tangeretin (p < 0.05). Metformin, an antihyperglycemic drug, produced comparable effects to tangeretin. In conclusion, tangeretin attenuates metabolic disorders and fatty liver induced by HFD in rats. The underlying mechanisms involve reducing oxidative stress, and inflammation and enhancing insulin sensitivity.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Poungrat Pakdeechote
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (I.Y.); (P.P.); (P.M.); (J.K.); (A.M.); (M.I.)
| |
Collapse
|
|
3
|
Lawler JM, Kamal KY, Botchlett RE, Woo SL, Li H, Hord JM, Fluckey JD, Wu C. Metformin ablates high fat diet-induced skeletal muscle hypertrophy and elevation of sarcolemmal GLUT4 when feeding is initiated in young adult male mice. Connect Tissue Res 2025; 66:121-135. [PMID: 40052722 DOI: 10.1080/03008207.2025.2471853] [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: 06/26/2024] [Accepted: 02/20/2025] [Indexed: 03/25/2025]
Abstract
A high-fat diet (HFD) and metabolic disease can impair insulin signaling in skeletal muscle, including a reduction in IRS-1 and GLUT-4 at the cell membrane. Other sarcolemmal proteins (e.g. caveolin-3, nNOS) within the dystrophin-glycoprotein complex (DGC) are partially lost with Type II diabetes. Thus, we hypothesized that a HFD would cause a significant loss of sarcolemmal DGC proteins and GLUT4, and the anti-diabetic drug metformin would mitigate the disruption of the DGC and preserve sarcolemmal GLUT4 on the soleus muscle. Eight-week-old mice were fed a high-fat diet for 12 weeks. After 8 weeks, one-half of the HFD mice received metformin for the remaining 4 weeks. HFD caused a marked increase in soleus muscle mass and fiber cross-sectional area and elevated sarcolemmal GLUT4, even though systemic insulin resistance was greater. HFD-induced muscle hypertrophy and elevated membrane GLUT4 were unexpectedly attenuated by metformin. In addition, IRS-1 positive staining was not reduced by HFD but rather enhanced in the metformin mice fed a high-fat diet. Sarcolemmal staining of dystrophin and caveolin-3 was reduced by HFD but not in the metformin group, while nNOS intensity was unaffected by HFD and metformin. These findings suggest that skeletal muscles in young adult mice can compensate for a high-fat diet and insulin resistance, with a minor disruption of the DGC, by maintaining cell membrane nNOS and IRS-1 and elevating GLUT4. We postulate that a window of compensatory GLUT4 and nNOS signaling allows calorically dense food to enhance skeletal muscle fiber size when introduced in adolescence.
Collapse
Affiliation(s)
- John M Lawler
- Redox Biology & Cell Signaling Laboratory, Kinesiology and Sport Management Department, Texas A&M University, College Station, TX, USA
- Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Khaled Y Kamal
- Redox Biology & Cell Signaling Laboratory, Kinesiology and Sport Management Department, Texas A&M University, College Station, TX, USA
- Department of Kinesiology, Iowa State University, Ames, IA, USA
| | - Rachel E Botchlett
- Redox Biology & Cell Signaling Laboratory, Kinesiology and Sport Management Department, Texas A&M University, College Station, TX, USA
| | - Shih Lung Woo
- Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Honggui Li
- Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Jeff M Hord
- Redox Biology & Cell Signaling Laboratory, Kinesiology and Sport Management Department, Texas A&M University, College Station, TX, USA
- Department of Molecular Physiology and Biophysics, Carver School of Medicine, University of Iowa, Iowa City, IA, USA
| | - James D Fluckey
- Muscle Biology Laboratory, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA
| | - Chaodong Wu
- Department of Nutrition, Texas A&M University, College Station, TX, USA
| |
Collapse
|
|
4
|
Imierska M, Zabielski P, Roszczyc-Owsiejczuk K, Pogodzińska K, Błachnio-Zabielska A. Impact of reduced hepatic ceramide levels in high-fat diet mice on glucose metabolism. J Nutr Biochem 2025; 135:109785. [PMID: 39427846 DOI: 10.1016/j.jnutbio.2024.109785] [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: 01/22/2024] [Revised: 09/27/2024] [Accepted: 10/15/2024] [Indexed: 10/22/2024]
Abstract
Dysregulation of insulin action in hepatocytes, common in obesity, significantly contributes to insulin resistance, type 2 diabetes, and metabolic syndrome. Previous research highlights ceramides' role in these conditions. This study explores the impact of ceramides by silencing the serine palmitoyltransferase (Sptlc2) gene, crucial for the initial ceramide biosynthesis, using hydrodynamic gene delivery. Male C57BL/6 mice were randomly divided into three groups: one on a low-fat diet (LFD) receiving scrambled shRNA plasmids, another on a high-fat diet (HFD) with scrambled shRNA plasmids, and a third on HFD with a plasmid targeting Sptlc2. Analyses included RT-PCR for gene expression, western blot for protein levels, and UHPLC/MS/MS for lipid profiling. Glucose metabolism was evaluated via oral glucose tolerance tests, homeostatic model assessment of insulin resistance, and glucose-6-phosphate analysis. Results showed that HFD induces insulin resistance by inhibiting insulin signaling and increasing active lipid levels in hepatocytes. Sptlc2 silencing reduced ceramide accumulation, improving insulin signaling and glucose metabolism. Notably, ceramide synthesis inhibition did not significantly affect other lipid levels, highlighting ceramide's critical role in hepatic insulin resistance.
Collapse
Affiliation(s)
- Monika Imierska
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, Bialystok, Poland
| | - Piotr Zabielski
- Department of Medical Biology, Medical University of Bialystok, Bialystok, Poland
| | - Kamila Roszczyc-Owsiejczuk
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, Bialystok, Poland
| | - Karolina Pogodzińska
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, Bialystok, Poland
| | - Agnieszka Błachnio-Zabielska
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, Bialystok, Poland.
| |
Collapse
|
|
5
|
Roszczyc-Owsiejczuk K, Zabielski P, Imierska M, Pogodzińska K, Sadowska P, Błachnio-Zabielska A. Downregulation of CerS4 Instead of CerS2 in Liver Effectively Alleviates Hepatic Insulin Resistance in HFD Male Mice. Endocrinology 2024; 165:bqae118. [PMID: 39233348 DOI: 10.1210/endocr/bqae118] [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: 01/17/2024] [Revised: 04/27/2024] [Accepted: 09/04/2024] [Indexed: 09/06/2024]
Abstract
OBJECTIVE Consumption of a high-fat diet (HFD) induces insulin resistance (IRes), significantly affecting the maintenance of normal glucose homeostasis. Nevertheless, despite decades of extensive research, the mechanisms and pathogenesis of IRes remain incomplete. Recent studies have primarily explored lipid intermediates such as diacylglycerol (DAG), given a limited knowledge about the role of ceramide (Cer), which is a potential mediator of the IRes in the liver. METHODS In order to investigate the role of Cer produced by CerS2 and CerS4 for the purpose of inducing the hepatic IRes, we utilized a unique in vivo model employing shRNA-mediated hydrodynamic gene delivery in the liver of HFD-fed C57BL/6J mice. RESULTS Downregulation of CerS4 instead of CerS2 reduced specific liver Cers, notably C18:0-Cer and C24:0-Cer, as well as acylcarnitine levels. It concurrently promoted glycogen accumulation, leading to enhanced insulin sensitivity and glucose homeostasis. CONCLUSION Those findings demonstrate that CerS4 downregulating lowers fasting blood glucose levels and mitigates the HFD-induced hepatic IRes. It suggests that inhibiting the CerS4-mediated C18:0-Cer synthesis holds a promise to effectively address insulin resistance in obesity.
Collapse
Affiliation(s)
- Kamila Roszczyc-Owsiejczuk
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, 15-222 Bialystok, Poland
| | - Piotr Zabielski
- Department of Medical Biology, Medical University of Bialystok, 15-222 Bialystok, Poland
| | - Monika Imierska
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, 15-222 Bialystok, Poland
| | - Karolina Pogodzińska
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, 15-222 Bialystok, Poland
| | - Patrycja Sadowska
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, 15-222 Bialystok, Poland
| | - Agnieszka Błachnio-Zabielska
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, 15-222 Bialystok, Poland
| |
Collapse
|
|
6
|
Ramos-Molina B, Rossell J, Pérez-Montes de Oca A, Pardina E, Genua I, Rojo-López MI, Julián MT, Alonso N, Julve J, Mauricio D. Therapeutic implications for sphingolipid metabolism in metabolic dysfunction-associated steatohepatitis. Front Endocrinol (Lausanne) 2024; 15:1400961. [PMID: 38962680 PMCID: PMC11220194 DOI: 10.3389/fendo.2024.1400961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 06/03/2024] [Indexed: 07/05/2024] Open
Abstract
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), a leading cause of chronic liver disease, has increased worldwide along with the epidemics of obesity and related dysmetabolic conditions characterized by impaired glucose metabolism and insulin signaling, such as type 2 diabetes mellitus (T2D). MASLD can be defined as an excessive accumulation of lipid droplets in hepatocytes that occurs when the hepatic lipid metabolism is totally surpassed. This metabolic lipid inflexibility constitutes a central node in the pathogenesis of MASLD and is frequently linked to the overproduction of lipotoxic species, increased cellular stress, and mitochondrial dysfunction. A compelling body of evidence suggests that the accumulation of lipid species derived from sphingolipid metabolism, such as ceramides, contributes significantly to the structural and functional tissue damage observed in more severe grades of MASLD by triggering inflammatory and fibrogenic mechanisms. In this context, MASLD can further progress to metabolic dysfunction-associated steatohepatitis (MASH), which represents the advanced form of MASLD, and hepatic fibrosis. In this review, we discuss the role of sphingolipid species as drivers of MASH and the mechanisms involved in the disease. In addition, given the absence of approved therapies and the limited options for treating MASH, we discuss the feasibility of therapeutic strategies to protect against MASH and other severe manifestations by modulating sphingolipid metabolism.
Collapse
Affiliation(s)
- Bruno Ramos-Molina
- Group of Obesity, Diabetes & Metabolism, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain
| | - Joana Rossell
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | | | - Eva Pardina
- Department de Biochemistry & Molecular Biology, Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain
| | - Idoia Genua
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Marina I. Rojo-López
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
| | - María Teresa Julián
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Núria Alonso
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Josep Julve
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | - Didac Mauricio
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Faculty of Medicine, University of Vic/Central University of Catalonia (UVIC/UCC), Vic, Spain
| |
Collapse
|
|
7
|
Xu S, Chen Y, Gong Y. Improvement of Theaflavins on Glucose and Lipid Metabolism in Diabetes Mellitus. Foods 2024; 13:1763. [PMID: 38890991 PMCID: PMC11171799 DOI: 10.3390/foods13111763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 05/28/2024] [Accepted: 06/03/2024] [Indexed: 06/20/2024] Open
Abstract
In diabetes mellitus, disordered glucose and lipid metabolisms precipitate diverse complications, including nonalcoholic fatty liver disease, contributing to a rising global mortality rate. Theaflavins (TFs) can improve disorders of glycolipid metabolism in diabetic patients and reduce various types of damage, including glucotoxicity, lipotoxicity, and other associated secondary adverse effects. TFs exert effects to lower blood glucose and lipids levels, partly by regulating digestive enzyme activities, activation of OATP-MCT pathway and increasing secretion of incretins such as GIP. By the Ca2+-CaMKK ꞵ-AMPK and PI3K-AKT pathway, TFs promote glucose utilization and inhibit endogenous glucose production. Along with the regulation of energy metabolism by AMPK-SIRT1 pathway, TFs enhance fatty acids oxidation and reduce de novo lipogenesis. As such, the administration of TFs holds significant promise for both the prevention and amelioration of diabetes mellitus.
Collapse
Affiliation(s)
- Shiyu Xu
- National Research Center of Engineering and Technology for Utilization of Botanical Functional Ingredients, Changsha 410128, China;
- Key Laboratory of Tea Science of Ministry of Education, Changsha 410128, China
| | - Ying Chen
- National Research Center of Engineering and Technology for Utilization of Botanical Functional Ingredients, Changsha 410128, China;
- Key Laboratory of Tea Science of Ministry of Education, Changsha 410128, China
| | - Yushun Gong
- Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Changsha 410128, China
- Key Laboratory for Evaluation and Utilization of Gene Resources of Horticultural Crops, Ministry of Agriculture and Rural Affairs of China, Hunan Agricultural University, Changsha 410128, China
| |
Collapse
|
|
8
|
Sztolsztener K, Chabowski A. Hepatic-Metabolic Activity of α-Lipoic Acid-Its Influence on Sphingolipid Metabolism and PI3K/Akt/mTOR Pathway in a Rat Model of Metabolic Dysfunction-Associated Steatotic Liver Disease. Nutrients 2024; 16:1501. [PMID: 38794739 PMCID: PMC11124255 DOI: 10.3390/nu16101501] [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: 04/25/2024] [Revised: 05/13/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
Excessive lipid deposition affects hepatic homeostasis and contributes to the development of insulin resistance as a crucial factor for the deterioration of simple steatosis to steatohepatitis. So, it is essential to search for an effective agent for a new therapy for hepatic steatosis development before it progresses to the more advanced stages. Our study aimed to evaluate the potential protective effect of α-lipoic acid (α-LA) administration on the intrahepatic metabolism of sphingolipid and insulin signaling transduction in rats with metabolic dysfunction-associated steatotic liver disease (MASLD). The experiment was conducted on male Wistar rats subjected to a standard diet or a high-fat diet (HFD) and an intragastrically α-LA administration for eight weeks. High-performance liquid chromatography (HPLC) was used to determine sphingolipid content. Immunoblotting was used to measure the expression of selected proteins from sphingolipid and insulin signaling pathways. Multiplex assay kit was used to assess the level of the phosphorylated form of proteins from PI3K/Akt/mTOR transduction. The results revealed that α-LA decreased sphinganine, dihydroceramide, and sphingosine levels and increased ceramide level. We also observed an increased the concentration of phosphorylated forms of sphingosine and sphinganine. Changes in the expression of proteins from sphingolipid metabolism were consistent with changes in sphingolipid pools. Treatment with α-LA activated the PI3K/Akt/mTOR pathway, which enhanced the hepatic phosphorylation of Akt and mTOR. Based on these data, we concluded that α-lipoic acid may alleviate glucose intolerance and may have a protective influence on the sphingolipid metabolism under HFD; thus, this antioxidant appears to protect from MASLD development and steatosis deterioration.
Collapse
Affiliation(s)
- Klaudia Sztolsztener
- Department of Physiology, Medical University of Bialystok, Mickiewicz 2C Str., 15-222 Bialystok, Poland;
| | | |
Collapse
|
|
9
|
Lee H, Cho S, Kim D, Lee T, Kim HS. Bioelectric medicine: unveiling the therapeutic potential of micro-current stimulation. Biomed Eng Lett 2024; 14:367-392. [PMID: 38645592 PMCID: PMC11026362 DOI: 10.1007/s13534-024-00366-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 02/16/2024] [Accepted: 02/18/2024] [Indexed: 04/23/2024] Open
Abstract
Bioelectric medicine (BEM) refers to the use of electrical signals to modulate the electrical activity of cells and tissues in the body for therapeutic purposes. In this review, we particularly focused on the microcurrent stimulation (MCS), because, this can take place at the cellular level with sub-sensory application unlike other stimuli. These extremely low-level currents mimic the body's natural electrical activity and are believed to promote various physiological processes. To date, MCS has limited use in the field of BEM with applications in several therapeutic purposes. However, recent studies provide hopeful signs that MCS is more scalable and widely applicable than what has been used so far. Therefore, this review delves into the landscape of MCS, shedding light on the multifaceted applications and untapped potential of MCS in the realm of healthcare. Particularly, we summarized the hierarchical mediation from cell to whole body responses by MCS including its physiological applications. Our final objective of this review is to contribute to the growing body of literature that unveils the captivating potential of BEM, with MCS poised at the intersection of technological innovation and the intricacies of the human body.
Collapse
Affiliation(s)
- Hana Lee
- Department of Biomedical Engineering, Yonsei University, Seoul, Gangwon 26493 South Korea
| | - Seungkwan Cho
- Gfyhealth Inc., Seongnam, Gyeonggi 13488 South Korea
| | - Doyong Kim
- Department of Biomedical Engineering, Yonsei University, Seoul, Gangwon 26493 South Korea
| | - Taehyun Lee
- Gfyhealth Inc., Seongnam, Gyeonggi 13488 South Korea
| | - Han Sung Kim
- Department of Biomedical Engineering, Yonsei University, Seoul, Gangwon 26493 South Korea
| |
Collapse
|
|
10
|
Zabielski P, Imierska M, Roszczyc-Owsiejczuk K, Kuźmicki M, Rogalski P, Daniluk J, Błachnio-Zabielska AU. The Role of Acyl-CoA Synthetase 1 in Bioactive Lipid Accumulation and the Development of Hepatic Insulin Resistance. Nutrients 2024; 16:1003. [PMID: 38613036 PMCID: PMC11013895 DOI: 10.3390/nu16071003] [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] [Revised: 03/25/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
The liver plays a crucial role in glucose metabolism. Obesity and a diet rich in fats (HFD) contribute to the accumulation of intracellular lipids. The aim of the study was to explore the involvement of acyl-CoA synthetase 1 (ACSL1) in bioactive lipid accumulation and the induction of liver insulin resistance (InsR) in animals fed an HFD. The experiments were performed on male C57BL/6 mice divided into the following experimental groups: 1. Animals fed a control diet; 2. animals fed HFD; and 3. HFD-fed animals with the hepatic ACSL1 gene silenced through a hydrodynamic gene delivery technique. Long-chain acyl-CoAs, sphingolipids, and diacylglycerols were measured by LC/MS/MS. Glycogen was measured by means of a commercially available kit. The protein expression and phosphorylation state of the insulin pathway was estimated by Western blot. HFD-fed mice developed InsR, manifested as an increase in fasting blood glucose levels (202.5 mg/dL vs. 130.5 mg/dL in the control group) and inhibition of the insulin pathway, which resulted in an increase in the rate of gluconeogenesis (0.420 vs. 0.208 in the control group) and a decrease in the hepatic glycogen content (1.17 μg/mg vs. 2.32 μg/mg in the control group). Hepatic ACSL1 silencing resulted in decreased lipid content and improved insulin sensitivity, accounting for the decreased rate of gluconeogenesis (0.348 vs. 0.420 in HFD(+/+)) and the increased glycogen content (4.3 μg/mg vs. 1.17 μg/mg in HFD(+/+)). The elevation of gluconeogenesis and the decrease in glycogenesis in the hepatic tissue of HFD-fed mice resulted from cellular lipid accumulation. Inhibition of lipid synthesis through silencing ACSL1 alleviated HFD-induced hepatic InsR.
Collapse
Affiliation(s)
- Piotr Zabielski
- Medical Biology Department, Medical University of Bialystok, 15-222 Bialystok, Poland;
| | - Monika Imierska
- Hygiene, Epidemiology and Metabolic Disorders Department, Medical University of Bialystok, Mickiewicza 2c, 15-222 Bialystok, Poland; (M.I.); (K.R.-O.)
| | - Kamila Roszczyc-Owsiejczuk
- Hygiene, Epidemiology and Metabolic Disorders Department, Medical University of Bialystok, Mickiewicza 2c, 15-222 Bialystok, Poland; (M.I.); (K.R.-O.)
| | - Mariusz Kuźmicki
- Gynecology and Gynecological Oncology Department, Medical University of Bialystok, 15-276 Bialystok, Poland;
| | - Paweł Rogalski
- Gastroenterology and Internal Medicine Department, Medical University of Bialystok, 15-276 Bialystok, Poland; (P.R.); (J.D.)
| | - Jarosław Daniluk
- Gastroenterology and Internal Medicine Department, Medical University of Bialystok, 15-276 Bialystok, Poland; (P.R.); (J.D.)
| | - Agnieszka U. Błachnio-Zabielska
- Hygiene, Epidemiology and Metabolic Disorders Department, Medical University of Bialystok, Mickiewicza 2c, 15-222 Bialystok, Poland; (M.I.); (K.R.-O.)
| |
Collapse
|
|
11
|
Yue F, Shi Y, Wu S, Xing L, He D, Wei L, Qiu A, Russell R, Zhang D. Metformin alleviates hepatic iron overload and ferroptosis through AMPK-ferroportin pathway in HFD-induced NAFLD. iScience 2023; 26:108560. [PMID: 38089577 PMCID: PMC10711470 DOI: 10.1016/j.isci.2023.108560] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 10/21/2023] [Accepted: 11/20/2023] [Indexed: 01/04/2025] Open
Abstract
Metformin prevents progression of non-alcoholic fatty liver disease (NAFLD). However, the potential mechanism is not entirely understood. Ferroptosis, a recently recognized nonapoptotic form of regulated cell death, has been reported to be involved in the pathogenesis of NAFLD. Here, we investigated the effects of metformin on ferroptosis and its potential mechanism in NAFLD. We found that metformin prevented the progression of NAFLD, and alleviated hepatic iron overload (HIO), ferroptosis and upregulated ferroportin (FPN) expression in vivo and in vitro. Mechanically, metformin reduced the lysosomal degradation pathway of FPN through activation AMPK, thus upregulated the expression of FPN protein, alleviated HIO and ferroptosis, and prevented progression of NAFLD. These findings discover a mechanism of metformin, suggesting that targeting FPN may have the therapeutic potential for treating NAFLD and related disorders.
Collapse
Affiliation(s)
- Fangzhi Yue
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- Key Laboratory of Diabetes Immunology, Ministry of Education, Central South University, Changsha 410011, Hunan, China
| | - Ying Shi
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Shanyu Wu
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Lin Xing
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Dan He
- College of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Lin Wei
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Anqi Qiu
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Ryan Russell
- Department of Health and Human Performance, College of Health Professions, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Dongmei Zhang
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- Hunan Engineering Research Center for Obesity and its Metabolic Complications, Xiangya Hospital, Central South University, Changsha 410008, China
| |
Collapse
|
|
12
|
Boachie J, Zammit V, Saravanan P, Adaikalakoteswari A. Metformin Inefficiency to Lower Lipids in Vitamin B12 Deficient HepG2 Cells Is Alleviated via Adiponectin-AMPK Axis. Nutrients 2023; 15:5046. [PMID: 38140305 PMCID: PMC10745523 DOI: 10.3390/nu15245046] [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: 10/23/2023] [Revised: 11/25/2023] [Accepted: 11/28/2023] [Indexed: 12/24/2023] Open
Abstract
Background: Prolonged metformin treatment decreases vitamin B12 (B12) levels, whereas low B12 is associated with dyslipidaemia. Some studies have reported that metformin has no effect on intrahepatic triglyceride (TG) levels. Although AMP-activated protein kinase (AMPK) activation via adiponectin lowers hepatic TG content, its role in B12 deficiency and metformin has not been explored. We investigated whether low B12 impairs the beneficial effect of metformin on hepatic lipid metabolism via the AMPK-adiponectin axis. Methods: HepG2 was cultured using custom-made B12-deficient Eagle's Minimal Essential Medium (EMEM) in different B12-medium concentrations, followed by a 24-h metformin/adiponectin treatment. Gene and protein expressions and total intracellular TG were measured, and radiochemical analysis of TG synthesis and seahorse mitochondria stress assay were undertaken. Results: With low B12, total intracellular TG and synthesized radiolabelled TG were increased. Regulators of lipogenesis, cholesterol and genes regulating fatty acids (FAs; TG; and cholesterol biosynthesis were increased. FA oxidation (FAO) and mitochondrial function were decreased, with decreased pAMPKα and pACC levels. Following metformin treatment in hepatocytes with low B12, the gene and protein expression of the above targets were not alleviated. However, in the presence of adiponectin, intrahepatic lipid levels with low B12 decreased via upregulated pAMPKα and pACC levels. Again, combined adiponectin and metformin treatment ameliorated the low B12 effect and resulted in increased pAMPKα and pACC, with a subsequent reduction in lipogenesis, increased FAO and mitochondrion function. Conclusions: Adiponectin co-administration with metformin induced a higher intrahepatic lipid-lowering effect. Overall, we emphasize the potential therapeutic implications for hepatic AMPK activation via adiponectin for a clinical condition associated with B12 deficiency and metformin treatment.
Collapse
Affiliation(s)
- Joseph Boachie
- Division of Metabolic and Vascular Health, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital-Walsgrave Campus, Coventry CV2 2DX, UK; (J.B.); (V.Z.); (P.S.)
| | - Victor Zammit
- Division of Metabolic and Vascular Health, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital-Walsgrave Campus, Coventry CV2 2DX, UK; (J.B.); (V.Z.); (P.S.)
| | - Ponnusamy Saravanan
- Division of Metabolic and Vascular Health, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital-Walsgrave Campus, Coventry CV2 2DX, UK; (J.B.); (V.Z.); (P.S.)
- Diabetes Centre, George Eliot Hospital NHS Trust, College Street, Nuneaton CV10 7DJ, UK
- Populations, Evidence and Technologies, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7HL, UK
| | - Antonysunil Adaikalakoteswari
- Division of Metabolic and Vascular Health, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital-Walsgrave Campus, Coventry CV2 2DX, UK; (J.B.); (V.Z.); (P.S.)
- Department of Bioscience, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
| |
Collapse
|
|
13
|
Ali Zarie A, Osman MA, Alshammari GM, Hassan AB, ElGasim Ahmed Yagoub A, Abdo Yahya M. Saudi date cultivars' seed extracts inhibit developing hepatic steatosis in rats fed a high-fat diet. Saudi J Biol Sci 2023; 30:103732. [PMID: 37588573 PMCID: PMC10425400 DOI: 10.1016/j.sjbs.2023.103732] [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: 05/09/2023] [Revised: 06/21/2023] [Accepted: 06/30/2023] [Indexed: 08/18/2023] Open
Abstract
This research aim was to assess the impact of the seed extracts of the date cultivars (Qatara, Barhi, and Ruthana) on rat's liver steatosis, oxidative stress, and inflammation triggered by feeding a high-fat diet (HFD). The experimental design was based on random partitioning into two groups; one that received the standard diet and another that received the HFD diet. The HFD rats were orally administered Lipitor or date seed extracts at 300 or 600 mg/kg/day for 4 weeks. Accordingly, feeding rats HFD significantly increased body and liver weights, hepatic and serum lipid levels, glucose, insulin, HOMA-IR, liver function enzymes, and inflammation markers, and decreased oxidative stress enzymes. Oral administration of Barhi and Ruthana date seed extracts significantly decreased body and liver weights. Serum and liver total cholesterol TC, Triglycerides TGs, and free fatty acids FFAs were also decreased as were AST, ALT, MAD, leptin, and CRP, with a concomitant increase in SOD, GSH, and CAT. Furthermore, similar to Lipitor, oral administration of the extracts reduced inflammation markers such as TNF-α, serum CRP, IL-6, IL-1β, and leptin while increasing IL-10 and adiponectin levels. Histological observation revealed that extract administration improved hepatocyte and parenchymal structures and decreased lipid deposition. In conclusion, both Barhi and Ruthana seed extracts showed strong hepatoprotective, anti-inflammatory, and antioxidant effects against HFD-induced liver steatosis. And date seeds have other beneficial potential for prevention and treatment of various diseases, which can be studied in the future.
Collapse
Affiliation(s)
- Arwa Ali Zarie
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | - Magdi A. Osman
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ghedeir M. Alshammari
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | - Amro B. Hassan
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | - Abu ElGasim Ahmed Yagoub
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammed Abdo Yahya
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| |
Collapse
|
|
14
|
Mucinski JM, McCaffrey JM, Rector RS, Kasumov T, Parks EJ. Relationship between hepatic and mitochondrial ceramides: a novel in vivo method to track ceramide synthesis. J Lipid Res 2023; 64:100366. [PMID: 37028768 PMCID: PMC10193228 DOI: 10.1016/j.jlr.2023.100366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 03/22/2023] [Accepted: 03/24/2023] [Indexed: 04/08/2023] Open
Abstract
Ceramides (CERs) are key intermediate sphingolipids implicated in contributing to mitochondrial dysfunction and the development of multiple metabolic conditions. Despite the growing evidence of CER role in disease risk, kinetic methods to measure CER turnover are lacking, particularly using in vivo models. The utility of orally administered 13C3, 15N l-serine, dissolved in drinking water, was tested to quantify CER 18:1/16:0 synthesis in 10-week-old male and female C57Bl/6 mice. To generate isotopic labeling curves, animals consumed either a control diet or high-fat diet (HFD; n = 24/diet) for 2 weeks and varied in the duration of the consumption of serine-labeled water (0, 1, 2, 4, 7, or 12 days; n = 4 animals/day/diet). Unlabeled and labeled hepatic and mitochondrial CERs were quantified using liquid chromatography tandem MS. Total hepatic CER content did not differ between the two diet groups, whereas total mitochondrial CERs increased with HFD feeding (60%, P < 0.001). Within hepatic and mitochondrial pools, HFD induced greater saturated CER concentrations (P < 0.05) and significantly elevated absolute turnover of 16:0 mitochondrial CER (mitochondria: 59%, P < 0.001 vs. liver: 15%, P = 0.256). The data suggest cellular redistribution of CERs because of the HFD. These data demonstrate that a 2-week HFD alters the turnover and content of mitochondrial CERs. Given the growing data on CERs contributing to hepatic mitochondrial dysfunction and the progression of multiple metabolic diseases, this method may now be used to investigate how CER turnover is altered in these conditions.
Collapse
Affiliation(s)
- Justine M Mucinski
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, USA
| | - Jonas M McCaffrey
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, USA
| | - R Scott Rector
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, USA; Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, University of Missouri, Columbia, Missouri, USA; Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, USA
| | - Takhar Kasumov
- Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Elizabeth J Parks
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, USA; Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, University of Missouri, Columbia, Missouri, USA.
| |
Collapse
|
|
15
|
Pakdeechote P, Poasakate A, Prasatthong P, Potue P, Khamseekaew J, Maneesai P. Mitigation effect of galangin against aortic dysfunction and hypertrophy in rats with metabolic syndrome. Heliyon 2023; 9:e16500. [PMID: 37251824 PMCID: PMC10213349 DOI: 10.1016/j.heliyon.2023.e16500] [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: 02/06/2023] [Revised: 05/08/2023] [Accepted: 05/18/2023] [Indexed: 05/31/2023] Open
Abstract
Vascular alterations induced by a high-fat diet (HFD) are involved in the development of hypertension. Galangin, a flavonoid, is the major active compound isolated from galangal and propolis. The objective of this study was to investigate the effect of galangin on aortic endothelial dysfunction and hypertrophy, and the mechanisms involved in HFD-induced metabolic syndrome (MS) in rats. Male Sprague-Dawley rats (220-240 g) were separated into three groups: control + vehicle, MS + vehicle, and MS + galangin (50 mg/kg). Rats with MS received HFD plus 15% fructose solution for 16 weeks. Galangin or vehicle was orally administered daily for the final four weeks. Galangin reduced body weight and mean arterial pressure in HFD rats (p < 0.05). It also reduced circulating fasting blood glucose, insulin, and total cholesterol levels (p < 0.05). Impaired vascular responses to the exogenous acetylcholine observed in the aortic ring of HFD rats were restored by galangin (p < 0.05). However, the response to sodium nitroprusside did not differ between the groups. Galangin enhanced the expression of the aortic endothelial nitric oxide synthase (eNOS) protein and increased circulating nitric oxide (NO) levels in the MS group (p < 0.05). Aortic hypertrophy in HFD rats was alleviated by galangin (p < 0.05). Increases in tumour necrosis factor-alpha (TNF-α), interleukin (IL)-6 levels, angiotensin-converting enzyme activity and angiotensin II (Ang II) concentrations in rats with MS were suppressed in galangin treated group (p < 0.05). Furthermore, galangin reduced the upregulation of angiotensin II type I receptor (AT1R) and transforming growth factor-beta (TGF-β) expression in rats with MS (p < 0.05). In conclusion, galangin alleviates metabolic disorders and improves aortic endothelial dysfunction and hypertrophy in the MS group. These effects were consistent with increased NO availability, reduced inflammation, and suppressing Ang II/AT1R/TGF-β signalling pathway.
Collapse
Affiliation(s)
- Poungrat Pakdeechote
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Anuson Poasakate
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Patoomporn Prasatthong
- Department of Health Science, Faculty of Science and Technology, Nakhon Sawan Rajabhat University, Nakhon Sawan 60000, Thailand
| | - Prapassorn Potue
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Juthamas Khamseekaew
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Putcharawipa Maneesai
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| |
Collapse
|
|
16
|
Lee H, Lee JH, Kim D, Hwang D, Lee M, Chung H, Kim TJ, Kim HS. Micro-Current Stimulation Can Modulate the Adipogenesis Process by Regulating the Insulin Signaling Pathway in 3T3-L1 Cells and ob/ ob Mice. Life (Basel) 2023; 13:404. [PMID: 36836760 PMCID: PMC9958996 DOI: 10.3390/life13020404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/17/2023] [Accepted: 01/24/2023] [Indexed: 02/04/2023] Open
Abstract
Obesity is a disease in which fat is abnormally or excessively accumulated in the body, and many studies have been conducted to overcome it with various techniques. In this study, we evaluated whether micro-current stimulation (MCS) can be applied to prevent obesity by regulating the adipogenesis through 3T3-L1 cells and ob/ob mice. To specify the intensity of MCS, Oil Red O staining was conducted with various intensities of MCS. Based on these, subsequent experiments used 200 and 400 μA for the intensity of MCS. The expressions of insulin signaling pathway-related proteins, including phosphorylation of IGF-1 and IR, were decreased in all MCS groups, and in turn, downstream signals such as Akt and ERK were decreased. In addition, MCS reduced the nucleus translocation of PPAR-γ and decreased the protein expression of C/EBP-α. In the ob/ob mouse model, MCS reduced body weight gain and abdominal adipose tissue volume. In particular, the concentration of triglycerides in serum was also decreased. Taken together, our findings showed that MCS inhibited lipid accumulation by regulating insulin signaling in 3T3-L1, and it was effective at reducing body weight and adipose tissue volume in ob/ob mice. These suggest that MCS may be a useful treatment approach for obesity.
Collapse
Affiliation(s)
- Hana Lee
- Department of Biomedical Engineering, Yonsei University, Wonju 26493, Republic of Korea
| | - Jin-Ho Lee
- Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea
| | - Doyong Kim
- Department of Biomedical Engineering, Yonsei University, Wonju 26493, Republic of Korea
| | - Donghyun Hwang
- Department of Biomedical Engineering, Yonsei University, Wonju 26493, Republic of Korea
| | - Minjoo Lee
- Department of Biomedical Engineering, Yonsei University, Wonju 26493, Republic of Korea
| | - Halim Chung
- Department of Biomedical Engineering, Yonsei University, Wonju 26493, Republic of Korea
| | - Tack-Joong Kim
- Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea
| | - Han Sung Kim
- Department of Biomedical Engineering, Yonsei University, Wonju 26493, Republic of Korea
| |
Collapse
|
|
17
|
Lou K, Sun P, Zhang C, Jiang Q, Pang S. X-box binding protein 1: A new metabolic mediator and drug target of metformin? Front Pharmacol 2022; 13:1013218. [PMID: 36438823 PMCID: PMC9691898 DOI: 10.3389/fphar.2022.1013218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 10/17/2022] [Indexed: 11/13/2022] Open
Abstract
Accumulating evidence has demonstrated that metformin improved hypertriglyceridemia. The present study aim to investigate the molecular mechanism by which metformin improves hypertriglyceridemia via regulation of diacylglycerol O-acyltransferase 2 (DGAT2) and X-box binding protein 1 (XBP1) in the liver and whether AMP-activated protein kinase (AMPK) is involved. Mice were fed a high-fat diet (HFD) or high-fat diet with metformin for 5 weeks to evaluate the effect of metformin on triglyceride (TG) levels and expression of DGAT2 and XBP1 in the liver. In vitro HepG2 cells or XBP1 knockout AML12 hepatocytes were stimulated with metformin, palmitic acid or small interfering RNA inducing XBP1 knockdown, or dominant-negative mutant AMPK plasmid. Metformin treatment reduced hepatic TG levels in the liver of HFD-fed mice. Expression of nuclear and cytoplasmic XBP1 protein and its downstream target gene DGAT2 decreased in the liver of HFD-fed mice and HepG2 cells after metformin treatment. AMPK inactivation or overexpression of XBP1 attenuates this effect. Our preliminary results demonstrate that metformin activates AMPK to reduce TG synthesis by inhibiting the XBP1-mediated DGAT2 pathway, at least in part, suggesting that XBP1 is a new metabolic mediator for metformin treatment of hypertriglyceridemia and associated metabolic disease.
Collapse
Affiliation(s)
- Kai Lou
- Department of Endocrinology, Jinan Central Hospital, Shandong University, Jinan, China
- Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Pei Sun
- Department of Endocrinology, Jinan Central Hospital, Shandong University, Jinan, China
- Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chunxue Zhang
- Department of Nuclear Medicine, Jinan Central Hospital, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qiang Jiang
- Department of Endocrinology, Jinan Central Hospital, Shandong University, Jinan, China
- Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Shuguang Pang
- Department of Endocrinology, Jinan Central Hospital, Shandong University, Jinan, China
- Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, China
- *Correspondence: Shuguang Pang,
| |
Collapse
|
|
18
|
Sharma A, Krick B, Li Y, Summers SA, Playdon MC, Welt C. The Use of Ceramides to Predict Metabolic Response to Metformin in Women With PCOS. J Endocr Soc 2022; 6:bvac131. [PMID: 36249411 PMCID: PMC9557973 DOI: 10.1210/jendso/bvac131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Indexed: 01/26/2023] Open
Abstract
Context Polycystic ovarian syndrome (PCOS) is a complex disorder in which metabolic abnormalities are associated with reproductive dysfunction. Women with PCOS have increased ceramide concentrations. Previous studies demonstrated that treating metabolic abnormalities of PCOS with metformin improved glucose effectiveness after 12 weeks. Objective We evaluated whether, in women with PCOS, lower baseline ceramide, diacylglycerol (DAG), and triacylglycerol (TAG) concentrations were associated with improved metabolic response to metformin. Methods Women (n = 29), aged 29 ± 5 years and diagnosed with PCOS by the NIH criteria underwent an intravenous glucose tolerance test (IVGTT) before and after 12-week treatment with metformin (1500 mg per day). Metabolic responders were defined by improved glucose effectiveness, specifically, the ability of glucose to stimulate uptake and suppress production, after metformin treatment. Results Twelve weeks of metformin resulted in weight loss (-1.7 ± 2.6 kg, P < 0.01) and a reduction in BMI (-0.6 ± 0.9 kg/m2, P < 0.01) with no change in HbA1c. The concentrations of Cer(d18:1/22:0), Cer(d18:1/24:0), total ceramides, total Cer(d16:0), total Cer(d18:2), DAG, dihydrosphingomyelin (DHSM), and TAG decreased after metformin treatment (P < 0.05). Baseline total Cer(d16:0) concentration <204.1 pmol/mL was 82% sensitive (AUC 0.72, P = 0.03) and total DHSM concentration <32237 pmol/mL was 100% specific (AUC 0.73, P = 0.03) in predicting improved metabolic response to metformin, as measured by IVGTT. Conclusion Lower total Cer(16:0) and DHSM concentrations are associated with a beneficial metabolic response to metformin in women with PCOS. Based on the known association between higher ceramide levels and type 2 diabetes, the data suggest that metformin improves metabolic parameters in women with mild metabolic derangements.
Collapse
Affiliation(s)
- Anu Sharma
- Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Benjamin Krick
- Cancer Control and Population Sciences, Huntsman Cancer Institute, Salt Lake City, UT, USA
| | - Ying Li
- Department of Nutrition & Integrative Physiology, University of Utah, Salt Lake City, UT, USA
| | - Scott A Summers
- Department of Nutrition & Integrative Physiology, University of Utah, Salt Lake City, UT, USA.,Diabetes and Metabolism Research Center, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Mary C Playdon
- Cancer Control and Population Sciences, Huntsman Cancer Institute, Salt Lake City, UT, USA.,Department of Nutrition & Integrative Physiology, University of Utah, Salt Lake City, UT, USA.,Diabetes and Metabolism Research Center, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Corrine Welt
- Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, UT, USA
| |
Collapse
|
|
19
|
Lipids Alterations Associated with Metformin in Healthy Subjects: An Investigation Using Mass Spectrometry Shotgun Approach. Int J Mol Sci 2022; 23:ijms231911478. [PMID: 36232780 PMCID: PMC9569788 DOI: 10.3390/ijms231911478] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 09/18/2022] [Accepted: 09/19/2022] [Indexed: 11/17/2022] Open
Abstract
Metformin is an orally effective insulin-sensitizing drug widely prescribed for treating type 2 diabetes mellitus (T2DM). Metformin has been reported to alter lipid metabolism. However, the molecular mechanisms behind its impact on lipid metabolism remain partially explored and understood. In the current study, mass spectrometry-based lipid profiling was used to investigate the lipidomic changes in the serum of 26 healthy individuals after a single-dose intake of metformin. Samples were analyzed at five-time points: preadministration, before the maximum concentration of metformin (Cmax), Cmax, after Cmax, and 36 h post-administration. A total of 762 molecules were significantly altered between the five-time points. Based on a comparison between baseline level and Cmax, metformin significantly increased and decreased the level of 33 and 192 lipids, respectively (FDR ≤ 0.05 and fold change cutoff of 1.5). The altered lipids are mainly involved in arachidonic acid metabolism, steroid hormone biosynthesis, and glycerophospholipid metabolism. Furthermore, several lipids acted in an opposed or similar manner to metformin levels and included fatty acyls, sterol lipids, glycerolipids, and glycerophospholipids. The significantly altered lipid species pointed to fundamental lipid signaling pathways that could be linked to the pleiotropic effects of metformin in T2DM, insulin resistance, polycystic ovary syndrome, cancer, and cardiovascular diseases.
Collapse
|
|
20
|
Sinha S, Haque M. Obesity, Diabetes Mellitus, and Vascular Impediment as Consequences of Excess Processed Food Consumption. Cureus 2022; 14:e28762. [PMID: 36105908 PMCID: PMC9441778 DOI: 10.7759/cureus.28762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2022] [Indexed: 12/15/2022] Open
Abstract
Regular intake of ready-to-eat meals is related to obesity and several noninfectious illnesses, such as cardiovascular diseases, hypertension, diabetes mellitus (DM), and tumors. Processed foods contain high calories and are often enhanced with excess refined sugar, saturated and trans fat, Na+ andphosphate-containing taste enhancers, and preservatives. Studies showed that monosodium glutamate (MSG) induces raised echelons of oxidative stress, and excessive hepatic lipogenesis is concomitant to obesity and type 2 diabetes mellitus (T2DM). Likewise, more than standard salt intake adversely affects the cardiovascular system, renal system, and central nervous system (CNS), especially the brain. Globally, excessive utilization of phosphate-containing preservatives and additives contributes unswervingly to excessive phosphate intake through food. In addition, communities and even health experts, including medical doctors, are not well-informed about the adverse effects of phosphate preservatives on human health. Dietary phosphate excess often leads to phosphate toxicity, ultimately potentiating kidney disease development. The mechanisms involved in phosphate-related adverse effects are not explainable. Study reports suggested that high blood level of phosphate causes vascular ossification through the deposition of Ca2+ and substantially alters fibroblast growth factor-23 (FGF23) and calcitriol.
Collapse
|
|
21
|
The melatonergic agonist agomelatine ameliorates high fat diet-induced obesity in mice through the modulation of the gut microbiome. Biomed Pharmacother 2022; 153:113445. [PMID: 36076560 DOI: 10.1016/j.biopha.2022.113445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 07/11/2022] [Accepted: 07/18/2022] [Indexed: 11/21/2022] Open
|
|
22
|
Zietzer A, Düsing P, Reese L, Nickenig G, Jansen F. Ceramide Metabolism in Cardiovascular Disease: A Network With High Therapeutic Potential. Arterioscler Thromb Vasc Biol 2022; 42:1220-1228. [PMID: 36004640 DOI: 10.1161/atvbaha.122.318048] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Growing evidence suggests that ceramides play an important role in the development of atherosclerotic and valvular heart disease. Ceramides are biologically active sphingolipids that are produced by a complex network of enzymes. Lowering cellular and tissue levels of ceramide by inhibiting the ceramide-producing enzymes counteracts atherosclerotic and valvular heart disease development in animal models. In vascular tissues, ceramides are produced in response to hyperglycemia and TNF (tumor necrosis factor)-α signaling and are involved in NO-signaling and inflammation. In humans, elevated blood ceramide levels are associated with cardiovascular events. Furthermore, important cardiovascular risk factors, such as obesity and diabetes, have been linked to ceramide accumulation. This review summarizes the basic mechanisms of how ceramides drive cardiovascular disease locally and links these findings to the intriguing results of human studies on ceramides as biomarkers for cardiovascular events. Moreover, we discuss the current state of interventions to therapeutically influence vascular ceramide metabolism, both locally and systemically.
Collapse
Affiliation(s)
- Andreas Zietzer
- Department of Internal Medicine II, University Hospital Bonn, University of Bonn, Germany
| | - Philip Düsing
- Department of Internal Medicine II, University Hospital Bonn, University of Bonn, Germany
| | - Laurine Reese
- Department of Internal Medicine II, University Hospital Bonn, University of Bonn, Germany
| | - Georg Nickenig
- Department of Internal Medicine II, University Hospital Bonn, University of Bonn, Germany
| | - Felix Jansen
- Department of Internal Medicine II, University Hospital Bonn, University of Bonn, Germany
| |
Collapse
|
|
23
|
Liang XH, Ren YL, Liang XY, Chen JY, Qu P, Tang X. Relationship between quality of life and adolescent glycolipid metabolism disorder: A cohort study. World J Diabetes 2022; 13:566-580. [PMID: 36051423 PMCID: PMC9329843 DOI: 10.4239/wjd.v13.i7.566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 04/29/2022] [Accepted: 06/20/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The prevalence of glucolipid metabolic disorders (GLMDs) in children and adolescents has a recognized association with cardiovascular diseases and type 2 diabetes mellitus in adulthood. Therefore, it is important to enhance our under-standing of the risk factors for GLMD in childhood and adolescence.
AIM To explore the relationship between quality of life (QoL) and adolescent GLMD.
METHODS This study included 1956 samples in 2019 from a cohort study established in 2014. The QoL scale and glycolipid indexes were collected during follow-up; other covariates of perinatal factors, physical measures, and socioeconomic indicators were collected and adjusted. A generalized linear regression model and logistic regression model were used to analyse the correlation between QoL and GLMD.
RESULTS Higher scores of QoL activity opportunity, learning ability and attitude, attitude towards doing homework, and living convenience domains correlated negatively with insulin and homeostasis model assessment insulin resistance (IR) levels. Psychosocial factors, QoL satisfaction factors, and total QoL scores had significant protective effects on insulin and IR levels. Activity opportunity, learning ability and attitude, attitude towards doing homework domains of QoL, psychosocial factor, and total score of QoL correlated positively with high density lipoprotein. In addition, the attitude towards doing homework domain was a protective factor for dyslipidaemia, IR > 3, and increased fasting blood glucose; four factors, QoL and total QoL score correlated significantly negatively with IR > 3. In subgroup analyses of sex, more domains of QoL correlated with insulin and triglyceride levels, dyslipidaemia, and IR > 3 in females. Poor QoL was associated with an increased prevalence of GLMD, and the effect was more pronounced in males than in females. Measures to improve the QoL of adolescents are essential to reduce rates of GLMD.
CONCLUSION Our study revealed that QoL scores mainly correlate negatively with the prevalence of GLMD in adolescents of the healthy population. The independent relationship between QoL and GLMD can be illustrated by adjusting for multiple covariates that may be associated with glycaemic index. In addition, among females, more QoL domains are associated with glycaemic index.
Collapse
Affiliation(s)
- Xiao-Hua Liang
- Department of Clinical Epidemiology and Biostatistics, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Health and Nutrition, Chongqing 400016, China
| | - Yang-Ling Ren
- Department of Clinical Epidemiology and Biostatistics, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Health and Nutrition, Chongqing 400016, China
| | - Xiao-Yue Liang
- Department of Clinical Epidemiology and Biostatistics, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Health and Nutrition, Chongqing 400016, China
| | - Jing-Yu Chen
- Ultrasound Department of Children’s Hospital of Chongqing Medical University, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Ping Qu
- Department of Clinical Epidemiology and Biostatistics, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Health and Nutrition, Chongqing 400016, China
| | - Xian Tang
- Department of Clinical Epidemiology and Biostatistics, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Health and Nutrition, Chongqing 400016, China
| |
Collapse
|
|
24
|
Contribution of specific ceramides to obesity-associated metabolic diseases. Cell Mol Life Sci 2022; 79:395. [PMID: 35789435 PMCID: PMC9252958 DOI: 10.1007/s00018-022-04401-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/20/2022] [Accepted: 05/26/2022] [Indexed: 12/04/2022]
Abstract
Ceramides are a heterogeneous group of bioactive membrane sphingolipids that play specialized regulatory roles in cellular metabolism depending on their characteristic fatty acyl chain lengths and subcellular distribution. As obesity progresses, certain ceramide molecular species accumulate in metabolic tissues and cause cell-type-specific lipotoxic reactions that disrupt metabolic homeostasis and lead to the development of cardiometabolic diseases. Several mechanisms for ceramide action have been inferred from studies in vitro, but only recently have we begun to better understand the acyl chain length specificity of ceramide-mediated signaling in the context of physiology and disease in vivo. New discoveries show that specific ceramides affect various metabolic pathways and that global or tissue-specific reduction in selected ceramide pools in obese rodents is sufficient to improve metabolic health. Here, we review the tissue-specific regulation and functions of ceramides in obesity, thus highlighting the emerging concept of selectively inhibiting production or action of ceramides with specific acyl chain lengths as novel therapeutic strategies to ameliorate obesity-associated diseases.
Collapse
|
|
25
|
Błachnio-Zabielska AU, Roszczyc-Owsiejczuk K, Imierska M, Pogodzińska K, Rogalski P, Daniluk J, Zabielski P. CerS1 but Not CerS5 Gene Silencing, Improves Insulin Sensitivity and Glucose Uptake in Skeletal Muscle. Cells 2022; 11:206. [PMID: 35053322 PMCID: PMC8773817 DOI: 10.3390/cells11020206] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 12/31/2021] [Accepted: 01/05/2022] [Indexed: 12/11/2022] Open
Abstract
Skeletal muscle is perceived as a major tissue in glucose and lipid metabolism. High fat diet (HFD) lead to the accumulation of intramuscular lipids, including: long chain acyl-CoA, diacylglycerols, and ceramides. Ceramides are considered to be one of the most important lipid groups in the generation of skeletal muscle insulin resistance. So far, it has not been clearly established whether all ceramides adversely affect the functioning of the insulin pathway, or whether there are certain ceramide species that play a pivotal role in the induction of insulin resistance. Therefore, we designed a study in which the expression of CerS1 and CerS5 genes responsible for the synthesis of C18:0-Cer and C16:0-Cer, respectively, was locally silenced in the gastrocnemius muscle of HFD-fed mice through in vivo electroporation-mediated shRNA plasmids. Our study indicates that HFD feeding induced both, the systemic and skeletal muscle insulin resistance, which was accompanied by an increase in the intramuscular lipid levels, decreased activation of the insulin pathway and, consequently, a decrease in the skeletal muscle glucose uptake. CerS1 silencing leads to a reduction in C18:0-Cer content, with a subsequent increase in the activity of the insulin pathway, and an improvement in skeletal muscle glucose uptake. Such effects were not visible in case of CerS5 silencing, which indicates that the accumulation of C18:0-Cer plays a decisive role in the induction of skeletal muscle insulin resistance.
Collapse
Affiliation(s)
- Agnieszka U. Błachnio-Zabielska
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, Mickiewicza 2c, 15-089 Bialystok, Poland; (K.R.-O.); (M.I.); (K.P.)
| | - Kamila Roszczyc-Owsiejczuk
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, Mickiewicza 2c, 15-089 Bialystok, Poland; (K.R.-O.); (M.I.); (K.P.)
| | - Monika Imierska
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, Mickiewicza 2c, 15-089 Bialystok, Poland; (K.R.-O.); (M.I.); (K.P.)
| | - Karolina Pogodzińska
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, Mickiewicza 2c, 15-089 Bialystok, Poland; (K.R.-O.); (M.I.); (K.P.)
| | - Paweł Rogalski
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland; (P.R.); (J.D.)
| | - Jarosław Daniluk
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland; (P.R.); (J.D.)
| | - Piotr Zabielski
- Department of Medical Biology, Medical University of Bialystok, 15-089 Bialystok, Poland
| |
Collapse
|
|
26
|
Ibrahim WS, Ahmed HMS, Mahmoud AAA, Mahmoud MF, Ibrahim IAAEH. Propranolol and low-dose isoproterenol ameliorate insulin resistance, enhance β-arrestin2 signaling, and reduce cardiac remodeling in high-fructose, high-fat diet-fed mice: Comparative study with metformin. Life Sci 2021; 286:120055. [PMID: 34662551 DOI: 10.1016/j.lfs.2021.120055] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 10/09/2021] [Accepted: 10/11/2021] [Indexed: 01/14/2023]
Abstract
AIMS β-Arrestin2 signaling has emerged as a promising therapeutic target for the management of insulin resistance and related complications. Moreover, recent studies have shown that certain G protein-coupled receptor (GPCR) ligands can modulate β-arrestin2 signaling. The current study examined the effects of the β-blocker propranolol and a low dose of the agonist isoproterenol (L-D-ISOPROT) on β-arrestin2 signaling, insulin resistance, and cardiac remodeling in high-fructose, high-fat diet (HFrHFD)-fed mice. In addition, the effects of these agents were compared to those of the clinical antidiabetic agent, metformin. MATERIALS AND METHODS Insulin resistance was induced by HFrHFD feeding for 16 weeks. Mice were then randomly allocated to groups receiving propranolol, L-D-ISOPROT, metformin, or vehicle (control) for 4 weeks starting on week 13 of HFrHFD feeding. Survival rate, body weight, visceral fat weight, blood glucose, serum insulin, insulin resistance index, hepatic β-arrestin2 signaling, heart weight, left and right ventricular thicknesses, cardiac fibrosis severity, serum endothelin-1, cardiac cardiotrophin-1, and cardiac β-arrestin2 signaling were then compared among groups. KEY FINDINGS HFrHFD for 16 weeks significantly increased insulin resistance index, cardiac fibrosis area, and serum endothelin-1, and reduced hepatic β-arrestin2 signaling, cardiac cardiotrophin-1, and cardiac β-arrestin2 signaling without significant changes in survival rate, body weight, visceral fat weight, heart weight, or left and right ventricular thicknesses. All three drugs reduced insulin resistance and cardiac remodeling parameters and enhanced β-arrestin2 signaling with variable efficacies. SIGNIFICANCE Propranolol and L-D-ISOPROT, like metformin, can reduce insulin-resistance and cardiac remodeling in HFrHFD-fed mice, possibly by upregulating β-arrestin2 signaling activity. Therefore, β-arrestin2-signaling modulation might be a promising strategy for insulin-resistance treatment.
Collapse
Affiliation(s)
- Wael S Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt; Department of Pharmacology, School of Pharmacy, Badr University in Cairo, Cairo, Egypt
| | - Hoda M S Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt; Medical Supply Chain, Abo-Hammad Health Administration, Ministry of Health, Egypt
| | - Amr A A Mahmoud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt
| | - Mona F Mahmoud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt
| | - Islam A A E-H Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt.
| |
Collapse
|
|
27
|
Metformin treatment reverses high fat diet- induced non-alcoholic fatty liver diseases and dyslipidemia by stimulating multiple antioxidant and anti-inflammatory pathways. Biochem Biophys Rep 2021; 28:101168. [PMID: 34825068 PMCID: PMC8605070 DOI: 10.1016/j.bbrep.2021.101168] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 10/18/2021] [Accepted: 11/01/2021] [Indexed: 01/06/2023] Open
Abstract
Purpose This current study investigated the effect of metformin treatment on hepatic oxidative stress and inflammation associated with nonalcoholic fatty liver disease (NADLD) in high fat diet (HFD) fed rats. Method Wistar rats were fed with a HFD or laboratory chow diet for 8 weeks. Metformin was administered orally at a dose of 200 mg/kg. Body weight, food and water intake were recorded on daily basis. Oral glucose tolerance test (OGTT), biochemical analysis and histological examinations were conducted on plasma and tissue samples. Antioxidant and anti-inflammatory mRNA expression was analyzed using reverse transcription polymeric chain reaction (RT-PCR). Results Metformin treatment for 8 weeks prevented HFD-induced weight gain and decreased fat deposition in HFD fed rats. Biochemical analysis revealed that metformin treatment significantly attenuated nitro-oxidative stress markers malondialdehyde (MDA), advanced protein oxidation product (APOP), and excessive nitric oxide (NO) levels in the liver of HFD fed rats. Gene expression analysis demonestrated that metformin treatment was associated with an enhanced expression of antioxidant genes such as Nrf-2, HO-1, SOD and catalase in liver of HFD fed rats. Metformin treatment also found to modulate the expression of fat metabolizing and anti-inflammatory genes including PPAR--γ, C/EBP-α, SREBP1c, FAS, AMPK and GLUT-4. Consistent with the biochemical and gene expression data, the histopathological examination unveiled that metformin treatment attenuated inflammatory cells infiltration, steatosis, hepatocyte necrosis, collagen deposition, and fibrosis in the liver of HFD fed rats. Conclusion In conclusion, this study suggests that metformin might be effective in the prevention and treatment of HFD-induced steatosis by reducing hepatic oxidative stress and inflammation in the liver.
Collapse
Key Words
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- AMPK, AMP-activated protein kinase
- APOP, advanced protein oxidation product
- AST, aspartate aminotransferase
- ATP, Adinosine triphosphate
- AUC, area under the curve
- CAT, catalase
- FAS, Fatty acid synthase
- HDL, high density lipoprotein
- HF, High fat
- HSCs, Hepatic stellate cells
- IACUC, Institutional Animal Care and Use Committee
- IL-6, interleukin-6
- Inflammation
- LDL, low density lipoprotein
- Lipid peroxidation
- MDA, Malondialdehyde
- MPO, Myeloperoxidase
- Met, Metformin
- Metformin
- NAFLD, nonalcoholic fatty liver disease
- NO, nitric oxide
- Non-alcoholic fatty liver disease
- OGTT, Oral glucose tolerance test
- Obesity
- PBS, Phosphate buffer saline
- PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1
- PPAR-γ, peroxisome proliferator-activated receptor γ
- ROS, reactive oxygen species
- SOD, Superoxide dismutase
- SREBP1c, sterol regulatory element-binding protein 1c
- TBA, Thiobarbituric acid
- TBARS, Thiobarbituric acid reactive substances
Collapse
|
|
28
|
Time-Dependent Changes in Hepatic Sphingolipid Accumulation and PI3K/Akt/mTOR Signaling Pathway in a Rat Model of NAFLD. Int J Mol Sci 2021; 22:ijms222212478. [PMID: 34830360 PMCID: PMC8618899 DOI: 10.3390/ijms222212478] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/16/2021] [Accepted: 11/18/2021] [Indexed: 01/26/2023] Open
Abstract
Increased lipid bioavailability in a diet favors lipid accumulation, enhancing hepatic lipotoxicity and contributing to insulin resistance (IR) development. The aim of our study was to examine time-dependent alterations in the intrahepatic content of sphingolipids and insulin signaling pathway in rats fed a high-fat diet (HFD). The experiment was conducted on male Wistar rats receiving a standard diet or HFD for five weeks. At the end of each experimental feeding week, liver sphingolipids were determined using high-performance liquid chromatography. The expression of proteins from the sphingolipid pathway and glucose transporter expression were assessed by Western blot. The content of phosphorylated form of proteins from the insulin pathway was detected by a multiplex assay kit. Our results revealed that HFD enhanced hepatic ceramide deposition by increasing the expression of selected proteins from sphingomyelin and salvage pathways in the last two weeks. Importantly, we observed a significant inhibition of Akt phosphorylation in the first week of HFD and stimulation of PTEN and mTOR phosphorylation at the end of HFD. These changes worsened the PI3K/Akt/mTOR signaling pathway. We may postulate that HFD-induced reduction in the insulin action in the time-dependent matter was exerted by excessive accumulation of sphingosine and sphinganine rather than ceramide.
Collapse
|
|
29
|
Gaggini M, Pingitore A, Vassalle C. Plasma Ceramides Pathophysiology, Measurements, Challenges, and Opportunities. Metabolites 2021; 11:metabo11110719. [PMID: 34822377 PMCID: PMC8622894 DOI: 10.3390/metabo11110719] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/15/2021] [Accepted: 10/19/2021] [Indexed: 01/22/2023] Open
Abstract
Ceramides are a family of lipid molecules, composed of sphingosine and a fatty acid, and transported by lipoproteins (primarily by low-density lipoproteins) in the bloodstream. They are not only structural lipids, but multifunctional and bioactive molecules with key roles in many important cellular pathways, such as inflammatory processes and apoptosis, representing potential biomarkers of cardiometabolic diseases as well as pharmacological targets. Recent data reported ceramide modulation by diet and aerobic exercise, suggesting nutrients and exercise-targeting sphingolipid pathways as a countermeasure, also in combination with other therapies, for risk and progression of chronic disease prevention and health maintenance. In this review, we focus on the available data regarding remarks on ceramide structure and metabolism, their pathophysiologic roles, and the effect of dietary habit and aerobic exercise on ceramide levels. Moreover, advancements and limitations of lipidomic techniques and simplification attempts to overcome difficulties of interpretation and to facilitate practical applications, such as the proposal of scores, are also discussed.
Collapse
Affiliation(s)
- Melania Gaggini
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (M.G.); (A.P.)
| | - Alessandro Pingitore
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (M.G.); (A.P.)
| | - Cristina Vassalle
- Fondazione CNR-Regione Toscana G. Monasterio, Via Moruzzi, 1, 56124 Pisa, Italy
- Correspondence: ; Tel.: +39-050-3153525
| |
Collapse
|
|
30
|
Jo S, Fang S. Therapeutic Strategies for Diabetes: Immune Modulation in Pancreatic β Cells. Front Endocrinol (Lausanne) 2021; 12:716692. [PMID: 34484126 PMCID: PMC8415970 DOI: 10.3389/fendo.2021.716692] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 07/30/2021] [Indexed: 12/14/2022] Open
Abstract
Increased incidence of type I and type II diabetes has been prevailed worldwide. Though the pathogenesis of molecular mechanisms remains still unclear, there are solid evidence that disturbed immune homeostasis leads to pancreatic β cell failure. Currently, autoimmunity and uncontrolled inflammatory signaling pathways have been considered the major factors in the pathogenesis of diabetes. Many components of immune system have been reported to implicate pancreatic β cell failure, including helper T cells, cytotoxic T cells, regulatory T cells and gut microbiota. Immune modulation of those components using small molecules and antibodies, and fecal microbiota transplantation are undergoing in many clinical trials for the treatment of type I and type II diabetes. In this review we will discuss the basis of molecular pathogenesis focusing on the disturbed immune homeostasis in type I and type II diabetes, leading to pancreatic β cell destruction. Finally, we will introduce current therapeutic strategies and clinical trials by modulation of immune system for the treatment of type I and type II diabetes patients.
Collapse
Affiliation(s)
- Sugyeong Jo
- Department of Medical Science, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Sungsoon Fang
- Department of Medical Science, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
- Severance Biomedical Science Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| |
Collapse
|
|
31
|
Galli M, Hameed A, Żbikowski A, Zabielski P. Aquaporins in insulin resistance and diabetes: More than channels! Redox Biol 2021; 44:102027. [PMID: 34090243 PMCID: PMC8182305 DOI: 10.1016/j.redox.2021.102027] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/09/2021] [Accepted: 05/24/2021] [Indexed: 12/12/2022] Open
Abstract
Aquaporins (AQPs) are part of the family of the integral membrane proteins. Their function is dedicated to the transport of water, glycerol, ammonia, urea, H2O2, and other small molecules across the biological membranes. Although for many years they were scarcely considered, AQPs have a relevant role in the development of many diseases. Recent discoveries suggest, that AQPs may play an important role in the process of fat accumulation and regulation of oxidative stress, two crucial aspects of insulin resistance and type-2 diabetes (T2D). Insulin resistance (IR) and T2D are multi-faceted systemic diseases with multiple connections to obesity and other comorbidities such as hypertension, dyslipidemia and metabolic syndrome. Both IR and T2D transcends different tissues and organs, creating the maze of mutual relationships between adipose fat depots, skeletal muscle, liver and other insulin-sensitive organs. AQPs with their heterogenous properties, distinctive tissue distribution and documented involvement in both the lipid metabolism and regulation of the oxidative stress appear to be feasible candidates in the search for the explanation to this third-millennium plague. A lot of research has been assigned to adipose tissue AQP7 and liver tissue AQP9, clarifying their relationship and coordinated work in the induction of hepatic insulin resistance. Novel research points also to other aquaporins, such as AQP11 which may be associated with the induction of insulin resistance and T2D through its involvement in hydrogen peroxide transport. In this review we collected recent discoveries in the field of AQP's involvement in the insulin resistance and T2D. Novel paths which connect AQPs with metabolic disorders can give new fuel to the research on obesity, insulin resistance and T2D - one of the most worrying problems of the modern society.
Collapse
Affiliation(s)
- Mauro Galli
- Department of Medical Biology, Medical University of Bialystok, 15-089, Bialystok, Poland.
| | - Ahsan Hameed
- Clinical Research Center, Medical University of Bialystok, 15-089, Bialystok, Poland.
| | - Arkadiusz Żbikowski
- Department of Medical Biology, Medical University of Bialystok, 15-089, Bialystok, Poland.
| | - Piotr Zabielski
- Department of Medical Biology, Medical University of Bialystok, 15-089, Bialystok, Poland.
| |
Collapse
|
|
32
|
Ge X, Wang C, Chen H, Liu T, Chen L, Huang Y, Zeng F, Liu B. Luteolin cooperated with metformin hydrochloride alleviates lipid metabolism disorders and optimizes intestinal flora compositions of high-fat diet mice. Food Funct 2021; 11:10033-10046. [PMID: 33135040 DOI: 10.1039/d0fo01840f] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Luteolin (LU) is a flavonoid compound and metformin hydrochloride (MH) is a kind of drug. Studies have shown that both LU and MH have the function of hypoglycemic effect. However, there are few reports indicating that LU cooperated with MH (LU·MH) can relieve lipid metabolism disorders and optimize intestinal flora compositions of high-fat diet mice. In this research, we investigated the effects of LU, MH and LU·MH on lipid metabolism disorders and intestinal flora composition in high-fat diet mice. The study found that compared with high-fat diet (HFD) alone, LU, MH and LU·MH could significantly reduce the lipid metabolism disorder. Furthermore, compared with LU or MH alone, the biochemical indicators of LU·MH were significantly improved and the results of the histopathological section also showed that LU·MH has stronger liver repair ability. It revealed that the potential mechanisms of the LU·MH alleviating lipid metabolism disorders were involved in the simultaneous regulation of SREBP-1c/FAS and SREBP-1c/ACC/Cpt-1. In addition, LU·MH could regulate the intestinal flora compositions. This includes significantly reducing the ratio of Firmicutes and Bacteroidetes(F/B) and at the family level, increasing the relative abundance of Lachnospiraceae, Helicobacteraceae, Marinifilaceae and Peptococcaceae to relieve lipid metabolism disorders. In conclusion, the work found that LU·MH regulates the signal pathway of SREBP-1c/FAS and SREBP-1c/ACC/Cpt-1 simultaneously and decreases the ratio of F/B, as well as increases the relative abundance of certain microbiota to alleviate the lipid metabolism disorders of HFD-fed mice.
Collapse
Affiliation(s)
- Xiaodong Ge
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China.
| | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Renton MC, McGee SL, Howlett KF. The role of protein kinase D (PKD) in intracellular nutrient sensing and regulation of adaptive responses to the obese environment. Obes Rev 2021; 22:e13145. [PMID: 32929844 DOI: 10.1111/obr.13145] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/19/2020] [Accepted: 09/01/2020] [Indexed: 12/16/2022]
Abstract
Obesity is associated with ectopic accumulation of lipids, which is implicated in the development of insulin resistance, type 2 diabetes mellitus and cardiovascular disease. As the global prevalence of obesity continues to rise, it is becoming increasingly important to understand the underlying cellular mechanisms of this disease. Protein kinase D (PKD) is an intracellular signalling kinase with well characterized roles in intracellular vesicle transport and secretion, cancer cell proliferation and cardiac hypertrophy. However, emerging evidence also highlights PKD as a novel nutrient sensor. PKD activation is mediated by the accumulation of the lipid intermediate diacylglycerol, and PKD activity in the liver, heart and adipose tissue increases upon feeding. In obesity, PKD signalling is linked to reduced insulin signalling and dysfunction in adipose tissue, liver and heart, whilst in the pancreas, PKD is essential for the compensatory increase in glucose-stimulated insulin secretion from β-cells during obesity. Collectively, these studies reveal aspects of PKD signalling that are involved in the tissue-specific responses to obesity. This review summarizes the emerging evidence suggesting that PKD plays an important role in regulating the adaptive response to the obese environment.
Collapse
Affiliation(s)
- Mark C Renton
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Science, Deakin University, Geelong, Australia
| | - Sean L McGee
- Institute for Mental and Physical Health and Clinical Translation, Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia
| | - Kirsten F Howlett
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Science, Deakin University, Geelong, Australia
| |
Collapse
|
|
34
|
Stevanović-Silva J, Beleza J, Coxito P, Pereira S, Rocha H, Gaspar TB, Gärtner F, Correia R, Martins MJ, Guimarães T, Martins S, Oliveira PJ, Ascensão A, Magalhães J. Maternal high-fat high-sucrose diet and gestational exercise modulate hepatic fat accumulation and liver mitochondrial respiratory capacity in mothers and male offspring. Metabolism 2021; 116:154704. [PMID: 33421507 DOI: 10.1016/j.metabol.2021.154704] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/12/2020] [Accepted: 12/27/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Maternal high-caloric nutrition and related gestational diabetes mellitus (GDM) are associated with a high-risk for developing metabolic complications later in life and in their offspring. In contrast, exercise is recognized as a non-pharmacological strategy against metabolic dysfunctions associated to lifestyle disorders. Therefore, we investigated whether gestational exercise delays the development of metabolic alterations in GDM mothers later in life, but also protects 6-week-old male offspring from adverse effects of maternal diet. METHODS Female Sprague-Dawley rats were fed with either control (C) or high-fat high-sucrose (HFHS) diet to induce GDM and submitted to gestational exercise during the 3 weeks of pregnancy. Male offspring were sedentary and fed with C-diet. RESULTS Sedentary HFHS-fed dams exhibited increased gestational body weight gain (p < 0.01) and glucose intolerance (p < 0.01), characteristic of GDM. Their offspring had normal glucose metabolism, but increased early-age body weight, which was reverted by gestational exercise. Gestational exercise also reduced offspring hepatic triglycerides accumulation (p < 0.05) and improved liver mitochondrial respiration capacity (p < 0.05), contributing to the recovery of liver bioenergetics compromised by maternal HFHS diet. Interestingly, liver mitochondrial respiration remained increased by gestational exercise in HFHS-fed dams despite prolonged HFHS consumption and exercise cessation. CONCLUSIONS Gestational exercise can result in liver mitochondrial adaptations in GDM animals, which can be preserved even after the exercise program cessation. Exposure to maternal GDM programs liver metabolic setting of male offspring, whereas gestational exercise appears as an important preventive tool against maternal diet-induced metabolic alterations.
Collapse
Affiliation(s)
- Jelena Stevanović-Silva
- Laboratory of Metabolism and Exercise (LaMetEx), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sport, University of Porto, 4200-450, Porto, Portugal.
| | - Jorge Beleza
- Department of Cell Biology, Physiology & Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Pedro Coxito
- Laboratory of Metabolism and Exercise (LaMetEx), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sport, University of Porto, 4200-450, Porto, Portugal
| | - Susana Pereira
- Laboratory of Metabolism and Exercise (LaMetEx), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sport, University of Porto, 4200-450, Porto, Portugal; CNC - Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, 3060-197 Cantanhede, Portugal
| | - Hugo Rocha
- Newborn Screening, Metabolism and Genetics Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, 4000-053 Porto, Portugal
| | - Tiago Bordeira Gaspar
- Institute for Research and Innovation in Health Sciences (i3S), University of Porto, 4200-135 Porto, Portugal; Cancer Signalling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal; Medical Faculty of University of Porto (FMUP), 4200-139 Porto, Portugal; Abel Salazar Biomedical Sciences Institute (ICBAS), University of Porto, 4050-313 Porto, Portugal
| | - Fátima Gärtner
- Institute for Research and Innovation in Health Sciences (i3S), University of Porto, 4200-135 Porto, Portugal; Department of Molecular Pathology and Immunology, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313, Porto, Portugal; Glycobiology in Cancer Group, Institute of Molecular Pathology and Immunology of University of Porto (Ipatimup), University of Porto, 4200-135 Porto, Portugal
| | - Rossana Correia
- HEMS - Histology and Electron Microscopy Institute for Research and Innovation in Health Sciences (i3S), University of Porto, 4200-135, Porto, Portugal,; Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
| | - Maria João Martins
- Institute for Research and Innovation in Health Sciences (i3S), University of Porto, 4200-135 Porto, Portugal; Department of Biomedicine, Biochemistry Unit, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Tiago Guimarães
- Department of Biomedicine, Biochemistry Unit, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal; Department of Clinical Pathology, São João Hospital Centre, EPE, 4200-319 Porto, Portugal
| | - Sandra Martins
- Department of Clinical Pathology, São João Hospital Centre, EPE, 4200-319 Porto, Portugal; EPIUnit, Institute of Public Health, University of Porto, 4050-091 Porto, Portugal
| | - Paulo J Oliveira
- CNC - Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, 3060-197 Cantanhede, Portugal
| | - António Ascensão
- Laboratory of Metabolism and Exercise (LaMetEx), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sport, University of Porto, 4200-450, Porto, Portugal
| | - José Magalhães
- Laboratory of Metabolism and Exercise (LaMetEx), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sport, University of Porto, 4200-450, Porto, Portugal
| |
Collapse
|
|
35
|
Boldarine VT, Joyce E, Pedroso AP, Telles MM, Oyama LM, Bueno AA, Ribeiro EB. Oestrogen replacement fails to fully revert ovariectomy-induced changes in adipose tissue monoglycerides, diglycerides and cholesteryl esters of rats fed a lard-enriched diet. Sci Rep 2021; 11:3841. [PMID: 33589704 PMCID: PMC7884784 DOI: 10.1038/s41598-021-82837-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 01/22/2021] [Indexed: 01/09/2023] Open
Abstract
Menopause may be accompanied by abdominal obesity and inflammation, conditions accentuated by high-fat intake, especially of saturated fat (SFA)-rich diets. We investigated the consequences of high-SFA intake on the fatty acid (FA) profile of monoglycerides, diglycerides and cholesteryl esters from retroperitoneal white adipose tissue (RET) of rats with ovariectomy-induced menopause, and the effect of oestradiol replacement. Wistar rats were either ovariectomized (Ovx) or sham operated (Sham) and fed either standard chow (C) or lard-enriched diet (L) for 12 weeks. Half of the Ovx rats received 17β-oestradiol replacement (Ovx + E2). Body weight and food intake were measured weekly. RET neutral lipids were chromatographically separated and FAs analysed by gas chromatography. Ovariectomy alone increased body weight, feed efficiency, RET mass, leptin and insulin levels, leptin/adiponectin ratio, HOMA-IR and HOMA-β indexes. OvxC + E2 showed attenuation in nearly all blood markers. HOMA-β index was restored in OvxL + E2. OvxC showed significantly disturbed SFA and polyunsaturated FA (PUFA) profile in RET cholesteryl esters (CE). OvxC also showed increased monounsaturated FA (MUFA) in the monoglyceride diglyceride (Mono-Di) fraction. Similar changes were not observed in OvxL, although increased SFA and decreased PUFA was observed in Mono-Di. Overall, HRT was only partially able to revert changes induced by ovariectomy. There appears to be increased mobilization of essential FA in Ovx via CE, which is a dynamic lipid species. The same results were not found in Mono-Di, which are more inert. HRT may be helpful to preserve FA profile in visceral fat, but possibly not wholly sufficient in reverting the metabolic effects induced by menopause.
Collapse
Affiliation(s)
- Valter Tadeu Boldarine
- Departamento de Fisiologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Botucatu 862, 2º andar, Vila Clementino, São Paulo, SP, 04023-062, Brasil.
| | - Ellen Joyce
- Department of Biological Sciences, College of Health, Life and Environmental Sciences, University of Worcester, Worcester, UK
| | - Amanda Paula Pedroso
- Departamento de Fisiologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Botucatu 862, 2º andar, Vila Clementino, São Paulo, SP, 04023-062, Brasil
| | - Mônica Marques Telles
- Departamento de Fisiologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Botucatu 862, 2º andar, Vila Clementino, São Paulo, SP, 04023-062, Brasil
| | - Lila Missae Oyama
- Departamento de Fisiologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Botucatu 862, 2º andar, Vila Clementino, São Paulo, SP, 04023-062, Brasil
| | - Allain Amador Bueno
- Department of Biological Sciences, College of Health, Life and Environmental Sciences, University of Worcester, Worcester, UK
| | - Eliane Beraldi Ribeiro
- Departamento de Fisiologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Botucatu 862, 2º andar, Vila Clementino, São Paulo, SP, 04023-062, Brasil
| |
Collapse
|
|
36
|
GPAT Gene Silencing in Muscle Reduces Diacylglycerols Content and Improves Insulin Action in Diet-Induced Insulin Resistance. Int J Mol Sci 2020; 21:ijms21197369. [PMID: 33036203 PMCID: PMC7583033 DOI: 10.3390/ijms21197369] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/23/2020] [Accepted: 10/02/2020] [Indexed: 02/03/2023] Open
Abstract
Skeletal muscle is an important tissue responsible for glucose and lipid metabolism. High-fat diet (HFD) consumption is associated with the accumulation of bioactive lipids: long chain acyl-CoA, diacylglycerols (DAG) and ceramides. This leads to impaired insulin signaling in skeletal muscle. There is little data on the involvement of DAG in the development of these disorders. Therefore, to clarify this enigma, the gene encoding glycerol-3-phosphate acyltransferase enzyme (GPAT, responsible for DAG synthesis) was silenced through shRNA interference in the gastrocnemius muscle of animals with diet-induced insulin resistance. This work shows that HFD induces insulin resistance, which is accompanied by an increase in the concentration of plasma fatty acids and the level of bioactive lipids in muscle. The increase in these lipids inhibits the insulin pathway and reduces muscle glucose uptake. GPAT silencing through electroporation with shRNA plasmid leads to a reduction in DAG and triacylglycerol (TAG) content, an increase in the activity of the insulin pathway and glucose uptake without a significant effect on ceramide content. This work clearly shows that DAG accumulation has a significant effect on the induction of muscle insulin resistance and that inhibition of DAG synthesis through GPAT modulation may be a potential target in the treatment of insulin resistance.
Collapse
|
|
37
|
Gao S, Chen Y, Hu R, Lu W, Yu L, Chen J, Liu S, Guo Y, Shen Q, Wang B, Fang W. Visualized analysis and evaluation of simultaneous controlled release of metformin hydrochloride and gliclazide from sandwiched osmotic pump capsule. Drug Dev Ind Pharm 2020; 46:1776-1786. [PMID: 32895014 DOI: 10.1080/03639045.2020.1821047] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The aim of this study was to develop the Metformin Hydrochloride and Gliclazide (MH-GZ) sandwiched osmotic pump capsule which could overcome the problems associated with short half-life and burst release. The system could deliver drugs with different solubility simultaneously at zero-order rate, in which MH-GZ were filled in both sides of the push layer respectively. The single factor and orthogonal test were employed to obtain the optimized formulation with the evaluation index of similarity factor (ƒ2). R language was used to visualized analyze the main influence factors of drug release and their correlations. Pharmacokinetic study was performed in beagle dogs compared to the marketed conventional product, which showed decreased Cmax, prolonged Tmax, and improved bioavailability, independent of pH and agitational speed but related to osmotic pressure differences across the semi permeable membrane. The designed sandwiched osmotic pump capsule proposed a promising substitute for the marketed product for the treatment of type 2 diabetes.
Collapse
Affiliation(s)
- Song Gao
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Yanjun Chen
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, China.,College of Biotechnology and Pharmaceutical Engineering, West Anhui University, Lu'an, Anhui, China
| | - Rongfeng Hu
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, China.,Anhui Province Key Laboratory of Chinese Medicinal Formula, Anhui University of Chinese Medicine, Hefei, Anhui, China.,Anhui Province Key Laboratory of Research and Development of Chinese Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, China.,Anhui Province Key Laboratory of Pharmaceutical Technology and Application, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Wenjie Lu
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Lingfei Yu
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Jiayi Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, USA
| | - Songlin Liu
- Anhui Huangshan Capsule Co., Ltd, Huangshan, Anhui, China
| | - Yuxing Guo
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, NY, USA
| | - Qiang Shen
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Bin Wang
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Wenyou Fang
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, China
| |
Collapse
|
|
38
|
Effects of Fish Oil and Grape Seed Extract Combination on Hepatic Endogenous Antioxidants and Bioactive Lipids in Diet-Induced Early Stages of Insulin Resistance in Rats. Mar Drugs 2020; 18:md18060318. [PMID: 32560216 PMCID: PMC7345288 DOI: 10.3390/md18060318] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/09/2020] [Accepted: 06/14/2020] [Indexed: 12/14/2022] Open
Abstract
Diacylglycerols (DAG) and ceramides have been suggested as early predictors of insulin resistance. This study was aimed to examine the combined effects of fish oil (FO) and grape seed extract (GSE) on hepatic endogenous antioxidants, DAG and ceramides in diet-induced early stages of insulin resistance. Thirty-five rats were fed one of the following diets: (1) a standard diet (STD group), (2) a high-fat high-sucrose diet (HFHS group), (3) an HFHS diet enriched with FO (FO group), (4) an HFHS diet enriched with GSE (GSE group) or (5) an HFHS diet enriched with FO and GSE (FO + GSE group). In the liver, endogenous antioxidants were measured using spectrophotometric and fluorometric techniques, and non-targeted lipidomics was conducted for the assessment of DAG and ceramides. After 24 weeks, the FO + GSE group showed increased glutathione peroxidase activity, as well as monounsaturated fatty acid and polyunsaturated fatty acid-containing DAG, and long-chain fatty acid-containing ceramides abundances compared to the STD group. The FO and GSE combination induced similar activation of the antioxidant system and bioactive lipid accumulation in the liver than the HFHS diet without supplementation. In addition, the FO and GSE combination increased the abundances of polyunsaturated fatty acid-containing DAG in the liver.
Collapse
|
|
39
|
Chaudhari K, Wang J, Xu Y, Winters A, Wang L, Dong X, Cheng EY, Liu R, Yang SH. Determination of metformin bio-distribution by LC-MS/MS in mice treated with a clinically relevant paradigm. PLoS One 2020; 15:e0234571. [PMID: 32525922 PMCID: PMC7289415 DOI: 10.1371/journal.pone.0234571] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 05/27/2020] [Indexed: 12/18/2022] Open
Abstract
Metformin, an anti-diabetes drug, has been recently emerging as a potential “anti-aging” intervention based on its reported beneficial actions against aging in preclinical studies. Nonetheless, very few metformin studies using mice have determined metformin concentrations and many effects of metformin have been observed in preclinical studies using doses/concentrations that were not relevant to therapeutic levels in human. We developed a liquid chromatography-tandem mass spectrometry protocol for metformin measurement in plasma, liver, brain, kidney, and muscle of mice. Young adult male and female C57BL/6 mice were voluntarily treated with metformin of 4 mg/ml in drinking water which translated to the maximum dose of 2.5 g/day in humans. A clinically relevant steady-state plasma metformin concentrations were achieved at 7 and 30 days after treatment in male and female mice. Metformin concentrations were slightly higher in muscle than in plasma, while, ~3 and 6-fold higher in the liver and kidney than in plasma, respectively. Low metformin concentration was found in the brain at ~20% of the plasma level. Furthermore, gender difference in steady-state metformin bio-distribution was observed. Our study established steady-state metformin levels in plasma, liver, muscle, kidney, and brain of normoglycemic mice treated with a clinically relevant dose, providing insight into future metformin preclinical studies for potential clinical translation.
Collapse
Affiliation(s)
- Kiran Chaudhari
- Department of Pharmacology and Neuroscience, Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
| | - Jianmei Wang
- Pharmaceutical analysis core lab, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
| | - Yong Xu
- Department of Pharmacology and Neuroscience, Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
| | - Ali Winters
- Department of Pharmacology and Neuroscience, Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
| | - Linshu Wang
- Department of Pharmacology and Neuroscience, Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
| | - Xiaowei Dong
- Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
| | - Eric Y. Cheng
- Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
| | - Ran Liu
- Department of Pharmacology and Neuroscience, Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
| | - Shao-Hua Yang
- Department of Pharmacology and Neuroscience, Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
- * E-mail:
| |
Collapse
|
|
40
|
Obesity, Bioactive Lipids, and Adipose Tissue Inflammation in Insulin Resistance. Nutrients 2020; 12:nu12051305. [PMID: 32375231 PMCID: PMC7284998 DOI: 10.3390/nu12051305] [Citation(s) in RCA: 246] [Impact Index Per Article: 49.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 12/11/2022] Open
Abstract
Obesity is a major risk factor for the development of insulin resistance and type 2 diabetes. The exact mechanism by which adipose tissue induces insulin resistance is still unclear. It has been demonstrated that obesity is associated with the adipocyte dysfunction, macrophage infiltration, and low-grade inflammation, which probably contributes to the induction of insulin resistance. Adipose tissue synthesizes and secretes numerous bioactive molecules, namely adipokines and cytokines, which affect the metabolism of both lipids and glucose. Disorders in the synthesis of adipokines and cytokines that occur in obesity lead to changes in lipid and carbohydrates metabolism and, as a consequence, may lead to insulin resistance and type 2 diabetes. Obesity is also associated with the accumulation of lipids. A special group of lipids that are able to regulate the activity of intracellular enzymes are biologically active lipids: long-chain acyl-CoAs, ceramides, and diacylglycerols. According to the latest data, the accumulation of these lipids in adipocytes is probably related to the development of insulin resistance. Recent studies indicate that the accumulation of biologically active lipids in adipose tissue may regulate the synthesis/secretion of adipokines and proinflammatory cytokines. Although studies have revealed that inflammation caused by excessive fat accumulation and abnormalities in lipid metabolism can contribute to the development of obesity-related insulin resistance, further research is needed to determine the exact mechanism by which obesity-related insulin resistance is induced.
Collapse
|
|
41
|
Li YP, Wang CY, Shang HT, Hu RR, Fu H, Xiao XF. A high-throughput and untargeted lipidomics approach reveals new mechanistic insight and the effects of salvianolic acid B on the metabolic profiles in coronary heart disease rats using ultra-performance liquid chromatography with mass spectrometry. RSC Adv 2020; 10:17101-17113. [PMID: 35521479 PMCID: PMC9053481 DOI: 10.1039/d0ra00049c] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 04/12/2020] [Indexed: 12/11/2022] Open
Abstract
High-throughput lipidomics provides the possibility for the development of new therapeutic drugs. Accordingly, herein, we reveal the protective role of salvianolic acid B (Sal B) in rats with coronary heart disease (CHD) and propose a new mechanism for its action through a high-throughput and non-targeted lipidomics strategy. A CHD animal model was induced by consecutive high-fat diet feeding with vitamin D3 injection. At the end of the 8th week, the serum sample was analyzed to explore the metabolic biomarker and pathway changes using untargeted lipidomics based on ultra-performance liquid chromatography with mass spectrometry (UPLC/MS). In addition, blood and heart tissue samples were collected and processed for the detection of biochemical indicators and liver histological observation. After salvianolic acid B treatment, the levels of LDH, CK, CK-MB, MYO, CTn1, TG, TC, LDL-c, and Apo(b) were significantly lower than that in the model group, while the levels of HDL-c and Apo(a1) were significantly higher than that in the model group. Furthermore, the histological features of fibrosis and steatosis were also evidently relieved in the model group. A total of twenty-six potential biomarkers were identified to express the lipid metabolic turbulence in the CHD animal models, of which twenty-two were regulated by salvianolic acid B trending to the normal state, including TG(20:0/20:4/o-18:0), PC(20:4/18:1(9Z)), PC(18:3/20:2), PA(18:0/18:2), LysoPE(18:2/0:0), SM(d18:0/22:1), PE(22:6/0:0), LysoPE (20:4/0:0), sphinganine, Cer(d18:0/18:0), PS(14:0/14:1), PC (18:0/16:0), LysoPC(17:0), PE(22:2/20:1), PC(20:3/20:4), PE(20:4/P-16:0), PS(20:3/18:0), cholesterol sulfate, TG(15:0/22:6/18:1), prostaglandin E2, arachidonic acid and sphingosine-1-phosphate. According to the metabolite enrichment and pathway analyses, the pharmacological activity of salvianolic acid B on CHD is mainly involved in three vital metabolic pathways including glycerophospholipid metabolism, sphingolipid metabolism and arachidonic acid metabolism. Thus, based on the lipidomics-guided biochemical analysis of the lipid biomarkers and pathways, Sal B protects against CHD with good therapeutic effect by regulating glycerophospholipid metabolism, sphingolipid metabolism and arachidonic acid metabolism, inhibiting oxidative stress damage and lipid peroxidation. High-throughput lipidomics provides the possibility for the development of new therapeutic drugs.![]()
Collapse
Affiliation(s)
- Ying-Peng Li
- Tianjin University of Traditional Chinese Medicine Tianjin 301617 China
| | - Cong-Ying Wang
- Tianjin University of Traditional Chinese Medicine Tianjin 301617 China
| | - Hong-Tao Shang
- Tianjin University of Traditional Chinese Medicine Tianjin 301617 China
| | - Rui-Rui Hu
- Tianjin University of Traditional Chinese Medicine Tianjin 301617 China
| | - Hui Fu
- Tianjin University of Traditional Chinese Medicine Tianjin 301617 China
| | - Xue-Feng Xiao
- Tianjin University of Traditional Chinese Medicine Tianjin 301617 China
| |
Collapse
|
|
42
|
Hilvo M, Vasile VC, Donato LJ, Hurme R, Laaksonen R. Ceramides and Ceramide Scores: Clinical Applications for Cardiometabolic Risk Stratification. Front Endocrinol (Lausanne) 2020; 11:570628. [PMID: 33133018 PMCID: PMC7550651 DOI: 10.3389/fendo.2020.570628] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 08/27/2020] [Indexed: 01/10/2023] Open
Abstract
Ceramides are bioactive lipids that have an important role in many cellular functions such as apoptosis and inflammation. During the past decade emerging clinical data have shown that ceramides are not only of great biochemical interest but may also have diagnostic utility. Ceramides have shown independent predictive value for negative cardiovascular outcomes as well as for the onset of type 2 diabetes. Based on abundant published data, risk score using the concentrations of circulating ceramides have been developed and adapted for routine clinical practice. Currently serum ceramides are used clinically as efficient risk stratifiers for primary and secondary prevention of atherosclerotic cardiovascular disease (CVD). A direct cause-effect relationship between CVD and ceramide has not been established to date. As ceramide-specific medications are being developed, conventional strategies such as lipid lowering agents and lifestyle interventions can be used to reduce overall risk. Ceramides can identify a very high-risk coronary heart disease category of patients in need for more intense medical attention, specifically those patients at higher risk as highlighted in the 2019 European Society of Cardiology guidelines for stable chronic coronary syndrome patients. In addition, the ceramide risk score may be used as a decision-making tool in primary prevention patients with moderate CVD risk. Finally, the ceramide risk score may have a unique utility as a motivational tool to increase patient's adherence to medical therapy and lifestyle changes.
Collapse
Affiliation(s)
| | - Vlad C. Vasile
- Department of Laboratory Medicine and Pathology and Department of Cardiovascular Diseases Mayo Clinic College of Medicine, Rochester, MN, United States
| | - Leslie J. Donato
- Department of Laboratory Medicine and Pathology and Department of Cardiovascular Diseases Mayo Clinic College of Medicine, Rochester, MN, United States
| | | | - Reijo Laaksonen
- Zora Biosciences Oy, Espoo, Finland
- Finnish Cardiovascular Research Center Tampere, Tampere University, Tampere, Finland
- *Correspondence: Reijo Laaksonen
| |
Collapse
|
|
43
|
Razak Hady H, Błachnio-Zabielska AU, Szczerbiński Ł, Zabielski P, Imierska M, Dadan J, Krętowski AJ. Ceramide Content in Liver Increases Along with Insulin Resistance in Obese Patients. J Clin Med 2019; 8:E2197. [PMID: 31842461 PMCID: PMC6947381 DOI: 10.3390/jcm8122197] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/02/2019] [Accepted: 12/11/2019] [Indexed: 12/15/2022] Open
Abstract
The liver plays a central role in the glucose and lipid metabolism. Studies performed on animal models have shown an important role of lipid accumulation in the induction of insulin resistance. We sought to explain whether in obese humans, the insulin resistance is associated with hepatic ceramide accumulation. The experiments were conducted on obese men and women. Each gender was divided into three groups: Normal glucose tolerance group (NGT), Impaired glucose tolerance group (IGT), and Type 2 diabetic subjects (T2D). Ceramide (Cer) content was analyzed with the use of LC/MS/MS. An oral glucose tolerance test (OGTT), glycosylated hemoglobin (HbA1c), percentage body fat (FAT%), and body mass index (BMI) was also measured. Total hepatic ceramide was significantly higher in T2D females as compared to NGT females (p < 0.05), whereas in males, total ceramide was significantly higher in IGT and T2D as compared to NGT (p < 0.05). In both, men and women, the highest increase in T2D subjects, was observed in C16:0-Cer, C18:0:-Cer, C22:0-Cer, and C24:0-Cer (p < 0.05) as compared to NGT group. Interestingly, glucose (at 0' and at 120' in OGTT) and HbA1c positively correlated with the ceramide species that most increased in T2D patients (C16:0-Cer, C18:0-Cer, C22:0-Cer, and C24:0-Cer). In men glucose and HbA1c significantly correlated with only C22:0-Cer. This is one of the few studies comparing hepatic ceramide content in severely obese patients. We found that, ceramide content increased in diabetic patients, both in men and women, and the content of ceramide correlated with glycemic parameters. These data indicate ceramide contribution to the induction of hepatic insulin resistance.
Collapse
Affiliation(s)
- Hady Razak Hady
- 1st Department of General Surgery and Endocrinology, Medical University Bialystok, 15-276 Bialystok, Poland; (H.R.H.); (J.D.)
| | | | - Łukasz Szczerbiński
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-276 Bialystok, Poland; (Ł.S.); (A.J.K.)
| | - Piotr Zabielski
- Department of Medical Biology, Medical University of Bialystok, 15-222 Bialystok, Poland;
| | - Monika Imierska
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, 15-222 Bialystok, Poland;
| | - Jacek Dadan
- 1st Department of General Surgery and Endocrinology, Medical University Bialystok, 15-276 Bialystok, Poland; (H.R.H.); (J.D.)
| | - Adam J. Krętowski
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-276 Bialystok, Poland; (Ł.S.); (A.J.K.)
- Clinical Research Centre, Medical University of Bialystok, 15-276 Bialystok, Poland
| |
Collapse
|
|
44
|
Pradas I, Rovira-Llopis S, Naudí A, Bañuls C, Rocha M, Hernandez-Mijares A, Pamplona R, Victor VM, Jové M. Metformin induces lipid changes on sphingolipid species and oxidized lipids in polycystic ovary syndrome women. Sci Rep 2019; 9:16033. [PMID: 31690730 PMCID: PMC6831788 DOI: 10.1038/s41598-019-52263-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 09/30/2019] [Indexed: 02/06/2023] Open
Abstract
Metformin is one of the treatments used for PCOS pathology decreasing body weight, plasma androgen, FSH and glucose levels. Unfortunately, there is little known about metformin's effects on lipid metabolism, a crucial process in PCOS pathology. We have employed a lipidomic approach to explore alterations in the plasma lipid profile of patients with PCOS following metformin treatment. The aim is to offer new insights about the effect of metformin in PCOS patients. Plasma samples were obtained from 27 subjects prior to and following 12 weeks of metformin treatment. A detailed biochemical characterization and lipidomic profile was performed. Metformin reduces BMI, HOMA-IR, FSH and androstenedione and increases DHEA-S but no changes were found in glucose levels after treatment. Multivariate statistics revealed a specific lipidomic signature due to the effect of 12 weeks of metformin treatment in PCOS patients. This signature includes changes in sphingolipid metabolism suggesting a crosstalk between these lipid species and the androgenic metabolism and a decrease in oxidized lipids reinforcing that metformin treatment improves oxidative stress status. Our study confirms the specific effect of metformin in lipid metabolism on women with PCOS after 12 weeks of treatment.
Collapse
Affiliation(s)
- Irene Pradas
- Department of Experimental Medicine, Lleida University-Institute for Research in Biomedicine of Lleida (UdL-IRBLleida), 25198, Lleida, Spain
| | - Susana Rovira-Llopis
- Foundation for the Promotion of Healthcare and Biomedical Research in the Valencian Community (FISABIO), Service of Endocrinology, University Hospital Dr. Peset, 46017, Valencia, Spain
| | - Alba Naudí
- Department of Experimental Medicine, Lleida University-Institute for Research in Biomedicine of Lleida (UdL-IRBLleida), 25198, Lleida, Spain
| | - Celia Bañuls
- Foundation for the Promotion of Healthcare and Biomedical Research in the Valencian Community (FISABIO), Service of Endocrinology, University Hospital Dr. Peset, 46017, Valencia, Spain
| | - Milagros Rocha
- Foundation for the Promotion of Healthcare and Biomedical Research in the Valencian Community (FISABIO), Service of Endocrinology, University Hospital Dr. Peset, 46017, Valencia, Spain
| | - Antonio Hernandez-Mijares
- Foundation for the Promotion of Healthcare and Biomedical Research in the Valencian Community (FISABIO), Service of Endocrinology, University Hospital Dr. Peset, 46017, Valencia, Spain
- Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia University, 46010, Valencia, Spain
- Department of Medicine, Valencia University, 46010, Valencia, Spain
| | - Reinald Pamplona
- Department of Experimental Medicine, Lleida University-Institute for Research in Biomedicine of Lleida (UdL-IRBLleida), 25198, Lleida, Spain
| | - Victor M Victor
- Foundation for the Promotion of Healthcare and Biomedical Research in the Valencian Community (FISABIO), Service of Endocrinology, University Hospital Dr. Peset, 46017, Valencia, Spain.
- Department of Physiology, Valencia University, 46010, Valencia, Spain.
| | - Mariona Jové
- Department of Experimental Medicine, Lleida University-Institute for Research in Biomedicine of Lleida (UdL-IRBLleida), 25198, Lleida, Spain.
| |
Collapse
|
|
45
|
Zong J, Li S, Wang Y, Mo W, Sun R, Yu M. Bromodomain-containing protein 2 promotes lipolysis via ERK/HSL signalling pathway in white adipose tissue of mice. Gen Comp Endocrinol 2019; 281:105-116. [PMID: 31121164 DOI: 10.1016/j.ygcen.2019.05.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 04/17/2019] [Accepted: 05/14/2019] [Indexed: 01/10/2023]
Abstract
White adipose tissue (WAT) dysfunction is prevalent among patients with type 2 diabetes mellitus (T2DM). Uncontrolled free fatty acid (FFA) release from WAT stores has detrimental effects on lipid metabolism, leading to insulin resistance. Bromodomain-containing protein 2 (Brd2) has emerged as a central transcriptional regulator of adipocyte differentiation and pancreatic β-cell bioactivity. A recent study shows that Brd2 overexpression leads to insulin resistance in mice. However, the mechanisms underlying these effects have not been fully elucidated. This study provides the first evidence that adenoviral-mediated Brd2 overexpression in the WAT of mice increases lipolysis-related gene expression in addition to significantly reducing WAT size and promoting plasma FFA release. Brd2 overexpression in adipocytes also inhibits fat synthesis-related gene expression, while activating hormone-sensitive lipase (HSL) expression and ERK-dependent perilipin 1 inhibition as well as promoting glycerol release, which are all involved in lipolysis. Collectively, these results indicate that Brd2 triggers insulin resistance via lipolysis-mediated FFA release.
Collapse
Affiliation(s)
- Jiuyu Zong
- The Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Fudan University, Shanghai 200032, China
| | - Shuting Li
- The Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Fudan University, Shanghai 200032, China
| | - Yuxiong Wang
- The Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Fudan University, Shanghai 200032, China
| | - Wei Mo
- The Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Fudan University, Shanghai 200032, China
| | - Ruixin Sun
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China.
| | - Min Yu
- The Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Fudan University, Shanghai 200032, China.
| |
Collapse
|
|
46
|
Lebeau PF, Byun JH, Platko K, MacDonald ME, Poon SV, Faiyaz M, Seidah NG, Austin RC. Diet-induced hepatic steatosis abrogates cell-surface LDLR by inducing de novo PCSK9 expression in mice. J Biol Chem 2019; 294:9037-9047. [PMID: 31004037 DOI: 10.1074/jbc.ra119.008094] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 04/09/2019] [Indexed: 12/11/2022] Open
Abstract
The worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly. Although this condition is generally benign, accumulating evidence now suggests that patients with NAFLD are also at increased risk of cardiovascular disease (CVD); the leading cause of death in developed nations. Despite the well-established role of the liver as a central regulator of circulating low-density lipoprotein (LDL) cholesterol levels, a known driver of CVD, the mechanism(s) by which hepatic steatosis contributes to CVD remains elusive. Interestingly, a recent study has shown that circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels correlate positively with liver steatosis grade. Given that PCSK9 degrades the LDL receptor (LDLR) and prevents the removal of LDL from the blood into the liver, in the present study we examined the effect of hepatic steatosis on LDLR expression and circulating LDL cholesterol levels. We now report that in a manner consistent with findings in patients, diet-induced steatosis increases circulating PCSK9 levels as a result of de novo expression in mice. We also report the finding that steatosis abrogates hepatic LDLR expression and increases circulating LDL levels in a PCSK9-dependent manner. These findings provide important mechanistic insights as to how hepatic steatosis modulates lipid regulatory genes, including PCSK9 and the LDLR, and also highlights a novel mechanism by which liver disease may contribute to CVD.
Collapse
Affiliation(s)
- Paul F Lebeau
- From the Department of Medicine, McMaster University, The Research Institute of St. Joe's Hamilton, Hamilton, Ontario L8N 4A6 and
| | - Jae Hyun Byun
- From the Department of Medicine, McMaster University, The Research Institute of St. Joe's Hamilton, Hamilton, Ontario L8N 4A6 and
| | - Khrystyna Platko
- From the Department of Medicine, McMaster University, The Research Institute of St. Joe's Hamilton, Hamilton, Ontario L8N 4A6 and
| | - Melissa E MacDonald
- From the Department of Medicine, McMaster University, The Research Institute of St. Joe's Hamilton, Hamilton, Ontario L8N 4A6 and
| | - Samantha V Poon
- From the Department of Medicine, McMaster University, The Research Institute of St. Joe's Hamilton, Hamilton, Ontario L8N 4A6 and
| | - Mahi Faiyaz
- From the Department of Medicine, McMaster University, The Research Institute of St. Joe's Hamilton, Hamilton, Ontario L8N 4A6 and
| | - Nabil G Seidah
- the Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute, University of Montreal, Montreal, Quebec H2W 1R7, Canada
| | - Richard C Austin
- From the Department of Medicine, McMaster University, The Research Institute of St. Joe's Hamilton, Hamilton, Ontario L8N 4A6 and
| |
Collapse
|
|
47
|
Green CJ, Marjot T, Tomlinson JW, Hodson L. Of mice and men: Is there a future for metformin in the treatment of hepatic steatosis? Diabetes Obes Metab 2019; 21:749-760. [PMID: 30456918 DOI: 10.1111/dom.13592] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 11/06/2018] [Accepted: 11/15/2018] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver diseases, of which the first stage is steatosis. It is one of the most common liver diseases in developed countries and there is a clear association between type 2 diabetes (T2DM) and NAFLD. It is estimated that 70% of people with T2DM have NAFLD and yet there is currently no licensed pharmacological agent to treat it. Whilst lifestyle modification may ameliorate liver fat, it is often difficult to achieve or sustain; thus, there is great interest in pharmacological treatments for NAFLD. Metformin is the first-line medication in the management of T2DM and evidence from animal and human studies has suggested that it may be useful in reducing liver fat via inhibition of lipogenesis and increased fatty acid oxidation. Findings from the majority of studies undertaken in rodent models clearly suggest that metformin may be a powerful therapeutic agent specifically to reduce liver fat accumulation; data from human studies are less convincing. In the present review we discuss the evidence for the specific effects of metformin treatment on liver fat accumulation in animal and human studies, as well as the underlying proposed mechanisms, to try and understand and reconcile the difference in findings between rodent and human work in this area.
Collapse
Affiliation(s)
- Charlotte J Green
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
| | - Thomas Marjot
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK
| |
Collapse
|
|
48
|
Lonardo A, Lugari S, Ballestri S, Nascimbeni F, Baldelli E, Maurantonio M. A round trip from nonalcoholic fatty liver disease to diabetes: molecular targets to the rescue? Acta Diabetol 2019; 56:385-396. [PMID: 30519965 DOI: 10.1007/s00592-018-1266-0] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 11/27/2018] [Indexed: 02/07/2023]
Abstract
Evidence suggests a close relationship between nonalcoholic fatty liver disease (NAFLD) and type two diabetes (T2D). On the grounds of prevalence of disease, both conditions account for a significant financial cost for health care systems and individuals. Aim of this review article is to explore the epidemiological basis and the putative molecular mechanisms underlying the association of NAFLD with T2D. Epidemiological studies have shown that NAFLD is associated to the development of incident T2D and either reversal or improvement of NAFLD will result into decreased risk of developing incident T2D. On the other side of the coin data have shown that T2D will worsen the course of NAFLD doubling the risk of disease progression (i.e. evolution from simple steatosis to advanced fibrosis, cirrhosis, hepatocellular carcinoma, liver transplant and death). Conversely, NAFLD will contribute to metabolic decompensation of T2D. The pathogenesis of T2D in NAFLD patients may be mediated by several hepatokines impairing metabolic control. Among these, Fetuin-B, which causes glucose intolerance and is increased in patients with T2D and NAFLD with fibrosis is one of the most promising. T2D may affect the progression of NAFLD by acting at different levels of the pathogenic cascade involving gut microbiota and expanded, inflamed, dysfunctional adipose tissue. In conclusion, T2D and NAFLD are mutually, closely and bi-directionally associated. An improved understanding of molecular pathogenesis underlying this bi-directional association may allow us to be able to prevent the development of T2D by halting the progression of NAFLD.
Collapse
Affiliation(s)
- Amedeo Lonardo
- Azienda Ospedaliero-Universitaria Modena, UO di Medicina Metabolica, Ospedale Civile di Baggiovara, Via Giardini 1135, 41125, Modena, Italy.
| | - Simonetta Lugari
- Università di Modena e Reggio Emilia, via del Pozzo, 71, 41124, Modena, Italy
| | - Stefano Ballestri
- Azienda USL di Modena, Ospedale Di Pavullo, UO di Medicina, Pavullo (Mo), Italy
| | - Fabio Nascimbeni
- Azienda Ospedaliero-Universitaria Modena, UO di Medicina Metabolica, Ospedale Civile di Baggiovara, Via Giardini 1135, 41125, Modena, Italy
| | - Enrica Baldelli
- Università di Modena e Reggio Emilia, via del Pozzo, 71, 41124, Modena, Italy
| | - Mauro Maurantonio
- Azienda Ospedaliero-Universitaria Modena, UO di Medicina Metabolica, Ospedale Civile di Baggiovara, Via Giardini 1135, 41125, Modena, Italy
| |
Collapse
|
|
49
|
DiNicolantonio JJ, McCarty M, OKeefe J. Association of moderately elevated trimethylamine N-oxide with cardiovascular risk: is TMAO serving as a marker for hepatic insulin resistance. Open Heart 2019; 6:e000890. [PMID: 30997120 PMCID: PMC6443140 DOI: 10.1136/openhrt-2018-000890] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/03/2019] [Indexed: 02/06/2023] Open
Affiliation(s)
| | | | - James OKeefe
- University of Missouri-Kansas City, Saint Lukes Mid America Heart Institute, Kansas City, Missouri, USA
| |
Collapse
|
|
50
|
Grycel S, Markowski AR, Hady HR, Zabielski P, Kojta I, Imierska M, Górski J, Blachnio-Zabielska AU. Metformin treatment affects adipocytokine secretion and lipid composition in adipose tissues of diet-induced insulin-resistant rats. Nutrition 2019; 63-64:126-133. [PMID: 30959381 DOI: 10.1016/j.nut.2019.01.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Revised: 01/09/2019] [Accepted: 01/25/2019] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Adipose tissue plays a central role in the pathogenesis of insulin resistance (IR) and type 2 diabetes. However, the molecular changes that promote these diseases are not completely understood. Several studies demonstrated that ceramide (Cer) and diacylglycerol (DAG) accumulation in muscle is associated with IR. The aim of this study was to explain whether a high-fat diet (HFD) leads to bioactive lipid accumulation in adipose tissue and how metformin affects the lipid content in adipocytes and the concentration of plasma adipocytokines. METHODS The experiments were conducted on male Wistar rats divided into three groups: control, HFD-fed, and HFD-fed and treated with metformin. Cer and DAGs were analyzed by liquid chromatography tandem mass spectrometry. Phosphorylation of hormone-sensitive lipase (HSL) was analyzed by Western blot. Oral glucose tolerance and insulin tolerance tests were also performed. Plasma adiponectin and tumor necrosis factor (TNF)-α concentration were measured by enzyme-linked immunosorbent assay. RESULTS HFD induced IR and elevated DAGs and Cer content in subcutaneous and visceral adipose tissues, which was accompanied by an increased phosphorylation of HSL. Metformin improved insulin sensitivity, decreased Cer and DAG levels, and attenuated the phosphorylation of HSL in both fat depots. Furthermore, we observed a strong correlation between adiponectin (negative) and TNF-α (positive) and bioactive lipids in both fat tissues. CONCLUSIONS These results indicated that bioactive lipids accumulation in adipose tissue influences the induction of IR and, at least in part, answered the question of what the insulin-sensitizing effect of metformin at the level of adipose tissue is.
Collapse
Affiliation(s)
| | - Adam R Markowski
- Department of Internal Medicine and Gastroenterology, Polish Red Cross Memorial Municipal Hospital, Bialystok, Poland
| | - Hady Razak Hady
- 1st Department of General Surgery and Endocrinology, Medical University Bialystok, Bialystok, Poland
| | - Piotr Zabielski
- Department of Medical Biology, Medical University of Bialystok, Bialystok, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | - Iwona Kojta
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, Bialystok, Poland
| | - Monika Imierska
- Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, Bialystok, Poland
| | - Jan Górski
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland; Department of Basic Sciences, Faculty of Health Sciences, Lomza State University of Applied Sciences, Lomza, Poland
| | | |
Collapse
|