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The Link between Obesity, Diabetes and Inflammation: Molecular Aspects

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 27036

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Special Issue Editor

Dr. Lucia La Sala

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Guest Editor

Department of Cardiovascular and Metabolic Diseases, IRCCS Multimedica, Via Fantoli 16/15, 20135 Milan, Italy
Interests: glycemic variability; redox systems; diabetes; insulin resistance; prediabetes; microRNA; extracellular vesicles; obesity; innate immune response; cutaneous and visceral adipose tissues; inflammation; signaling pathways
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

In recent years, the prevalence of chronic disease, such as cardiovascular and metabolic diseases, has constantly increased worldwide due to the rapid rise of the major risk factors, such as obesity and type 2 diabetes. Often, these conditions are concomitant, exacerbating the pre-existing inflammation. Obesity has been clearly identified as a major risk factor for diabetes in cats and for type 2 DM in humans. Obesity and diabetes are closely linked; the exact causes are linked to the activation of pro-inflammatory molecules triggering changes in metabolism. There is also evidence of the role of genetic and environmental factors in the occurrences of different types of DM between species. Deciphering the crosstalk between obesity and the aberrations related to diabetes might not only have fostered the understanding of the underlying pathophysiological mechanisms but also led to the detection of new biomarkers and for the development of novel therapeutic target.

This Special Issue will center on reviews and data manuscripts underlying molecular aspects about obesity, diabetes, and inflammation.

Dr. Lucia La Sala
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

obesity
diabetes
prediabetes
inflammation
adipose tissue
cytokines
immune system
atherosclerosis
metabolic syndrome
gene expression
microRNA
epigenetic changes
cardiovascular diseases
insulin resistance

Published Papers (7 papers)

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Research

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20 pages, 14511 KiB

Open AccessArticle

Histone Deacetylase 3 Regulates Adipocyte Phenotype at Early Stages of Differentiation

by Dalma Cricrí, Lara Coppi, Silvia Pedretti, Nico Mitro, Donatella Caruso, Emma De Fabiani and Maurizio Crestani

Int. J. Mol. Sci. 2021, 22(17), 9300; https://doi.org/10.3390/ijms22179300 - 27 Aug 2021

Cited by 6 | Viewed by 2260

Abstract

Obesity is a condition characterized by uncontrolled expansion of adipose tissue mass resulting in pathological weight gain. Histone deacetylases (HDACs) have emerged as crucial players in epigenetic regulation of adipocyte metabolism. Previously, we demonstrated that selective inhibition of class I HDACs improves white adipocyte functionality and promotes the browning phenotype of murine mesenchymal stem cells (MSCs) C3H/10T1/2 differentiated to adipocytes. These effects were also observed in db/db and diet induced obesity mouse models and in mice with adipose-selective inactivation of HDAC3, a member of class I HDACs. The molecular basis of class I HDACs action in adipose tissue is not deeply characterized and it is not known whether the effects of their inhibition are exerted on adipocyte precursors or mature adipocytes. Therefore, the aim of the present work was to explore the molecular mechanism of class I HDAC action in adipocytes by evaluating the effects of HDAC3-specific silencing at different stages of differentiation. HDAC3 was silenced in C3H/10T1/2 MSCs at different stages of differentiation to adipocytes. shRNA targeting HDAC3 was used to generate the knock-down model. Proper HDAC3 silencing was assessed by measuring both mRNA and protein levels of mouse HDAC3 via qPCR and western blot, respectively. Mitochondrial DNA content and gene expression were quantified via qPCR. HDAC3 silencing at the beginning of differentiation enhanced adipocyte functionality by amplifying the expression of genes regulating differentiation, oxidative metabolism, browning and mitochondrial activity, starting from 72 h after induction of differentiation and silencing. Insulin signaling was enhanced as demonstrated by increased AKT phosphorylation following HDAC3 silencing. Mitochondrial content/density did not change, while the increased expression of the transcriptional co-activator Ppargc1b suggests the observed phenotype was related to enhanced mitochondrial activity, which was confirmed by increased maximal respiration and proton leak linked to reduced coupling efficiency. Moreover, the expression of pro-inflammatory markers increased with HDAC3 early silencing. To the contrary, no differences in terms of gene expression were found when HDAC3 silencing occurred in terminally differentiated adipocyte. Our data demonstrated that early epigenetic events mediated by class I HDAC inhibition/silencing are crucial to commit adipocyte precursors towards the above-mentioned metabolic phenotype. Moreover, our data suggest that these effects are exerted on adipocyte precursors. Full article

(This article belongs to the Special Issue The Link between Obesity, Diabetes and Inflammation: Molecular Aspects)

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24 pages, 2367 KiB

Open AccessArticle

Skeletal Muscle Proteomic Profile Revealed Gender-Related Metabolic Responses in a Diet-Induced Obesity Animal Model

by Manuela Moriggi, Sara Belloli, Pietro Barbacini, Valentina Murtaj, Enrica Torretta, Linda Chaabane, Tamara Canu, Silvia Penati, Maria Luisa Malosio, Antonio Esposito, Cecilia Gelfi, Rosa Maria Moresco and Daniele Capitanio

Int. J. Mol. Sci. 2021, 22(9), 4680; https://doi.org/10.3390/ijms22094680 - 28 Apr 2021

Cited by 16 | Viewed by 3623

Abstract

Obesity is a chronic, complex pathology associated with a risk of developing secondary pathologies, including cardiovascular diseases, cancer, type 2 diabetes (T2DM) and musculoskeletal disorders. Since skeletal muscle accounts for more than 70% of total glucose disposal, metabolic alterations are strictly associated with the onset of insulin resistance and T2DM. The present study relies on the proteomic analysis of gastrocnemius muscle from 15 male and 15 female C56BL/J mice fed for 14 weeks with standard, 45% or 60% high-fat diets (HFD) adopting a label-free LC–MS/MS approach followed by bioinformatic pathway analysis. Results indicate changes in males due to HFD, with increased muscular stiffness (Col1a1, Col1a2, Actb), fiber-type switch from slow/oxidative to fast/glycolytic (decreased Myh7, Myl2, Myl3 and increased Myh2, Mylpf, Mybpc2, Myl1), increased oxidative stress and mitochondrial dysfunction (decreased respiratory chain complex I and V and increased complex III subunits). At variance, females show few alterations and activation of compensatory mechanisms to counteract the increase of fatty acids. Bioinformatics analysis allows identifying upstream molecules involved in regulating pathways identified at variance in our analysis (Ppargc1a, Pparg, Cpt1b, Clpp, Tp53, Kdm5a, Hif1a). These findings underline the presence of a gender-specific response to be considered when approaching obesity and related comorbidities. Full article

(This article belongs to the Special Issue The Link between Obesity, Diabetes and Inflammation: Molecular Aspects)

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14 pages, 3058 KiB

Open AccessArticle

A Systems Biology Approach to Investigating the Interaction between Serotonin Synthesis by Tryptophan Hydroxylase and the Metabolic Homeostasis

by Suhyeon Park, Yumin Kim, Jibeom Lee, Jeong Yun Lee, Hail Kim, Sunjae Lee and Chang-Myung Oh

Int. J. Mol. Sci. 2021, 22(5), 2452; https://doi.org/10.3390/ijms22052452 - 28 Feb 2021

Cited by 13 | Viewed by 3141

Abstract

Obesity has become a global public health and economic problem. Obesity is a major risk factor for a number of complications, such as type 2 diabetes, cardiovascular disease, fatty liver disease, and cancer. Serotonin (5-hydroxytryptamine [5-HT]) is a biogenic monoamine that plays various roles in metabolic homeostasis. It is well known that central 5-HT regulates appetite and mood. Several 5-HT receptor agonists and selective serotonin receptor uptake inhibitors (SSRIs) have shown beneficial effects on appetite and mood control in clinics. Although several genetic polymorphisms related to 5-HT synthesis and its receptors are strongly associated with obesity, there is little evidence of the role of peripheral 5-HT in human metabolism. In this study, we performed a systemic analysis of transcriptome data from the Genotype-Tissue Expression (GTEX) database. We investigated the expression of 5-HT and tryptophan hydroxylase (TPH), the rate-limiting enzyme of 5-HT biosynthesis, in the human brain and peripheral tissues. We also performed differential gene expression analysis and predicted changes in metabolites by comparing gene expressions of tissues with high TPH expression to the gene expressions of tissues with low TPH expression. Our analyses provide strong evidence that serotonin plays an important role in the regulation of metabolic homeostasis in humans. Full article

(This article belongs to the Special Issue The Link between Obesity, Diabetes and Inflammation: Molecular Aspects)

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Review

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16 pages, 743 KiB

Open AccessReview

Maternal Low-Grade Chronic Inflammation and Intrauterine Programming of Health and Disease

by Francesca Parisi, Roberta Milazzo, Valeria M. Savasi and Irene Cetin

Int. J. Mol. Sci. 2021, 22(4), 1732; https://doi.org/10.3390/ijms22041732 - 9 Feb 2021

Cited by 46 | Viewed by 5404

Abstract

Overweight and obesity during pregnancy have been associated with increased birth weight, childhood obesity, and noncommunicable diseases in the offspring, leading to a vicious transgenerational perpetuating of metabolic derangements. Key components in intrauterine developmental programming still remain to be identified. Obesity involves chronic low-grade systemic inflammation that, in addition to physiological adaptations to pregnancy, may potentially expand to the placental interface and lead to intrauterine derangements with a threshold effect. Animal models, where maternal inflammation is mimicked by single injections with lipopolysaccharide (LPS) resembling the obesity-induced immune profile, showed increased adiposity and impaired metabolic homeostasis in the offspring, similar to the phenotype observed after exposure to maternal obesity. Cytokine levels might be specifically important for the metabolic imprinting, as cytokines are transferable from maternal to fetal circulation and have the capability to modulate placental nutrient transfer. Maternal inflammation may induce metabolic reprogramming at several levels, starting from the periconceptional period with effects on the oocyte going through early stages of embryonic and placental development. Given the potential to reduce inflammation through inexpensive, widely available therapies, examinations of the impact of chronic inflammation on reproductive and pregnancy outcomes, as well as preventive interventions, are now needed. Full article

(This article belongs to the Special Issue The Link between Obesity, Diabetes and Inflammation: Molecular Aspects)

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21 pages, 1534 KiB

Open AccessReview

Potential Role of Insulin Growth-Factor-Binding Protein 2 as Therapeutic Target for Obesity-Related Insulin Resistance

by Hatim Boughanem, Elena M. Yubero-Serrano, José López-Miranda, Francisco J. Tinahones and Manuel Macias-Gonzalez

Int. J. Mol. Sci. 2021, 22(3), 1133; https://doi.org/10.3390/ijms22031133 - 24 Jan 2021

Cited by 26 | Viewed by 4242

Abstract

Evidence from observational and in vitro studies suggests that insulin growth-factor-binding protein type 2 (IGFBP2) is a promising protein in non-communicable diseases, such as obesity, insulin resistance, metabolic syndrome, or type 2 diabetes. Accordingly, great efforts have been carried out to explore the role of IGFBP2 in obesity state and insulin-related diseases, which it is typically found decreased. However, the physiological pathways have not been explored yet, and the relevance of IGFBP2 as an important pathway integrator of metabolic disorders is still unknown. Here, we review and discuss the molecular structure of IGFBP2 as the first element of regulating the expression of IGFBP2. We highlight an update of the association between low serum IGFBP2 and an increased risk of obesity, type 2 diabetes, metabolic syndrome, and low insulin sensitivity. We hypothesize mechanisms of IGFBP2 on the development of obesity and insulin resistance in an insulin-independent manner, which meant that could be evaluated as a therapeutic target. Finally, we cover the most interesting lifestyle modifications that regulate IGFBP2, since lifestyle factors (diet and/or physical activity) are associated with important variations in serum IGFBP2. Full article

(This article belongs to the Special Issue The Link between Obesity, Diabetes and Inflammation: Molecular Aspects)

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16 pages, 656 KiB

Open AccessReview

Does microRNA Perturbation Control the Mechanisms Linking Obesity and Diabetes? Implications for Cardiovascular Risk

by Lucia La Sala, Maurizio Crestani, Silvia Garavelli, Paola de Candia and Antonio E. Pontiroli

Int. J. Mol. Sci. 2021, 22(1), 143; https://doi.org/10.3390/ijms22010143 - 25 Dec 2020

Cited by 15 | Viewed by 3290

Abstract

Metabolic disorders such as obesity and type 2 diabetes (T2D) are considered the major risk factors for the development of cardiovascular diseases (CVD). Although the pathological mechanisms underlying the mutual development of obesity and T2D are difficult to define, a better understanding of the molecular aspects is of utmost importance to identify novel therapeutic targets. Recently, a class of non-coding RNAs, called microRNAs (miRNAs), are emerging as key modulators of metabolic abnormalities. There is increasing evidence supporting the role of intra- and extracellular miRNAs as determinants of the crosstalk between adipose tissues, liver, skeletal muscle and other organs, triggering the paracrine communication among different tissues. miRNAs may be considered as risk factors for CVD due to their correlation with cardiovascular events, and in particular, may be related to the most prominent risk factors. In this review, we describe the associations observed between miRNAs expression levels and the most common cardiovascular risk factors. Furthermore, we sought to depict the molecular aspect of the interplay between obesity and diabetes, investigating the role of microRNAs in the interorgan crosstalk. Finally, we discussed the fascinating hypothesis of the loss of protective factors, such as antioxidant defense systems regulated by such miRNAs. Full article

(This article belongs to the Special Issue The Link between Obesity, Diabetes and Inflammation: Molecular Aspects)

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8 pages, 5259 KiB

Open AccessReview

Clock Genes, Inflammation and the Immune System—Implications for Diabetes, Obesity and Neurodegenerative Diseases

by Elaine Vieira, Gerardo Gabriel Mirizio, Geovana Reichert Barin, Rosângela Vieira de Andrade, Nidah Fawzi Said Nimer and Lucia La Sala

Int. J. Mol. Sci. 2020, 21(24), 9743; https://doi.org/10.3390/ijms21249743 - 21 Dec 2020

Cited by 29 | Viewed by 4287

Abstract

Inflammation is a common feature of several diseases, including obesity, diabetes and neurodegenerative disorders. Circadian clock genes are expressed and oscillate in many cell types such as macrophages, neurons and pancreatic β cells. During inflammation, these endogenous clocks control the temporal gating of cytokine production, the antioxidant response, chemokine attraction and insulin secretion, among other processes. Deletion of clock genes in macrophages or brain-resident cells induces a higher production of inflammatory cytokines and chemokines, and this is often accompanied by an increased oxidative stress. In the context of obesity and diabetes, a high-fat diet disrupts the function of clock genes in macrophages and in pancreatic β cells, contributing to inflammation and systemic insulin resistance. Recently, it has been shown that the administration of natural and synthetic ligands or pharmacological enhancers of the circadian clock function can selectively regulate the production and release of pro-inflammatory cytokines and improve the metabolic function in vitro and in vivo. Thus, a better understanding of the circadian regulation of the immune system could have important implications for the management of metabolic and neurodegenerative diseases. Full article

(This article belongs to the Special Issue The Link between Obesity, Diabetes and Inflammation: Molecular Aspects)

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