International Journal of Molecular Sciences

Research

17 pages, 3414 KiB

Open AccessArticle

AMPK Activation Is Important for the Preservation of Insulin Sensitivity in Visceral, but Not in Subcutaneous Adipose Tissue of Postnatally Overfed Rat Model of Polycystic Ovary Syndrome

by Bojana Mićić, Ana Teofilović, Ana Djordjevic, Nataša Veličković, Djuro Macut and Danijela Vojnović Milutinović

Int. J. Mol. Sci. 2022, 23(16), 8942; https://doi.org/10.3390/ijms23168942 - 11 Aug 2022

Cited by 5 | Viewed by 2079

Abstract

Polycystic ovary syndrome (PCOS) is a well-known reproductive syndrome usually associated with obesity, insulin resistance, and hyperinsulinemia. Although the first signs of PCOS begin early in adolescence, it is underexplored whether peripubertal obesity predisposes women to PCOS metabolic disturbances. To highlight that, we [...] Read more.

Polycystic ovary syndrome (PCOS) is a well-known reproductive syndrome usually associated with obesity, insulin resistance, and hyperinsulinemia. Although the first signs of PCOS begin early in adolescence, it is underexplored whether peripubertal obesity predisposes women to PCOS metabolic disturbances. To highlight that, we examined the impact of postnatal overfeeding-induced obesity, achieved by litter size reduction during the suckling period, on metabolic disturbances associated with visceral and subcutaneous adipose tissue (VAT and SAT) function in the 5α-dihydrotestosterone (5α-DHT)-induced animal model of PCOS. We analyzed markers of insulin signaling, lipid metabolism, and energy sensing in the VAT and SAT. Our results showed that postnatally overfed DHT-treated Wistar rats had increased VAT mass with hypertrophic adipocytes, together with hyperinsulinemia and increased HOMA index. In the VAT of these animals, insulin signaling remained unchanged while lipogenic markers decreased, which was accompanied by increased AMPK activation. In the SAT of the same animals, markers of lipogenesis and lipolysis increased, while the activity of AMPK decreased. Taken together, obtained results showed that postnatal overfeeding predisposes development of PCOS systemic insulin resistance, most likely as a result of worsened metabolic function of SAT, while VAT preserved its tissue insulin sensitivity through increased activity of AMPK. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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16 pages, 1616 KiB

Open AccessArticle

Unraveling the Transcriptional Dynamics of NASH Pathogenesis Affecting Atherosclerosis

by Anita M. van den Hoek, Serdar Özsezen, Martien P. M. Caspers, Arianne van Koppen, Roeland Hanemaaijer and Lars Verschuren

Int. J. Mol. Sci. 2022, 23(15), 8229; https://doi.org/10.3390/ijms23158229 - 26 Jul 2022

Cited by 6 | Viewed by 2816

Abstract

The prevalence of non-alcoholic steatohepatitis (NASH) is rapidly increasing and associated with cardiovascular disease (CVD), the major cause of mortality in NASH patients. Although sharing common risk factors, the mechanisms by which NASH may directly contribute to the development to CVD remain poorly [...] Read more.

The prevalence of non-alcoholic steatohepatitis (NASH) is rapidly increasing and associated with cardiovascular disease (CVD), the major cause of mortality in NASH patients. Although sharing common risk factors, the mechanisms by which NASH may directly contribute to the development to CVD remain poorly understood. The aim of this study is to gain insight into key molecular processes of NASH that drive atherosclerosis development. Thereto, a time-course study was performed in Ldlr−/−.Leiden mice fed a high-fat diet to induce NASH and atherosclerosis. The effects on NASH and atherosclerosis were assessed and transcriptome analysis was performed. Ldlr−/−.Leiden mice developed obesity, hyperlipidemia and insulin resistance, with steatosis and hepatic inflammation preceding atherosclerosis development. Transcriptome analysis revealed a time-dependent increase in pathways related to NASH and fibrosis followed by an increase in pro-atherogenic processes in the aorta. Gene regulatory network analysis identified specific liver regulators related to lipid metabolism (SC5D, LCAT and HMGCR), inflammation (IL1A) and fibrosis (PDGF, COL3A1), linked to a set of aorta target genes related to vascular inflammation (TNFA) and atherosclerosis signaling (CCL2 and FDFT1). The present study reveals pathogenic liver processes that precede atherosclerosis development and identifies hepatic key regulators driving the atherogenic pathways and regulators in the aorta. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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14 pages, 2644 KiB

Open AccessArticle

DEPP Deficiency Contributes to Browning of White Adipose Tissue

by Fusheng Guo, Yanlin Zhu, Yaping Han, Xuhui Feng, Zhifu Pan, Ying He, Yong Li and Lihua Jin

Int. J. Mol. Sci. 2022, 23(12), 6563; https://doi.org/10.3390/ijms23126563 - 12 Jun 2022

Cited by 4 | Viewed by 2688

Abstract

Decidual protein induced by progesterone (DEPP) was originally identified as a modulator in the process of decidualization in the endometrium. Here, we define that DEPP is involved in adipose tissue thermogenesis, which contributes to metabolic regulation. Knockdown of DEPP suppressed adipocyte differentiation and [...] Read more.

Decidual protein induced by progesterone (DEPP) was originally identified as a modulator in the process of decidualization in the endometrium. Here, we define that DEPP is involved in adipose tissue thermogenesis, which contributes to metabolic regulation. Knockdown of DEPP suppressed adipocyte differentiation and lipid accumulation in 3T3-L1 cells, induced expression of brown adipose tissue (BAT) markers in primary brown adipocyte and induced mouse embryonic fibroblasts (MEFs) differentiation to brown adipocytes. Moreover, DEPP deficiency in mice induced white adipocyte browning and enhanced BAT activity. Cold exposure stimulated more browning of white adipose tissue (WAT) and maintained higher body temperature in DEPP knockout mice compared to that in wild-type control mice. DEPP deficiency also protected mice against high-fat-diet-induced insulin resistance. Mechanistic studies demonstrated that DEPP competitively binds SIRT1, inhibiting the interaction between peroxisome proliferator-activated receptor gamma (PPARγ) and Sirtuin 1 (SIRT1). Collectively, these findings suggest that DEPP plays a crucial role in orchestrating thermogenesis through regulating adipocyte programs and thus might be a potential target for the treatment of metabolic disorders. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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16 pages, 3050 KiB

Open AccessArticle

Contrasting Health Effects of Bacteroidetes and Firmicutes Lies in Their Genomes: Analysis of P450s, Ferredoxins, and Secondary Metabolite Clusters

by Bridget Valeria Zinhle Nkosi, Tiara Padayachee, Dominik Gront, David R. Nelson and Khajamohiddin Syed

Int. J. Mol. Sci. 2022, 23(9), 5057; https://doi.org/10.3390/ijms23095057 - 2 May 2022

Cited by 25 | Viewed by 3364

Abstract

Species belonging to the bacterial phyla Bacteroidetes and Firmicutes represent over 90% of the gastrointestinal microbiota. Changes in the ratio of these two bacterial groups were found to have contrasting health effects, including obesity and inflammatory diseases. Despite the availability of many bacterial [...] Read more.

Species belonging to the bacterial phyla Bacteroidetes and Firmicutes represent over 90% of the gastrointestinal microbiota. Changes in the ratio of these two bacterial groups were found to have contrasting health effects, including obesity and inflammatory diseases. Despite the availability of many bacterial genomes, comparative genomic studies on the gene pools of these two bacterial groups concerning cytochrome P450 monooxygenases (P450s), ferredoxins, and secondary metabolite biosynthetic gene clusters (smBGCs) are not reported. This study is aimed to address this research gap. The study revealed the presence of diverse sets of P450s, ferredoxins, and smBGCs in their genomes. Bacteroidetes species have the highest number of P450 families, ferredoxin cluster-types, and smBGCs compared to Firmicutes species. Only four P450 families, three ferredoxin cluster types, and five smBGCs are commonly shared between these two bacterial groups. Considering the above facts, we propose that the contrasting effects of these two bacterial groups on the host are partly due to the distinct nature of secondary metabolites produced by these organisms. Thus, the cause of the contrasting health effects of these two bacterial groups lies in their gene pools. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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12 pages, 2460 KiB

Open AccessArticle

Apolipoprotein CIII Reduction Protects White Adipose Tissues against Obesity-Induced Inflammation and Insulin Resistance in Mice

by Patricia Recio-López, Ismael Valladolid-Acebes, Per-Olof Berggren and Lisa Juntti-Berggren

Int. J. Mol. Sci. 2022, 23(1), 62; https://doi.org/10.3390/ijms23010062 - 22 Dec 2021

Cited by 3 | Viewed by 3200

Abstract

Apolipoprotein CIII (apoCIII) is proinflammatory and increases in high-fat diet (HFD)-induced obesity and insulin resistance. We have previously shown that reducing apoCIII improves insulin sensitivity in vivo by complex mechanisms involving liver and brown adipose tissue. In this study the focus was on [...] Read more.

Apolipoprotein CIII (apoCIII) is proinflammatory and increases in high-fat diet (HFD)-induced obesity and insulin resistance. We have previously shown that reducing apoCIII improves insulin sensitivity in vivo by complex mechanisms involving liver and brown adipose tissue. In this study the focus was on subcutaneous (SAT) and visceral (VAT) white adipose tissue (WAT). Mice were either given HFD for 14 weeks and directly from start also treated with antisense oligonucleotide (ASO) against apoCIII or given HFD for 10 weeks and HFD+ASO for an additional 14 weeks. Both groups had animals treated with inactive (Scr) ASO as controls and in parallel chow-fed mice were injected with saline. Preventing an increase or lowering apoCIII in the HFD-fed mice decreased adipocytes’ size, reduced expression of inflammatory cytokines and increased expression of genes related to thermogenesis and beiging. Isolated adipocytes from both VAT and SAT from the ASO-treated mice had normal insulin-induced inhibition of lipolysis compared to cells from Scr-treated mice. In conclusion, the HFD-induced metabolic derangements in WATs can be prevented and reversed by lowering apoCIII. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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18 pages, 5564 KiB

Open AccessArticle

Neuregulin 4 Downregulation Induces Insulin Resistance in 3T3-L1 Adipocytes through Inflammation and Autophagic Degradation of GLUT4 Vesicles

by Francisco Díaz-Sáez, Carla Blanco-Sinfreu, Adrià Archilla-Ortega, David Sebastian, Montserrat Romero, Maria Isabel Hernández-Alvarez, Sílvia Mora, Xavier Testar, Wifredo Ricart, José Manuel Fernández-Real, José María Moreno-Navarrete, Julián Aragonés, Marta Camps, Antonio Zorzano and Anna Gumà

Int. J. Mol. Sci. 2021, 22(23), 12960; https://doi.org/10.3390/ijms222312960 - 30 Nov 2021

Cited by 16 | Viewed by 3674

Abstract

The adipokine Neuregulin 4 (Nrg4) protects against obesity-induced insulin resistance. Here, we analyze how the downregulation of Nrg4 influences insulin action and the underlying mechanisms in adipocytes. Validated shRNA lentiviral vectors were used to generate scramble (Scr) and Nrg4 knockdown (KD) 3T3-L1 adipocytes. [...] Read more.

The adipokine Neuregulin 4 (Nrg4) protects against obesity-induced insulin resistance. Here, we analyze how the downregulation of Nrg4 influences insulin action and the underlying mechanisms in adipocytes. Validated shRNA lentiviral vectors were used to generate scramble (Scr) and Nrg4 knockdown (KD) 3T3-L1 adipocytes. Adipogenesis was unaffected in Nrg4 KD adipocytes, but there was a complete impairment of the insulin-induced 2-deoxyglucose uptake, which was likely the result of reduced insulin receptor and Glut4 protein. Downregulation of Nrg4 enhanced the expression of proinflammatory cytokines. Anti-inflammatory agents recovered the insulin receptor, but not Glut4, content. Proteins enriched in Glut4 storage vesicles such as the insulin-responsive aminopeptidase (IRAP) and Syntaxin-6 as well as TBC1D4, a protein involved in the intracellular retention of Glut4 vesicles, also decreased by Nrg4 KD. Insulin failed to reduce autophagy in Nrg4 KD adipocytes, observed by a minor effect on mTOR phosphorylation, at the time that proteins involved in autophagy such as LC3-II, Rab11, and Clathrin were markedly upregulated. The lysosomal activity inhibitor bafilomycin A1 restored Glut4, IRAP, Syntaxin-6, and TBC1D4 content to those found in control adipocytes. Our study reveals that Nrg4 preserves the insulin responsiveness by preventing inflammation and, in turn, benefits the insulin regulation of autophagy. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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16 pages, 2112 KiB

Open AccessArticle

Cardioprotective Effects of Palmitoleic Acid (C16:1n7) in a Mouse Model of Catecholamine-Induced Cardiac Damage Are Mediated by PPAR Activation

by Iris Rosa Betz, Sarah Julia Qaiyumi, Madeleine Goeritzer, Arne Thiele, Sarah Brix, Niklas Beyhoff, Jana Grune, Robert Klopfleisch, Franziska Greulich, Nina Henriette Uhlenhaut, Ulrich Kintscher and Anna Foryst-Ludwig

Int. J. Mol. Sci. 2021, 22(23), 12695; https://doi.org/10.3390/ijms222312695 - 24 Nov 2021

Cited by 5 | Viewed by 2935

Abstract

Palmitoleic acid (C16:1n7) has been identified as a regulator of physiological cardiac hypertrophy. In the present study, we aimed to investigate the molecular pathways involved in C16:1n7 responses in primary murine cardiomyocytes (PCM) and a mouse model of isoproterenol (ISO)-induced cardiac damage. PCMs [...] Read more.

Palmitoleic acid (C16:1n7) has been identified as a regulator of physiological cardiac hypertrophy. In the present study, we aimed to investigate the molecular pathways involved in C16:1n7 responses in primary murine cardiomyocytes (PCM) and a mouse model of isoproterenol (ISO)-induced cardiac damage. PCMs were stimulated with C16:1n7 or a vehicle. Afterwards, RNA sequencing was performed using an Illumina HiSeq sequencer. Confirmatory analysis was performed in PCMs and HL-1 cardiomyocytes. For an in vivo study, 129 sv mice were orally treated with a vehicle or C16:1n7 for 22 days. After 5 days of pre-treatment, the mice were injected with ISO (25 mg/kg/d s. c.) for 4 consecutive days. Cardiac phenotyping was performed using echocardiography. In total, 129 genes were differentially expressed in PCMs stimulated with C16:1n7, including Angiopoietin-like factor 4 (Angptl4) and Pyruvate Dehydrogenase Kinase 4 (Pdk4). Both Angptl4 and Pdk4 are proxisome proliferator-activated receptor α/δ (PPARα/δ) target genes. Our in vivo results indicated cardioprotective and anti-fibrotic effects of C16:1n7 application in mice. This was associated with the C16:1n7-dependent regulation of the cardiac PPAR-specific signaling pathways. In conclusion, our experiments demonstrated that C16:1n7 might have protective effects on cardiac fibrosis and inflammation. Our study may help to develop future lipid-based therapies for catecholamine-induced cardiac damage. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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23 pages, 5967 KiB

Open AccessArticle

Implication of N-Methyl-d-Aspartate Receptor in Homocysteine-Induced Age-Related Macular Degeneration

by Yara A. Samra, Dina Kira, Pragya Rajpurohit, Riyaz Mohamed, Leah A. Owen, Akbar Shakoor, Ivana K. Kim, Margaret M. DeAngelis, Nader Sheibani, Mohamed Al-Shabrawey and Amany Tawfik

Int. J. Mol. Sci. 2021, 22(17), 9356; https://doi.org/10.3390/ijms22179356 - 28 Aug 2021

Cited by 6 | Viewed by 3502

Abstract

Age-related macular degeneration (AMD) is a leading cause of vision loss. Elevated homocysteine (Hcy) (Hyperhomocysteinemia) (HHcy) has been reported in AMD. We previously reported that HHcy induces AMD-like features. This study suggests that N-Methyl-d-aspartate receptor (NMDAR) activation in the retinal [...] Read more.

Age-related macular degeneration (AMD) is a leading cause of vision loss. Elevated homocysteine (Hcy) (Hyperhomocysteinemia) (HHcy) has been reported in AMD. We previously reported that HHcy induces AMD-like features. This study suggests that N-Methyl-d-aspartate receptor (NMDAR) activation in the retinal pigment epithelium (RPE) is a mechanism for HHcy-induced AMD. Serum Hcy and cystathionine-β-synthase (CBS) were assessed by ELISA. The involvement of NMDAR in Hcy-induced AMD features was evaluated (1) in vitro using ARPE-19 cells, primary RPE isolated from HHcy mice (CBS), and mouse choroidal endothelial cells (MCEC); (2) in vivo using wild-type mice and mice deficient in RPE NMDAR (NMDAR^R^−/−) with/without Hcy injection. Isolectin-B4, Ki67, HIF-1α, VEGF, NMDAR1, and albumin were assessed by immunofluorescence (IF), Western blot (WB), Optical coherence tomography (OCT), and fluorescein angiography (FA) to evaluate retinal structure, fluorescein leakage, and choroidal neovascularization (CNV). A neovascular AMD patient’s serum showed a significant increase in Hcy and a decrease in CBS. Hcy significantly increased HIF-1α, VEGF, and NMDAR in RPE cells, and Ki67 in MCEC. Hcy-injected WT mice showed disrupted retina and CNV. Knocking down RPE NMDAR improved retinal structure and CNV. Our findings underscore the role of RPE NMDAR in Hcy-induced AMD features; thus, NMDAR inhibition could serve as a promising therapeutic target for AMD. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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14 pages, 2873 KiB

Open AccessArticle

Pleiotrophin Deficiency Induces Browning of Periovarian Adipose Tissue and Protects against High-Fat Diet-Induced Hepatic Steatosis

by Agata Zuccaro, Begoña Zapatería, María Gracia Sánchez-Alonso, María Haro, María Limones, Gloria Terrados, Adriana Izquierdo, Patricia Corrales, Gema Medina-Gómez, Gonzalo Herradón, Julio Sevillano and María del Pilar Ramos-Álvarez

Int. J. Mol. Sci. 2021, 22(17), 9261; https://doi.org/10.3390/ijms22179261 - 26 Aug 2021

Cited by 4 | Viewed by 3119

Abstract

(1) Background: Pleiotrophin preserves insulin sensitivity, regulates adipose tissue lipid turnover and plasticity, energy metabolism and thermogenesis. The aim of this study was to determine the role of pleiotrophin in hepatic lipid metabolism and in the metabolic crosstalk between the liver and brown [...] Read more.

(1) Background: Pleiotrophin preserves insulin sensitivity, regulates adipose tissue lipid turnover and plasticity, energy metabolism and thermogenesis. The aim of this study was to determine the role of pleiotrophin in hepatic lipid metabolism and in the metabolic crosstalk between the liver and brown and white adipose tissue (AT) in a high-fat diet-induced (HFD) obesity mice model. (2) Methods: We analyzed circulating variables, lipid metabolism (hepatic lipid content and mRNA expression), brown AT thermogenesis (UCP-1 expression) and periovarian AT browning (brown adipocyte markers mRNA and immunodetection) in Ptn^−/− mice either fed with standard-chow diet or with HFD and in their corresponding Ptn^+/+ counterparts. (3) Results: HFD-Ptn^−/− mice are protected against the development of HFD-induced insulin resistance, had lower liver lipid content and lower expression of the key enzymes involved in triacylglycerides and fatty acid synthesis in liver. HFD-Ptn^−/− mice showed higher UCP-1 expression in brown AT. Moreover, Ptn deletion increased the expression of specific markers of brown/beige adipocytes and was associated with the immunodetection of UCP-1 enriched multilocular adipocytes in periovarian AT. (4) Conclusions: Ptn deletion protects against the development of HFD-induced insulin resistance and liver steatosis, by increasing UCP-1 expression in brown AT and promoting periovarian AT browning. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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12 pages, 3407 KiB

Open AccessArticle

The Essential Role of PRAK in Preserving Cardiac Function and Insulin Resistance in High-Fat Diet-Induced Diabetes

by Jianfeng Du, Yu Tina Zhao, Hao Wang, Ling X. Zhang, Gangjian Qin, Shougang Zhuang, Marshall Kadin, Y. Eugene Chin, Paul Y. Liu and Ting C. Zhao

Int. J. Mol. Sci. 2021, 22(15), 7995; https://doi.org/10.3390/ijms22157995 - 27 Jul 2021

Cited by 5 | Viewed by 2852

Abstract

Regulated/activated protein kinase (PRAK) plays a crucial role in modulating biological function. However, the role of PRAK in mediating cardiac dysfunction and metabolic disorders remains unclear. We examined the effects of deletion of PRAK on modulating cardiac function and insulin resistance in mice [...] Read more.

Regulated/activated protein kinase (PRAK) plays a crucial role in modulating biological function. However, the role of PRAK in mediating cardiac dysfunction and metabolic disorders remains unclear. We examined the effects of deletion of PRAK on modulating cardiac function and insulin resistance in mice exposed to a high-fat diet (HFD). Wild-type and PRAK^−/− mice at 8 weeks old were exposed to either chow food or HFD for a consecutive 16 weeks. Glucose tolerance tests and insulin tolerance tests were employed to assess insulin resistance. Echocardiography was employed to assess myocardial function. Western blot was used to determine the molecular signaling involved in phosphorylation of IRS-1, AMPKα, ERK-44/42, and irisin. Real time-PCR was used to assess the hypertrophic genes of the myocardium. Histological analysis was employed to assess the hypertrophic response, interstitial myocardial fibrosis, and apoptosis in the heart. Western blot was employed to determine cellular signaling pathway. HFD-induced metabolic stress is indicated by glucose intolerance and insulin intolerance. PRAK knockout aggravated insulin resistance, as indicated by glucose intolerance and insulin intolerance testing as compared with wild-type littermates. As compared with wild-type mice, hyperglycemia and hypercholesterolemia were manifested in PRAK-knockout mice following high-fat diet intervention. High-fat diet intervention displayed a decline in fractional shortening and ejection fraction. However, deletion of PRAK exacerbated the decline in cardiac function as compared with wild-type mice following HFD treatment. In addition, PRAK knockout mice enhanced the expression of myocardial hypertrophic genes including ANP, BNP, and βMHC in HFD treatment, which was also associated with an increase in cardiomyocyte size and interstitial fibrosis. Western blot indicated that deletion of PRAK induces decreases in phosphorylation of IRS-1, AMPKα, and ERK44/42 as compared with wild-type controls. Our finding indicates that deletion of PRAK promoted myocardial dysfunction, cardiac remodeling, and metabolic disorders in response to HFD. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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26 pages, 1537 KiB

Open AccessReview

Recent Advances in Molecular Research on Hydrogen Sulfide (H₂S) Role in Diabetes Mellitus (DM)—A Systematic Review

by Constantin Munteanu, Mariana Rotariu, Marius Turnea, Gabriela Dogaru, Cristina Popescu, Aura Spînu, Ioana Andone, Ruxandra Postoiu, Elena Valentina Ionescu, Carmen Oprea, Irina Albadi and Gelu Onose

Int. J. Mol. Sci. 2022, 23(12), 6720; https://doi.org/10.3390/ijms23126720 - 16 Jun 2022

Cited by 25 | Viewed by 2829

Abstract

Abundant experimental data suggest that hydrogen sulfide (H₂S) is related to the pathophysiology of Diabetes Mellitus (DM). Multiple molecular mechanisms, including receptors, membrane ion channels, signalingmolecules, enzymes, and transcription factors, are known to be responsible for the H₂S biological [...] Read more.

Abundant experimental data suggest that hydrogen sulfide (H₂S) is related to the pathophysiology of Diabetes Mellitus (DM). Multiple molecular mechanisms, including receptors, membrane ion channels, signalingmolecules, enzymes, and transcription factors, are known to be responsible for the H₂S biological actions; however, H₂S is not fully documented as a gaseous signaling molecule interfering with DM and vascular-linked pathology. In recent decades, multiple approaches regarding therapeutic exploitation of H₂S have been identified, either based on H₂S exogenous apport or on its modulated endogenous biosynthesis. This paper aims to synthesize and systematize, as comprehensively as possible, the recent literature-related data regarding the therapeutic/rehabilitative role of H₂S in DM. This review was conducted following the “Preferred reporting items for systematic reviews and meta-analyses” (PRISMA) methodology, interrogating five international medically renowned databases by specific keyword combinations/“syntaxes” used contextually, over the last five years (2017–2021). The respective search/filtered and selection methodology we applied has identified, in the first step, 212 articles. After deploying the next specific quest steps, 51 unique published papers qualified for minute analysis resulted. To these bibliographic resources obtained through the PRISMA methodology, in order to have the best available information coverage, we added 86 papers that were freely found by a direct internet search. Finally, we selected for a connected meta-analysis eight relevant reports that included 1237 human subjects elicited from clinical trial registration platforms. Numerous H₂S releasing/stimulating compounds have been produced, some being used in experimental models. However, very few of them were further advanced in clinical studies, indicating that the development of H₂S as a therapeutic agent is still at the beginning. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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35 pages, 3317 KiB

Open AccessReview

Recent Advances in Understanding Nrf2 Agonism and Its Potential Clinical Application to Metabolic and Inflammatory Diseases

by Min-Ji Kim and Jae-Han Jeon

Int. J. Mol. Sci. 2022, 23(5), 2846; https://doi.org/10.3390/ijms23052846 - 5 Mar 2022

Cited by 44 | Viewed by 5855

Abstract

Oxidative stress is a major component of cell damage and cell fat, and as such, it occupies a central position in the pathogenesis of metabolic disease. Nuclear factor-erythroid-derived 2-related factor 2 (Nrf2), a key transcription factor that coordinates expression of genes encoding antioxidant [...] Read more.

Oxidative stress is a major component of cell damage and cell fat, and as such, it occupies a central position in the pathogenesis of metabolic disease. Nuclear factor-erythroid-derived 2-related factor 2 (Nrf2), a key transcription factor that coordinates expression of genes encoding antioxidant and detoxifying enzymes, is regulated primarily by Kelch-like ECH-associated protein 1 (Keap1). However, involvement of the Keap1–Nrf2 pathway in tissue and organism homeostasis goes far beyond protection from cellular stress. In this review, we focus on evidence for Nrf2 pathway dysfunction during development of several metabolic/inflammatory disorders, including diabetes and diabetic complications, obesity, inflammatory bowel disease, and autoimmune diseases. We also review the beneficial role of current molecular Nrf2 agonists and summarize their use in ongoing clinical trials. We conclude that Nrf2 is a promising target for regulation of numerous diseases associated with oxidative stress and inflammation. However, more studies are needed to explore the role of Nrf2 in the pathogenesis of metabolic/inflammatory diseases and to review safety implications before therapeutic use in clinical practice. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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12 pages, 1066 KiB

Open AccessReview

Metabolic Effects of CCN5/WISP2 Gene Deficiency and Transgenic Overexpression in Mice

by Tara Alami and Jun-Li Liu

Int. J. Mol. Sci. 2021, 22(24), 13418; https://doi.org/10.3390/ijms222413418 - 14 Dec 2021

Cited by 6 | Viewed by 3492

Abstract

CCN5/WISP2 is a matricellular protein, the expression of which is under the regulation of Wnt signaling and IGF-1. Our initial characterization supports the notion that CCN5 might promote the proliferation and survival of pancreatic β-cells and thus improve the metabolic profile of the [...] Read more.

CCN5/WISP2 is a matricellular protein, the expression of which is under the regulation of Wnt signaling and IGF-1. Our initial characterization supports the notion that CCN5 might promote the proliferation and survival of pancreatic β-cells and thus improve the metabolic profile of the animals. More recently, the roles of endogenous expression of CCN5 and its ectopic, transgenic overexpression on metabolic regulation have been revealed through two reports. Here, we attempt to compare the experimental findings from those studies, side-by-side, in order to further establish its roles in metabolic regulation. Prominent among the discoveries was that a systemic deficiency of CCN5 gene expression caused adipocyte hypertrophy, increased adipogenesis, and lipid accumulation, resulting in insulin resistance and glucose intolerance, which were further exacerbated upon high-fat diet feeding. On the other hand, the adipocyte-specific and systemic overexpression of CCN5 caused an increase in lean body mass, improved insulin sensitivity, hyperplasia of cardiomyocytes, and increased heart mass, but decreased fasting glucose levels. CCN5 is clearly a regulator of adipocyte proliferation and maturation, affecting lean/fat mass ratio and insulin sensitivity. Not all results from these models are consistent; moreover, several important aspects of CCN5 physiology are yet to be explored. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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14 pages, 2165 KiB

Open AccessReview

Adipose-Derived Lipid-Binding Proteins: The Good, the Bad and the Metabolic Diseases

by Laurie Frances, Geneviève Tavernier and Nathalie Viguerie

Int. J. Mol. Sci. 2021, 22(19), 10460; https://doi.org/10.3390/ijms221910460 - 28 Sep 2021

Cited by 18 | Viewed by 3184

Abstract

Adipose tissue releases a large range of bioactive factors called adipokines, many of which are involved in inflammation, glucose homeostasis and lipid metabolism. Under pathological conditions such as obesity, most of the adipokines are upregulated and considered as deleterious, due to their pro-inflammatory, [...] Read more.

Adipose tissue releases a large range of bioactive factors called adipokines, many of which are involved in inflammation, glucose homeostasis and lipid metabolism. Under pathological conditions such as obesity, most of the adipokines are upregulated and considered as deleterious, due to their pro-inflammatory, pro-atherosclerotic or pro-diabetic properties, while only a few are downregulated and would be designated as beneficial adipokines, thanks to their counteracting properties against the onset of comorbidities. This review focuses on six adipose-derived lipid-binding proteins that have emerged as key factors in the development of obesity and diabetes: Retinol binding protein 4 (RBP4), Fatty acid binding protein 4 (FABP4), Apolipoprotein D (APOD), Lipocalin-2 (LCN2), Lipocalin-14 (LCN14) and Apolipoprotein M (APOM). These proteins share structural homology and capacity to bind small hydrophobic molecules but display opposite effects on glucose and lipid metabolism. RBP4 and FABP4 are positively associated with metabolic syndrome, while APOD and LCN2 are ubiquitously expressed proteins with deleterious or beneficial effects, depending on their anatomical site of expression. LCN14 and APOM have been recently identified as adipokines associated with healthy metabolism. Recent findings on these lipid-binding proteins exhibiting detrimental or protective roles in human and murine metabolism and their involvement in metabolic diseases are also discussed. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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25 pages, 1278 KiB

Open AccessReview

Recent Advancements in the Medical Treatment of Diabetic Retinal Disease

by Maja Szymanska, Daanyaal Mahmood, Timothy E. Yap and Maria F. Cordeiro

Int. J. Mol. Sci. 2021, 22(17), 9441; https://doi.org/10.3390/ijms22179441 - 31 Aug 2021

Cited by 12 | Viewed by 5780

Abstract

Diabetic retinal disease remains one of the most common complications of diabetes mellitus (DM) and a leading cause of preventable blindness. The mainstay of management involves glycemic control, intravitreal, and laser therapy. However, intravitreal therapy commonly requires frequent hospital visits and some patients [...] Read more.

Diabetic retinal disease remains one of the most common complications of diabetes mellitus (DM) and a leading cause of preventable blindness. The mainstay of management involves glycemic control, intravitreal, and laser therapy. However, intravitreal therapy commonly requires frequent hospital visits and some patients fail to achieve a significant improvement in vision. Novel and long-acting therapies targeting a range of pathways are warranted, while evidence to support optimal combinations of treatments is currently insufficient. Improved understanding of the molecular pathways involved in pathogenesis is driving the development of therapeutic agents not only targeting visible microvascular disease and metabolic derangements, but also inflammation and accelerated retinal neurodegeneration. This review summarizes the current and emerging treatments of diabetic retinal diseases and provides an insight into the future of managing this important condition. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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11 pages, 708 KiB

Open AccessReview

Anti-Inflammatory Therapy for Atherosclerosis: Focusing on Cytokines

by Anastasia V. Poznyak, Dwaipayan Bharadwaj, Gauri Prasad, Andrey V. Grechko, Margarita A. Sazonova and Alexander N. Orekhov

Int. J. Mol. Sci. 2021, 22(13), 7061; https://doi.org/10.3390/ijms22137061 - 30 Jun 2021

Cited by 51 | Viewed by 5283

Abstract

Atherosclerosis is a well-known global health problem. Despite the high prevalence of the disease, numerous aspects of pathogenesis remain unclear. Subsequently, there are still no cure or adequate preventive measures available. Atherogenesis is now considered a complex interplay between lipid metabolism alterations, oxidative [...] Read more.

Atherosclerosis is a well-known global health problem. Despite the high prevalence of the disease, numerous aspects of pathogenesis remain unclear. Subsequently, there are still no cure or adequate preventive measures available. Atherogenesis is now considered a complex interplay between lipid metabolism alterations, oxidative stress, and inflammation. Inflammation in atherogenesis involves cellular elements of both innate (such as macrophages and monocytes) and adaptive immunity (such as B-cells and T-cells), as well as various cytokines cascades. Because inflammation is, in general, a well-investigated therapeutic target, and strategies for controlling inflammation have been successfully used to combat a number of other diseases, inflammation seems to be the preferred target for the treatment of atherosclerosis as well. In this review, we summarized data on targeting the most studied inflammatory molecular targets, CRP, IL-1β, IL-6, IFN-γ, and TNF-α. Studies in animal models have shown the efficacy of anti-inflammatory therapy, while clinical studies revealed the incompetence of existing data, which blocks the development of an effective atheroprotective drug. However, all data on cytokine targeting give evidence that anti-inflammatory therapy can be a part of a complex treatment. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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20 pages, 736 KiB

Open AccessReview

Mitochondrial Dysfunction and Chronic Inflammation in Polycystic Ovary Syndrome

by Siarhei A. Dabravolski, Nikita G. Nikiforov, Ali H. Eid, Ludmila V. Nedosugova, Antonina V. Starodubova, Tatyana V. Popkova, Evgeny E. Bezsonov and Alexander N. Orekhov

Int. J. Mol. Sci. 2021, 22(8), 3923; https://doi.org/10.3390/ijms22083923 - 10 Apr 2021

Cited by 74 | Viewed by 11344

Abstract

Polycystic ovarian syndrome (PCOS) is the most common endocrine–metabolic disorder affecting a vast population worldwide; it is linked with anovulation, mitochondrial dysfunctions and hormonal disbalance. Mutations in mtDNA have been identified in PCOS patients and likely play an important role in PCOS aetiology [...] Read more.

Polycystic ovarian syndrome (PCOS) is the most common endocrine–metabolic disorder affecting a vast population worldwide; it is linked with anovulation, mitochondrial dysfunctions and hormonal disbalance. Mutations in mtDNA have been identified in PCOS patients and likely play an important role in PCOS aetiology and pathogenesis; however, their causative role in PCOS development requires further investigation. As a low-grade chronic inflammation disease, PCOS patients have permanently elevated levels of inflammatory markers (TNF-α, CRP, IL-6, IL-8, IL-18). In this review, we summarise recent data regarding the role of mtDNA mutations and mitochondrial malfunctions in PCOS pathogenesis. Furthermore, we discuss recent papers dedicated to the identification of novel biomarkers for early PCOS diagnosis. Finally, traditional and new mitochondria-targeted treatments are discussed. This review intends to emphasise the key role of oxidative stress and chronic inflammation in PCOS pathogenesis; however, the exact molecular mechanism is mostly unknown and requires further investigation. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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19 pages, 2502 KiB

Open AccessReview

NLRP3 Inflammasome: Potential Role in Obesity Related Low-Grade Inflammation and Insulin Resistance in Skeletal Muscle

by Gonzalo Jorquera, Javier Russell, Matías Monsalves-Álvarez, Gonzalo Cruz, Denisse Valladares-Ide, Carla Basualto-Alarcón, Genaro Barrientos, Manuel Estrada and Paola Llanos

Int. J. Mol. Sci. 2021, 22(6), 3254; https://doi.org/10.3390/ijms22063254 - 23 Mar 2021

Cited by 29 | Viewed by 5756

Abstract

Among multiple mechanisms, low-grade inflammation is critical for the development of insulin resistance as a feature of type 2 diabetes. The nucleotide-binding oligomerization domain-like receptor family (NOD-like) pyrin domain containing 3 (NLRP3) inflammasome has been linked to the development of insulin resistance in [...] Read more.

Among multiple mechanisms, low-grade inflammation is critical for the development of insulin resistance as a feature of type 2 diabetes. The nucleotide-binding oligomerization domain-like receptor family (NOD-like) pyrin domain containing 3 (NLRP3) inflammasome has been linked to the development of insulin resistance in various tissues; however, its role in the development of insulin resistance in the skeletal muscle has not been explored in depth. Currently, there is limited evidence that supports the pathological role of NLRP3 inflammasome activation in glucose handling in the skeletal muscle of obese individuals. Here, we have centered our focus on insulin signaling in skeletal muscle, which is the main site of postprandial glucose disposal in humans. We discuss the current evidence showing that the NLRP3 inflammasome disturbs glucose homeostasis. We also review how NLRP3-associated interleukin and its gasdermin D-mediated efflux could affect insulin-dependent intracellular pathways. Finally, we address pharmacological NLRP3 inhibitors that may have a therapeutical use in obesity-related metabolic alterations. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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11 pages, 696 KiB

Open AccessReview

Mushroom-Derived Medicine? Preclinical Studies Suggest Potential Benefits of Ergothioneine for Cardiometabolic Health

by Daniel Lam-Sidun, Kia M. Peters and Nica M. Borradaile

Int. J. Mol. Sci. 2021, 22(6), 3246; https://doi.org/10.3390/ijms22063246 - 23 Mar 2021

Cited by 21 | Viewed by 6969

Abstract

Medicinal use of mushrooms has been documented since ancient times, and in the modern world, mushrooms have a longstanding history of use in Eastern medicine. Recent interest in plant-based diets in Westernized countries has brought increasing attention to the use of mushrooms and [...] Read more.

Medicinal use of mushrooms has been documented since ancient times, and in the modern world, mushrooms have a longstanding history of use in Eastern medicine. Recent interest in plant-based diets in Westernized countries has brought increasing attention to the use of mushrooms and mushroom-derived compounds in the prevention and treatment of chronic diseases. Edible mushrooms are the most abundant food sources of the modified amino acid, ergothioneine. This compound has been shown to accumulate in almost all cells and tissues, but preferentially in those exposed to oxidative stress and injury. The demonstrated cytoprotectant effect of ergothioneine has led many to suggest a potential therapeutic role for this compound in chronic conditions that involve ongoing oxidative stress and inflammation, including cardiovascular and metabolic diseases. However, the in vivo effects of ergothioneine and its underlying therapeutic mechanisms in the whole organism are not as clear. Moreover, there are no well-defined, clinical prevention and intervention trials of ergothioneine in chronic disease. This review highlights the cellular and molecular mechanisms of action of ergothioneine and its potential as a Traditional, Complementary and Alternative Medicine for the promotion of cardiometabolic health and the management of the most common manifestations of cardiometabolic disease. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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21 pages, 871 KiB

Open AccessHypothesis

Priming, Triggering, Adaptation and Senescence (PTAS): A Hypothesis for a Common Damage Mechanism of Steatohepatitis

by Peter M. Abuja, Kurt Zatloukal and Helmut Denk

Int. J. Mol. Sci. 2021, 22(22), 12545; https://doi.org/10.3390/ijms222212545 - 21 Nov 2021

Viewed by 2167

Abstract

Understanding the pathomechanism of steatohepatitis (SH) is hampered by the difficulty of distinguishing between causes and consequences, by the broad spectrum of aetiologies that can produce the phenotype, and by the long time-span during which SH develops, often without clinical symptoms. We propose [...] Read more.

Understanding the pathomechanism of steatohepatitis (SH) is hampered by the difficulty of distinguishing between causes and consequences, by the broad spectrum of aetiologies that can produce the phenotype, and by the long time-span during which SH develops, often without clinical symptoms. We propose that SH develops in four phases with transitions: (i) priming lowers stress defence; (ii) triggering leads to acute damage; (iii) adaptation, possibly associated with cellular senescence, mitigates tissue damage, leads to the phenotype, and preserves liver function at a lower level; (iv) finally, senescence prevents neoplastic transformation but favours fibrosis (cirrhosis) and inflammation and further reduction in liver function. Escape from senescence eventually leads to hepatocellular carcinoma. This hypothesis for a pathomechanism of SH is supported by clinical and experimental observations. It allows organizing the various findings to uncover remaining gaps in our knowledge and, finally, to provide possible diagnostic and intervention strategies for each stage of SH development. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Research of Metabolic Disorders)

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