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Central and Peripheral Molecular Mechanisms of Metabolism Regulation 3.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 13227

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Guest Editor
Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli “Federico II”, Via Pansini, 5, 80131 Napoli, Italy
Interests: obesity; DNA methylation
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Special Issue Information

Dear Colleagues,

Control of the peripheral organ metabolism and whole-body energy homeostasis are realized through a tight integration among hormonal, dietary, and nervous physiological mechanisms. Topics of special interest are the mechanisms by which dietary nutrients and drugs, acting on peripheral targets directly or indirectly at various levels of the microbiota–gut–brain axis, affect metabolism and inflammatory processes which, in turn, influence eating behavior and impact the course of many diseases; similarly, the molecular mechanisms linking cell metabolism and growth are of interest for the understanding of metabolic alteration in cancer cells. Despite growing progress in this area, many questions remain unresolved, particularly with regard to the mechanisms of metabolism control at a molecular level. Indeed, a better understanding of how the metabolism is dysregulated in a disease state can lead to the potential development of new drugs targeting metabolic pathways. To contribute to a greater body of knowledge in this field, this Special Issue aims to collect original papers and reviews dealing with central and peripheral molecular mechanisms underlying metabolism regulation and their disruption in diseases with significant metabolic implications, including cardiovascular diseases, obesity, neurodegenerative diseases, and cancer. Papers addressing dietary and hormone molecular mechanisms of control of adipose tissue, muscle, bone, or liver metabolism, as well as the central molecular mechanisms of metabolism control and energy balance, are welcome.

Prof. Dr. Mariarosaria Santillo
Dr. Simona Damiano
Guest Editors

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Keywords

  • cell metabolism
  • diet
  • energy homeostasis
  • hypothalamus
  • metabolic diseases
  • adipose tissue
  • muscle metabolism
  • bone metabolism
  • liver metabolism
  • inflammation
  • obesity
  • hormones
  • neurodegenerative diseases
  • cancer metabolism

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Published Papers (7 papers)

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Research

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24 pages, 4595 KiB  
Article
Mitochondrial DNA Instability Supersedes Parkin Mutations in Driving Mitochondrial Proteomic Alterations and Functional Deficits in Polg Mutator Mice
by Andrew J. Trease, Steven Totusek, Eliezer Z. Lichter, Kelly L. Stauch and Howard S. Fox
Int. J. Mol. Sci. 2024, 25(12), 6441; https://doi.org/10.3390/ijms25126441 - 11 Jun 2024
Viewed by 183
Abstract
Mitochondrial quality control is essential in mitochondrial function. To examine the importance of Parkin-dependent mechanisms in mitochondrial quality control, we assessed the impact of modulating Parkin on proteome flux and mitochondrial function in a context of reduced mtDNA fidelity. To accomplish this, we [...] Read more.
Mitochondrial quality control is essential in mitochondrial function. To examine the importance of Parkin-dependent mechanisms in mitochondrial quality control, we assessed the impact of modulating Parkin on proteome flux and mitochondrial function in a context of reduced mtDNA fidelity. To accomplish this, we crossed either the Parkin knockout mouse or ParkinW402A knock-in mouse lines to the Polg mitochondrial mutator line to generate homozygous double mutants. In vivo longitudinal isotopic metabolic labeling was followed by isolation of liver mitochondria and synaptic terminals from the brain, which are rich in mitochondria. Mass spectrometry and bioenergetics analysis were assessed. We demonstrate that slower mitochondrial protein turnover is associated with loss of mtDNA fidelity in liver mitochondria but not synaptic terminals, and bioenergetic function in both tissues is impaired. Pathway analysis revealed loss of mtDNA fidelity is associated with disturbances of key metabolic pathways, consistent with its association with metabolic disorders and neurodegeneration. Furthermore, we find that loss of Parkin leads to exacerbation of Polg-driven proteomic consequences, though it may be bioenergetically protective in tissues exhibiting rapid mitochondrial turnover. Finally, we provide evidence that, surprisingly, dis-autoinhibition of Parkin (ParkinW402A) functionally resembles Parkin knockout and fails to rescue deleterious Polg-driven effects. Our study accomplishes three main outcomes: (1) it supports recent studies suggesting that Parkin dependence is low in response to an increased mtDNA mutational load, (2) it provides evidence of a potential protective role of Parkin insufficiency, and (3) it draws into question the therapeutic attractiveness of enhancing Parkin function. Full article
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21 pages, 2831 KiB  
Article
Antioxidant, Anti-Inflammatory and Pro-Differentiative Effects of Chlorogenic Acid on M03-13 Human Oligodendrocyte-like Cells
by Giuliana La Rosa, Concetta Sozio, Luca Pipicelli, Maddalena Raia, Anna Palmiero, Mariarosaria Santillo and Simona Damiano
Int. J. Mol. Sci. 2023, 24(23), 16731; https://doi.org/10.3390/ijms242316731 - 24 Nov 2023
Cited by 1 | Viewed by 1196
Abstract
Chlorogenic acid (CGA), a polyphenol found mainly in coffee and tea, exerts antioxidant, anti-inflammatory and anti-apoptotic effects at the gastrointestinal level. However, although CGA is known to cross the blood–brain barrier (BBB), its effects on the CNS are still unknown. Oligodendrocytes (OLs), the [...] Read more.
Chlorogenic acid (CGA), a polyphenol found mainly in coffee and tea, exerts antioxidant, anti-inflammatory and anti-apoptotic effects at the gastrointestinal level. However, although CGA is known to cross the blood–brain barrier (BBB), its effects on the CNS are still unknown. Oligodendrocytes (OLs), the myelin-forming cells in the CNS, are the main target in demyelinating neuroinflammatory diseases such as multiple sclerosis (MS). We evaluated the antioxidant, anti-inflammatory and anti-apoptotic roles of CGA in M03-13, an immortalized human OL cell line. We found that CGA reduces intracellular superoxide ions, mitochondrial reactive oxygen species (ROS) and NADPH oxidases (NOXs) /dual oxidase 2 (DUOX2) protein levels. The stimulation of M03-13 cells with TNFα activates the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kB) pathway, leading to an increase in superoxide ion, NOXs/DUOX2 and phosphorylated extracellular regulated protein kinase (pERK) levels. In addition, tumor necrosis factor alpha (TNF-α) stimulation induces caspase 8 activation and the cleavage of poly-ADP-ribose polymerase (PARP). All these TNFα-induced effects are reversed by CGA. Furthermore, CGA induces a blockade of proliferation, driving cells to differentiation, resulting in increased mRNA levels of myelin basic protein (MBP) and proteolipid protein (PLP), which are major markers of mature OLs. Overall, these data suggest that dietary supplementation with this polyphenol could play an important beneficial role in autoimmune neuroinflammatory diseases such as MS. Full article
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21 pages, 2394 KiB  
Article
Effect of Organic Selenium on the Homeostasis of Trace Elements, Lipid Peroxidation, and mRNA Expression of Antioxidant Proteins in Mouse Organs
by Inga Staneviciene, Dovydas Levinas, Ilona Sadauskiene, Arunas Liekis, Dale Viezeliene, Lolita Kursvietiene, Rima Naginiene, Dale Baranauskiene, Vaida Simakauskiene, Paulina Vaitkiene, Giedre Miniotaite and Jurgita Sulinskiene
Int. J. Mol. Sci. 2023, 24(11), 9704; https://doi.org/10.3390/ijms24119704 - 2 Jun 2023
Cited by 2 | Viewed by 1397
Abstract
(1) In this study we determined the effect of long-term selenomethionine administration on the oxidative stress level and changes in antioxidant protein/enzyme activity; mRNA expression; and the levels of iron, zinc, and copper. (2) Experiments were performed on 4–6-week-old BALB/c mice, which were [...] Read more.
(1) In this study we determined the effect of long-term selenomethionine administration on the oxidative stress level and changes in antioxidant protein/enzyme activity; mRNA expression; and the levels of iron, zinc, and copper. (2) Experiments were performed on 4–6-week-old BALB/c mice, which were given selenomethionine (0.4 mg Se/kg b.w.) solution for 8 weeks. The element concentration was determined via inductively coupled plasma mass spectrometry. mRNA expression of SelenoP, Cat, and Sod1 was quantified using real-time quantitative reverse transcription. Malondialdehyde content and catalase activity were determined spectrophotometrically. (3) After long-term SeMet administration, the amount of Se increased by 12-fold in mouse blood, 15-fold in the liver, and 42-fold in the brain, as compared to that in the control. Exposure to SeMet decreased amounts of Fe and Cu in blood, but increased Fe and Zn levels in the liver and increased the levels of all examined elements in the brain. Se increased malondialdehyde content in the blood and brain but decreased it in liver. SeMet administration increased the mRNA expression of selenoprotein P, dismutase, and catalase, but decreased catalase activity in brain and liver. (4) Eight-week-long selenomethionine consumption elevated Se levels in the blood, liver, and especially in the brain and disturbed the homeostasis of Fe, Zn, and Cu. Moreover, Se induced lipid peroxidation in the blood and brain, but not in the liver. In response to SeMet exposure, significant up-regulation of the mRNA expression of catalase, superoxide dismutase 1, and selenoprotein P in the brain, and especially in the liver, was determined. Full article
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13 pages, 1899 KiB  
Article
Impaired Organokine Regulation in Non-Diabetic Obese Subjects: Halfway to the Cardiometabolic Danger Zone
by Hajnalka Lőrincz, Balázs Ratku, Sára Csiha, Ildikó Seres, Zoltán Szabó, György Paragh, Mariann Harangi and Sándor Somodi
Int. J. Mol. Sci. 2023, 24(4), 4115; https://doi.org/10.3390/ijms24044115 - 18 Feb 2023
Cited by 3 | Viewed by 1540
Abstract
Altered organokine expression contributes to increased cardiometabolic risk in obesity. Our aim was to evaluate the associations of serum afamin with glucose homeostasis, atherogenic dyslipidemia, and other adipokines in severe obesity to clarify the early metabolic alterations. 106 non-diabetic obese (NDO) subjects and [...] Read more.
Altered organokine expression contributes to increased cardiometabolic risk in obesity. Our aim was to evaluate the associations of serum afamin with glucose homeostasis, atherogenic dyslipidemia, and other adipokines in severe obesity to clarify the early metabolic alterations. 106 non-diabetic obese (NDO) subjects and 62 obese patients with type 2 diabetes matched for age, gender, and body mass index (BMI) were enrolled in this study. We compared their data with 49 healthy, lean controls. Serum afamin and retinol-binding protein 4 (RBP4), as well as plasma plasminogen activator inhibitor-1 (PAI-1), were measured with ELISA, and lipoprotein subfractions were analyzed using Lipoprint gel electrophoresis. Afamin and PAI-1 found to be significantly higher in the NDO and T2M group (p < 0.001 and p < 0.001, respectively) than in the controls. In contrast, RBP4 was unexpectedly lower in the NDO and T2DM group compared to controls (p < 0.001). Afamin showed negative correlations with mean LDL size and RBP4, but positive correlations with anthropometric, glucose/lipid parameters, and PAI-1 in both the overall patients and the in NDO + T2DM groups. BMI, glucose, intermediate HDL, and small HDL were predictors of afamin. Afamin may serve as a biomarker for the severity of cardiometabolic disturbances in obesity. The complexity of organokine patterns in NDO subjects draws attention to the diverse spectrum of obesity-related comorbidities. Full article
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Review

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31 pages, 1477 KiB  
Review
Dysregulated Liver Metabolism and Polycystic Ovarian Syndrome
by Muhammad Sohaib Khan, Hee-Sun Kim, Ranhee Kim, Sang Ho Yoon and Sang Geon Kim
Int. J. Mol. Sci. 2023, 24(8), 7454; https://doi.org/10.3390/ijms24087454 - 18 Apr 2023
Cited by 2 | Viewed by 3152
Abstract
A significant fraction of couples around the world suffer from polycystic ovarian syndrome (PCOS), a disease defined by the characteristics of enhanced androgen synthesis in ovarian theca cells, hyperandrogenemia, and ovarian dysfunction in women. Most of the clinically observable symptoms and altered blood [...] Read more.
A significant fraction of couples around the world suffer from polycystic ovarian syndrome (PCOS), a disease defined by the characteristics of enhanced androgen synthesis in ovarian theca cells, hyperandrogenemia, and ovarian dysfunction in women. Most of the clinically observable symptoms and altered blood biomarker levels in the patients indicate metabolic dysregulation and adaptive changes as the key underlying mechanisms. Since the liver is the metabolic hub of the body and is involved in steroid-hormonal detoxification, pathological changes in the liver may contribute to female endocrine disruption, potentially through the liver-to-ovary axis. Of particular interest are hyperglycemic challenges and the consequent changes in liver-secretory protein(s) and insulin sensitivity affecting the maturation of ovarian follicles, potentially leading to female infertility. The purpose of this review is to provide insight into emerging metabolic mechanisms underlying PCOS as the primary culprit, which promote its incidence and aggravation. Additionally, this review aims to summarize medications and new potential therapeutic approaches for the disease. Full article
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21 pages, 1423 KiB  
Review
Dietary Polyphenols, Microbiome, and Multiple Sclerosis: From Molecular Anti-Inflammatory and Neuroprotective Mechanisms to Clinical Evidence
by Giuliana La Rosa, Maria Serena Lonardo, Nunzia Cacciapuoti, Espedita Muscariello, Bruna Guida, Raffaella Faraonio, Mariarosaria Santillo and Simona Damiano
Int. J. Mol. Sci. 2023, 24(8), 7247; https://doi.org/10.3390/ijms24087247 - 14 Apr 2023
Cited by 10 | Viewed by 2591
Abstract
Multiple sclerosis (MS) is a multifactorial, immune-mediated disease caused by complex gene-environment interactions. Dietary factors modulating the inflammatory status through the control of the metabolic and inflammatory pathways and the composition of commensal gut microbiota, are among the main environmental factors involved in [...] Read more.
Multiple sclerosis (MS) is a multifactorial, immune-mediated disease caused by complex gene-environment interactions. Dietary factors modulating the inflammatory status through the control of the metabolic and inflammatory pathways and the composition of commensal gut microbiota, are among the main environmental factors involved in the pathogenesis of MS. There is no etiological therapy for MS and the drugs currently used, often accompanied by major side effects, are represented by immunomodulatory substances capable of modifying the course of the disease. For this reason, nowadays, more attention is paid to alternative therapies with natural substances with anti-inflammatory and antioxidant effects, as adjuvants of classical therapies. Among natural substances with beneficial effects on human health, polyphenols are assuming an increasing interest due to their powerful antioxidant, anti-inflammatory, and neuroprotective effects. Beneficial properties of polyphenols on the CNS are achieved through direct effects depending on their ability to cross the blood-brain barrier and indirect effects exerted in part via interaction with the microbiota. The aim of this review is to examine the literature about the molecular mechanism underlying the protective effects of polyphenols in MS achieved by experiments conducted in vitro and in animal models of the disease. Significant data have been accumulated for resveratrol, curcumin, luteolin, quercetin, and hydroxytyrosol, and therefore we will focus on the results obtained with these polyphenols. Clinical evidence for the use of polyphenols as adjuvant therapy in MS is restricted to a smaller number of substances, mainly curcumin and epigallocatechin gallate. In the last part of the review, a clinical trial studying the effects of these polyphenols in MS patients will also be revised. Full article
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19 pages, 1630 KiB  
Review
The Central Noradrenergic System in Neurodevelopmental Disorders: Merging Experimental and Clinical Evidence
by Alessandro Galgani, Emanuele Bartolini, Marta D’Amora, Ugo Faraguna and Filippo Sean Giorgi
Int. J. Mol. Sci. 2023, 24(6), 5805; https://doi.org/10.3390/ijms24065805 - 18 Mar 2023
Cited by 4 | Viewed by 2693
Abstract
The aim of this article is to highlight the potential role of the locus-coeruleus–noradrenergic (LC-NA) system in neurodevelopmental disorders (NdDs). The LC is the main brain noradrenergic nucleus, key in the regulation of arousal, attention, and stress response, and its early maturation and [...] Read more.
The aim of this article is to highlight the potential role of the locus-coeruleus–noradrenergic (LC-NA) system in neurodevelopmental disorders (NdDs). The LC is the main brain noradrenergic nucleus, key in the regulation of arousal, attention, and stress response, and its early maturation and sensitivity to perinatal damage make it an interesting target for translational research. Clinical data shows the involvement of the LC-NA system in several NdDs, suggesting a pathogenetic role in the development of such disorders. In this context, a new neuroimaging tool, LC Magnetic Resonance Imaging (MRI), has been developed to visualize the LC in vivo and assess its integrity, which could be a valuable tool for exploring morphological alterations in NdD in vivo in humans. New animal models may be used to test the contribution of the LC-NA system to the pathogenic pathways of NdD and to evaluate the efficacy of NA-targeting drugs. In this narrative review, we provide an overview of how the LC-NA system may represent a common pathophysiological and pathogenic mechanism in NdD and a reliable target for symptomatic and disease-modifying drugs. Further research is needed to fully understand the interplay between the LC-NA system and NdD. Full article
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