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Insulin Signaling and Fat Homeostasis in Metabolic and Neurodegenerative Disorders

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

Deadline for manuscript submissions: closed (29 September 2022) | Viewed by 25641

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Special Issue Editors

Prof. Dr. Maria Gisella Cavallo

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Guest Editor

Department Experimental Medicin, Sapienza University, Policlin Umberto I, Viale Regina Elena 324, I-00161 Rome, Italy
Interests: metabolic disease; obesity; adipose tissue; diabetes; NAFLD

Prof. Dr. Marco Giorgio Baroni

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Guest Editor

Department of Clinical Medicine, Public Health, Life and Environmental Sciences (MeSVA), University of L'Aquila, L'Aquila, Italy
Interests: diabetes; atherosclerosis; cardiovascular disease; genetics; obesity

Dr. Eugenio Barone

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Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
Interests: insulin signaling; insulin resistance; aging; Alzheimer’s disease; Down syndrome; neurodegeneration; mitochondrial bioenergetics
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Special Issue Information

Dear Colleagues,

Alterations of insulin signaling leading to reduced insulin sensitivity are increasingly recognized as key elements in a variety of chronic noncommunicable diseases, including diabetes, metabolic syndrome, MAFLD, and cardiovascular and neurodegenerative diseases.

In recent years, new molecular mechanisms/pathways have emerged, which increase our comprehension of how these diseases develop and progress. These advances in the field of chronic noncommunicable diseases have identified new potential mechanisms implicated in the development of these disorders (i.e., signaling molecules, adipokines, genetic, epigenetic reprogramming, new biomarkers) that could lead to the development of new approaches and pharmacological targets aimed at preventing and/or overturning these disorders and the associated complications.

The aim of this Special Issue is to bring together research papers and review articles that will drive the focus on the present knowledge in the context of chronic noncommunicable diseases, with a special focus on diabetes, metabolic syndrome, MAFLD, and cardiovascular and neurodegenerative diseases, with the purpose of better understanding the pathways involved in these alterations, and ultimately shedding light on newer approaches to prevent or reverse these diseases.

Prof. Dr. Maria Gisella Cavallo
Prof. Dr. Marco Giorgio Baroni
Prof. Dr. Eugenio Barone
Guest Editors

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Keywords

Insulin
Diabetes
MAFLD
Neurodegeneration
Obesity
Cardiovascular alterations
Oxidative stress
Inflammation
Fat homeostasis
Dementia
Brain metabolism

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Published Papers (8 papers)

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Research

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11 pages, 505 KiB

Open AccessArticle

Neurotensin Gene rs2234762 C>G Variant Associates with Reduced Circulating Pro-NT Levels and Predicts Lower Insulin Resistance in Overweight/Obese Children

by Federica Sentinelli, Ilaria Barchetta, Flavia Agata Cimini, Sara Dule, Diego Bailetti, Efisio Cossu, Arcangelo Barbonetti, Maria Totaro, Olle Melander, Maria Gisella Cavallo and Marco Giorgio Baroni

Int. J. Mol. Sci. 2023, 24(7), 6460; https://doi.org/10.3390/ijms24076460 - 30 Mar 2023

Cited by 3 | Viewed by 1814

Abstract

Neurotensin (NT) is a small protein implicated in the regulation of energy balance which acts as both a neurotransmitter in the central nervous system and as a gastrointestinal peptide. In the gut, NT is secreted after fat ingestion and promotes the absorption of fatty acids. The circulating levels of its precursor, pro-NT, predicts the presence and development of metabolic and cardiovascular diseases. Despite the extensive knowledge on the dynamic changes that occur to pro-NT = after fat load, the determinants of fasting pro-NT are unknown. The aim of this study was to determine the possible genetic regulation of plasma pro-NT. The NT gene (NTS) was sequenced for potential functional variants, evaluating its entire genomic and potentially regulatory regions, in DNA from 28 individuals, stratified by low and high pro-NT levels. The identified variant differently distributed in the two pro-NT subgroups was genotyped in a cohort of nine hundred and thirty-two overweight/obese children and adolescents. A total of seven sequence variations across the NTS gene, none of them located in coding regions, were identified. The rs2234762 polymorphism, sited in the NTS gene promoter, was statistically more frequent in the lowest pro-NTS level group. Carriers of the rs2234762 variant showed lower pro-NT levels, after adjusting for sex, age, BMI, triglycerides and the Tanner stage. Having NTS rs2234762 predicted less pronounced insulin resistance at the 6.5-year follow-up with OR: 0.46 (0.216–0.983), at the logistic regression analysis adjusted for age, sex and BMI. In conclusion, the NTS rs2234762 gene variant is a determinant of reduced circulating pro-NT levels in overweight and obese children, which predisposes this group to a more favorable metabolic profile and a reduced insulin resistance later in life, independently from metabolic confounders. Full article

(This article belongs to the Special Issue Insulin Signaling and Fat Homeostasis in Metabolic and Neurodegenerative Disorders)

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18 pages, 4021 KiB

Open AccessArticle

Ceruloplasmin-Deficient Mice Show Dysregulation of Lipid Metabolism in Liver and Adipose Tissue Reduced by a Protein Replacement

by Sara Raia, Antonio Conti, Alan Zanardi, Barbara Ferrini, Giulia Maria Scotti, Enrica Gilberti, Giuseppe De Palma, Samuel David and Massimo Alessio

Int. J. Mol. Sci. 2023, 24(2), 1150; https://doi.org/10.3390/ijms24021150 - 6 Jan 2023

Cited by 7 | Viewed by 2224

Abstract

Ceruloplasmin is a ferroxidase that plays a role in iron homeostasis; its deficiency fosters inter alia iron accumulation in the liver, which expresses the soluble form of the protein secreted into the bloodstream. Ceruloplasmin is also secreted by the adipose tissue, but its role in adipocytes has been poorly investigated. We hypothesized that ceruloplasmin might have a role in iron/lipid interplay. We investigated iron/lipid dysmetabolism in the liver and adipose tissue of the ceruloplasmin-deficient mouse (CpKO) model of aceruloplasminemia and evaluated the effectiveness of ceruloplasmin replacement. We found that CpKO mice were overweight, showing adipose tissue accumulation, liver iron deposition and steatosis. In the adipose tissue of CpKO mice, iron homeostasis was not altered. Conversely, the levels of adiponectin and leptin adipokines behaved opposite to the wild-type. Increased macrophage infiltration was observed in adipose tissue and liver of CpKO mice, indicating tissue inflammation. The treatment of CpKO mice with ceruloplasmin limited liver iron accumulation and steatosis without normalizing the expression of iron homeostasis-related proteins. In the CpKO mice, the protein replacement limited macrophage infiltration in both adipose and hepatic tissues reduced the level of serum triglycerides, and partially recovered adipokines levels in the adipose tissue. These results underline the link between iron and lipid dysmetabolism in ceruloplasmin-deficient mice, suggesting that ceruloplasmin in adipose tissue has an anti-inflammatory role rather than a role in iron homeostasis. Furthermore, these data also indicate that ceruloplasmin replacement therapy may be effective at a systemic level. Full article

(This article belongs to the Special Issue Insulin Signaling and Fat Homeostasis in Metabolic and Neurodegenerative Disorders)

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14 pages, 2430 KiB

Open AccessArticle

Ketogenic Diet Increases Serum and White Adipose Tissue SIRT1 Expression in Mice

by Rossella Tozzi, Federica Campolo, Enke Baldini, Mary Anna Venneri, Carla Lubrano, Salvatore Ulisse, Lucio Gnessi and Stefania Mariani

Int. J. Mol. Sci. 2022, 23(24), 15860; https://doi.org/10.3390/ijms232415860 - 13 Dec 2022

Cited by 5 | Viewed by 3109

Abstract

Overnutrition and its sequelae have become a global concern due to the increasing incidence of obesity and insulin resistance. A ketogenic diet (KD) is widely used as a dietary treatment for metabolic disorders. Sirtuin1 (SIRT1), a metabolic sensor which regulates fat homeostasis, is modulated by dietary interventions. However, the influence of nutritional ketosis on SIRT1 is still debated. We examined the effect of KD on adipose tissue, liver, and serum levels of SIRT1 in mice. Adult C57BL/6J male mice were randomly assigned to two isocaloric dietary groups and fed with either high-fat KD or normal chow (NC) for 4 weeks. Serum SIRT1, beta-hydroxybutyrate (βHB), glucose, and triglyceride levels, as well as SIRT1 expression in visceral (VAT), subcutaneous (SAT), and brown (BAT) adipose tissues, and in the liver, were measured. KD-fed mice showed an increase in serum βHB in parallel with serum SIRT1 (r = 0.732, p = 0.0156), and increased SIRT1 protein expression in SAT and VAT. SIRT1 levels remained unchanged in BAT and in the liver, which developed steatosis. Normal glycemia and triglycerides were observed. Under a KD, serum and white fat phenotypes show higher SIRT1, suggesting that one of the molecular mechanisms underlying a KD’s potential benefits on metabolic health involves a synergistic interaction with SIRT1. Full article

(This article belongs to the Special Issue Insulin Signaling and Fat Homeostasis in Metabolic and Neurodegenerative Disorders)

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23 pages, 26506 KiB

Open AccessArticle

An Association between Insulin Resistance and Neurodegeneration in Zebrafish Larval Model (Danio rerio)

by Nurliyana Najwa Md Razip, Suzita Mohd Noor, Anwar Norazit, Norshariza Nordin, Nurshafika Mohd Sakeh and Huzwah Khaza’ai

Int. J. Mol. Sci. 2022, 23(15), 8290; https://doi.org/10.3390/ijms23158290 - 27 Jul 2022

Cited by 6 | Viewed by 2590

Abstract

Background: Type 2 diabetes mellitus has recently been identified as a mediator of neurodegeneration. However, the molecular mechanisms have not been clearly elucidated. We aimed to investigate insulin resistance associated with neurodegenerative events in zebrafish larvae. Methods: Larvae aged 72 h-post-fertilization (hpf) were induced to insulin resistance by immersion in 250 nM insulin and were then reinduced with 100 nM insulin at 96 hpf. This model was validated by a glucose levels assay, qPCR analysis of selected genes (akt, pepck, zglut3 and claudin-5a) and Oil Red-O (ORO) staining of the yolk sac for lipid distribution. The association of insulin resistance and neurodegeneration was validated by malondialdehyde (MDA), glutathione (GSH) assays, and by integrating next-generation sequencing with database for annotation, visualization and integrated discovery (DAVID). Results: There was a significant increase in glucose levels at 180 min in the insulin-resistant group. However, it decreased at 400 min after the re-challenge. Insulin-signaling mediators, akt and pepck, were showed significantly downregulated up to 400 min after insulin immersion (p < 0.05). Meanwhile, claudin-5a assessed blood–brain barrier (BBB) integrity and showed significant deterioration after 400 min of post-insulin immersion. ORO staining remarked the increase in yolk sac size in the insulin-resistant group. After the confirmation of insulin resistance, MDA levels increased significantly in the insulin-resistant group compared to the control group in the following parameters. Furthermore, dysregulated MAPK- and Wnt/Ca²⁺-signaling pathways were observed in the insulin-resistant group, disrupting energy metabolism and causing BBB injury. Conclusions: We conclude that the insulin-resistant zebrafish larvae alter the metabolic physiology associated with neurodegeneration. Full article

(This article belongs to the Special Issue Insulin Signaling and Fat Homeostasis in Metabolic and Neurodegenerative Disorders)

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13 pages, 315 KiB

Open AccessArticle

Deep Resequencing of 9 Candidate Genes Identifies a Role for ARAP1 and IGF2BP2 in Modulating Insulin Secretion Adjusted for Insulin Resistance in Obese Southern Europeans

by Diego Bailetti, Federica Sentinelli, Sabrina Prudente, Flavia Agata Cimini, Ilaria Barchetta, Maria Totaro, Alessia Di Costanzo, Arcangelo Barbonetti, Frida Leonetti, Maria Gisella Cavallo and Marco Giorgio Baroni

Int. J. Mol. Sci. 2022, 23(3), 1221; https://doi.org/10.3390/ijms23031221 - 22 Jan 2022

Cited by 5 | Viewed by 2083

Abstract

Type 2 diabetes is characterized by impairment in insulin secretion, with an established genetic contribution. We aimed to evaluate common and low-frequency (1–5%) variants in nine genes strongly associated with insulin secretion by targeted sequencing in subjects selected from the extremes of insulin release measured by the disposition index. Collapsing data by gene and/or function, the association between disposition index and nonsense variants were significant, also after adjustment for confounding factors (OR = 0.25, 95% CI = 0.11–0.59, p = 0.001). Evaluating variants individually, three novel variants in ARAP1, IGF2BP2 and GCK, out of eight reaching significance singularly, remained associated after adjustment. Constructing a genetic risk model combining the effects of the three variants, only carriers of the ARAP1 and IGF2BP2 variants were significantly associated with a reduced probability to be in the lower, worst, extreme of insulin secretion (OR = 0.223, 95% CI = 0.105–0.473, p < 0.001). Observing a high number of normal glucose tolerance between carriers, a regression posthoc analysis was performed. Carriers of genetic risk model variants had higher probability to be normoglycemic, also after adjustment (OR = 2.411, 95% CI = 1.136–5.116, p = 0.022). Thus, in our southern European cohort, nonsense variants in all nine candidate genes showed association with better insulin secretion adjusted for insulin resistance, and we established the role of ARAP1 and IGF2BP2 in modulating insulin secretion. Full article

(This article belongs to the Special Issue Insulin Signaling and Fat Homeostasis in Metabolic and Neurodegenerative Disorders)

Review

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19 pages, 1076 KiB

Open AccessReview

New Insights in the Control of Fat Homeostasis: The Role of Neurotensin

by Ilaria Barchetta, Marco Giorgio Baroni, Olle Melander and Maria Gisella Cavallo

Int. J. Mol. Sci. 2022, 23(4), 2209; https://doi.org/10.3390/ijms23042209 - 17 Feb 2022

Cited by 15 | Viewed by 3823

Abstract

Neurotensin (NT) is a small peptide with pleiotropic functions, exerting its primary actions by controlling food intake and energy balance. The first evidence of an involvement of NT in metabolism came from studies on the central nervous system and brain circuits, where NT acts as a neurotransmitter, producing different effects in relation to the specific region involved. Moreover, newer interesting chapters on peripheral NT and metabolism have emerged since the first studies on the NT-mediated regulation of gut lipid absorption and fat homeostasis. Intriguingly, NT enhances fat absorption from the gut lumen in the presence of food with a high fat content, and this action may explain the strong association between high circulating levels of pro-NT, the NT stable precursor, and the increased incidence of metabolic disorders, cardiovascular diseases, and cancer observed in large population studies. This review aims to provide a synthetic overview of the main regulatory effects of NT on several biological pathways, particularly those involving energy balance, and will focus on new evidence on the role of NT in controlling fat homeostasis, thus influencing the risk of unfavorable cardio–metabolic outcomes and overall mortality in humans. Full article

(This article belongs to the Special Issue Insulin Signaling and Fat Homeostasis in Metabolic and Neurodegenerative Disorders)

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11 pages, 573 KiB

Open AccessReview

Role of GALNT2 on Insulin Sensitivity, Lipid Metabolism and Fat Homeostasis

by Alessandra Antonucci, Antonella Marucci, Vincenzo Trischitta and Rosa Di Paola

Int. J. Mol. Sci. 2022, 23(2), 929; https://doi.org/10.3390/ijms23020929 - 15 Jan 2022

Cited by 9 | Viewed by 2702

Abstract

O-linked glycosylation, the greatest form of post-translational modifications, plays a key role in regulating the majority of physiological processes. It is, therefore, not surprising that abnormal O-linked glycosylation has been related to several human diseases. Recently, GALNT2, which encodes the GalNAc-transferase 2 involved in the first step of O-linked glycosylation, has attracted great attention as a possible player in many highly prevalent human metabolic diseases, including atherogenic dyslipidemia, type 2 diabetes and obesity, all clustered on the common ground of insulin resistance. Data available both in human and animal models point to GALNT2 as a molecule that shapes the risk of the aforementioned abnormalities affecting diverse protein functions, which eventually cause clinically distinct phenotypes (a typical example of pleiotropism). Pathways linking GALNT2 to dyslipidemia and insulin resistance have been partly identified, while those for type 2 diabetes and obesity are yet to be understood. Here, we will provide a brief overview on the present knowledge on GALNT2 function and dysfunction and propose novel insights on the complex pathogenesis of the aforementioned metabolic diseases, which all impose a heavy burden for patients, their families and the entire society. Full article

(This article belongs to the Special Issue Insulin Signaling and Fat Homeostasis in Metabolic and Neurodegenerative Disorders)

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20 pages, 726 KiB

Open AccessReview

Diabetes and Cognitive Impairment: A Role for Glucotoxicity and Dopaminergic Dysfunction

by Francesca Chiara Pignalosa, Antonella Desiderio, Paola Mirra, Cecilia Nigro, Giuseppe Perruolo, Luca Ulianich, Pietro Formisano, Francesco Beguinot, Claudia Miele, Raffaele Napoli and Francesca Fiory

Int. J. Mol. Sci. 2021, 22(22), 12366; https://doi.org/10.3390/ijms222212366 - 16 Nov 2021

Cited by 52 | Viewed by 6340

Abstract

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia, responsible for the onset of several long-term complications. Recent evidence suggests that cognitive dysfunction represents an emerging complication of DM, but the underlying molecular mechanisms are still obscure. Dopamine (DA), a neurotransmitter essentially known for its relevance in the regulation of behavior and movement, modulates cognitive function, too. Interestingly, alterations of the dopaminergic system have been observed in DM. This review aims to offer a comprehensive overview of the most relevant experimental results assessing DA’s role in cognitive function, highlighting the presence of dopaminergic dysfunction in DM and supporting a role for glucotoxicity in DM-associated dopaminergic dysfunction and cognitive impairment. Several studies confirm a role for DA in cognition both in animal models and in humans. Similarly, significant alterations of the dopaminergic system have been observed in animal models of experimental diabetes and in diabetic patients, too. Evidence is accumulating that advanced glycation end products (AGEs) and their precursor methylglyoxal (MGO) are associated with cognitive impairment and alterations of the dopaminergic system. Further research is needed to clarify the molecular mechanisms linking DM-associated dopaminergic dysfunction and cognitive impairment and to assess the deleterious impact of glucotoxicity. Full article

(This article belongs to the Special Issue Insulin Signaling and Fat Homeostasis in Metabolic and Neurodegenerative Disorders)

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