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Stress-Response Pathways in Obesity and Metabolic Diseases
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Stress-Response Pathways in Obesity and Metabolic Diseases

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: 20 March 2025 | Viewed by 8476

Special Issue Editor

Dr. Dionysios Chartoumpekis

E-Mail Website
Guest Editor
Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
Interests: obesity; diabetes; adipocyte; fatty liver disease; insulin resistance; stress-response signaling; Nrf2; notch
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Special Issue Information

Dear Colleagues, 

The prevalence of obesity is increasing worldwide. The World Health Organization estimate that, in 2016, more than 1.9 billion adults were overweight or obese. Several comorbidities are associated with obesity, such as type 2 diabetes, dyslipidemia, cardiovascular disease and cancer. The combination of basic and translational research is necessary to further elucidate the mechanisms that contribute to the emergence of the obese phenotype and its metabolic complications at the hypothalamus and at peripheral tissues (muscle, liver, adipose tissue, etc.).

In this Special Issue, we will focus on the stress response pathways occurring during obesity and their relationship with metabolic fluctuations at the cellular, tissue and organismal level. The stressors that are associated with obesity are related but not limited to: excessive calorie intake (nutritional stress); increases in reactive oxygen and electrophilic species (oxidative and electrophilic stress); and the local availability of oxygen, nutrients and metabolites at the tissue/cellular level. Hence, the stress response is involved in multiple processes, such as the antioxidant–cytoprotective response, the integrated stress response, and metabolic signaling adaptations, opening up new possibilities for its involvement with insulin resistance and other concomitant comorbidities of obesity.

This Special Issue is led by Dr. Dionysios Chartoumpekis and supported by our GE's assistant editors, Dr. Anthony Bougas <[email protected]> (University of Edinburgh, UK) and Dr. Aristea Psilopanagioti <[email protected]> (University of Patras, Greece). Having formed a multidisciplinary editorial team, we welcome basic and translational research and review articles that describe novel findings on pathways affected by the stress response during obesity or by treatments such as GLP-1 agonists or bariatric surgery.

Descriptive or mechanistic studies with novel findings related to model organisms or humans, open-ended research utilizing high-throughput screen methods (metabolomics, proteomics, RNA-seq, etc.) as well as translational studies are welcome. Last but not least, studies on pharmacological interventions with naturally occurring or synthetic compounds that can modulate stress response pathways and affect the outcomes of obesity are also welcome.

We look forward to this Special Issue becoming a multidisciplinary forum that will highlight research on the expanding field of stress response signaling in obesity.

Dr. Dionysios Chartoumpekis
Guest Editor

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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.

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Keywords

  • obesity
  • diabetes
  • reactive oxygen species
  • Nrf2
  • GLP-1
  • fatty liver
  • fasting
  • antioxidants
  • energy homeostasis
  • hypothalamus
  • nesfatin-1

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Published Papers (4 papers)

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Research

19 pages, 5139 KiB  
Article
Forced Hepatic Expression of NRF2 or NQO1 Impedes Hepatocyte Lipid Accumulation in a Lipodystrophy Mouse Model
by Nobunao Wakabayashi, Yoko Yagishita, Tanvi Joshi and Thomas W. Kensler
Int. J. Mol. Sci. 2023, 24(17), 13345; https://doi.org/10.3390/ijms241713345 - 28 Aug 2023
Cited by 4 | Viewed by 1714
Abstract
Lipodystrophy is a disorder featuring loss of normal adipose tissue depots due to impaired production of normal adipocytes. It leads to a gain of fat deposition in ectopic tissues such as liver and skeletal muscle that results in steatosis, dyslipidemia, and insulin resistance. [...] Read more.
Lipodystrophy is a disorder featuring loss of normal adipose tissue depots due to impaired production of normal adipocytes. It leads to a gain of fat deposition in ectopic tissues such as liver and skeletal muscle that results in steatosis, dyslipidemia, and insulin resistance. Previously, we established a Rosa NIC/NIC::AdiCre lipodystrophy model mouse. The lipodystrophic phenotype that included hepatomegaly accompanied with hepatic damage due to higher lipid accumulation was attenuated substantially by amplified systemic NRF2 signaling in mice with hypomorphic expression of Keap1; whole-body Nrf2 deletion abrogated this protection. To determine whether hepatic-specific NRF2 signaling would be sufficient for protection against hepatomegaly and fatty liver development, direct, powerful, transient expression of Nrf2 or its target gene Nqo1 was achieved by administration through hydrodynamic tail vein injection of pCAG expression vectors of dominant-active Nrf2 and Nqo1 in Rosa NIC/NIC::AdiCre mice fed a 9% fat diet. Both vectors enabled protection from hepatic damage, with the pCAG-Nqo1 vector being the more effective as seen with a ~50% decrease in hepatic triglyceride levels. Therefore, activating NRF2 signaling or direct elevation of NQO1 in the liver provides new possibilities to partially reduce steatosis that accompanies lipodystrophy. Full article
(This article belongs to the Special Issue Stress-Response Pathways in Obesity and Metabolic Diseases)
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12 pages, 2340 KiB  
Article
Role of Oxidative Stress on Insulin Resistance in Diet-Induced Obesity Mice
by Bruno Luiz da Silva Pieri, Matheus Scarpatto Rodrigues, Hemelin Resende Farias, Gustavo de Bem Silveira, Victória de Souza Gomes da Cunha Ribeiro, Paulo Cesar Lock Silveira and Claudio Teodoro De Souza
Int. J. Mol. Sci. 2023, 24(15), 12088; https://doi.org/10.3390/ijms241512088 - 28 Jul 2023
Cited by 5 | Viewed by 1765
Abstract
Insulin resistance is the link between obesity and type 2 diabetes mellitus. The molecular mechanism by which obese individuals develop insulin resistance has not yet been fully elucidated; however, inconclusive and contradictory studies have shown that oxidative stress may be involved in the [...] Read more.
Insulin resistance is the link between obesity and type 2 diabetes mellitus. The molecular mechanism by which obese individuals develop insulin resistance has not yet been fully elucidated; however, inconclusive and contradictory studies have shown that oxidative stress may be involved in the process. Thus, this study aimed to evaluate the effect of reactive species on the mechanism of insulin resistance in diet-induced obese mice. Obese insulin-resistant mice were treated with N-acetylcysteine (NAC; 50 mg/kg per day, for 15 days) by means of oral gavage. Twenty-four hours after the last NAC administration, the animals were euthanized and their tissues were extracted for biochemical and molecular analyses. NAC supplementation induced improved insulin resistance and fasting glycemia, without modifications in food intake, body weight, and adiposity. Obese mice showed increased dichlorofluorescein (DCF) oxidation, reduced catalase (CAT) activity, and reduced glutathione levels (GSH). However, treatment with NAC increased GSH and CAT activity and reduced DCF oxidation. The gastrocnemius muscle of obese mice showed an increase in nuclear factor kappa B (NFκB) and protein tyrosine phosphatase (PTP1B) levels, as well as c-Jun N-terminal kinase (JNK) phosphorylation compared to the control group; however, NAC treatment reversed these changes. Considering the molecules involved in insulin signaling, there was a reduction in insulin receptor substrate (IRS) and protein kinase B (Akt) phosphorylation. However, NAC administration increased IRS and Akt phosphorylation and IRS/PI3k (phosphoinositide 3-kinase) association. The results demonstrated that oxidative stress-associated obesity could be a mechanism involved in insulin resistance, at least in this animal model. Full article
(This article belongs to the Special Issue Stress-Response Pathways in Obesity and Metabolic Diseases)
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12 pages, 4483 KiB  
Article
Five-Aminolevulinic Acid (5-ALA) Induces Heme Oxygenase-1 and Ameliorates Palmitic Acid-Induced Endoplasmic Reticulum Stress in Renal Tubules
by Shintaro Hamada, Yukari Mae, Tomoaki Takata, Hinako Hanada, Misaki Kubo, Sosuke Taniguchi, Takuji Iyama, Takaaki Sugihara and Hajime Isomoto
Int. J. Mol. Sci. 2023, 24(12), 10151; https://doi.org/10.3390/ijms241210151 - 15 Jun 2023
Cited by 2 | Viewed by 1800
Abstract
Steatosis, or ectopic lipid deposition, is the fundamental pathophysiology of non-alcoholic steatohepatitis and chronic kidney disease. Steatosis in the renal tubule causes endoplasmic reticulum (ER) stress, leading to kidney injury. Thus, ER stress could be a therapeutic target in steatonephropathy. Five-aminolevulinic acid (5-ALA) [...] Read more.
Steatosis, or ectopic lipid deposition, is the fundamental pathophysiology of non-alcoholic steatohepatitis and chronic kidney disease. Steatosis in the renal tubule causes endoplasmic reticulum (ER) stress, leading to kidney injury. Thus, ER stress could be a therapeutic target in steatonephropathy. Five-aminolevulinic acid (5-ALA) is a natural product that induces heme oxygenase (HO)-1, which acts as an antioxidant. This study aimed to investigate the therapeutic potential of 5-ALA in lipotoxicity-induced ER stress in human primary renal proximal tubule epithelial cells. Cells were stimulated with palmitic acid (PA) to induce ER stress. Cellular apoptotic signals and expression of genes involved in the ER stress cascade and heme biosynthesis pathway were analyzed. The expression of glucose-regulated protein 78 (GRP78), a master regulator of ER stress, increased significantly, followed by increased cellular apoptosis. Administration of 5-ALA induced a remarkable increase in HO-1 expression, thus ameliorating PA-induced GRP78 expression and apoptotic signals. BTB and CNC homology 1 (BACH1), a transcriptional repressor of HO-1, was significantly downregulated by 5-ALA treatment. HO-1 induction attenuates PA-induced renal tubular injury by suppressing ER stress. This study demonstrates the therapeutic potential of 5-ALA against lipotoxicity through redox pathway. Full article
(This article belongs to the Special Issue Stress-Response Pathways in Obesity and Metabolic Diseases)
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16 pages, 6258 KiB  
Article
Glucagon-like Peptide-1 Receptor in the Human Hypothalamus Is Associated with Body Mass Index and Colocalizes with the Anorexigenic Neuropeptide Nucleobindin-2/Nesfatin-1
by Aristea Psilopanagioti, Sofia Nikou, Souzana Logotheti, Marina Arbi, Dionysios V. Chartoumpekis and Helen Papadaki
Int. J. Mol. Sci. 2022, 23(23), 14899; https://doi.org/10.3390/ijms232314899 - 28 Nov 2022
Cited by 3 | Viewed by 2194
Abstract
Data on animals emphasize the importance of the neuronal glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) for feeding suppression, although it is unclear whether astrocytes participate in the transduction of anorectic GLP-1R-dependent signals. In humans, the brain circuitry underlying these effects remains insufficiently investigated. The [...] Read more.
Data on animals emphasize the importance of the neuronal glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) for feeding suppression, although it is unclear whether astrocytes participate in the transduction of anorectic GLP-1R-dependent signals. In humans, the brain circuitry underlying these effects remains insufficiently investigated. The present study aimed to explore GLP-1R protein expression in the human hypothalamus and its correlation with body mass index (BMI). Sections of hypothalamus from 28 autopsy cases, 11 with normal weight (BMI < 25 kg/m2) and 17 with non-normal weight (BMI ≥ 25 kg/m2), were examined using immunohistochemistry and double immunofluorescence labeling. Prominent GLP-1R immunoexpression was detected in neurons of several hypothalamic nuclei, including paraventricular, supraoptic, and infundibular nuclei; the lateral hypothalamic area (LH); and basal forebrain nuclei. Interestingly, in the LH, GLP-1R was significantly decreased in individuals with BMI ≥ 25 kg/m2 compared with their normal weight counterparts (p = 0.03). Furthermore, GLP-1R was negatively correlated (τb = −0.347, p = 0.024) with BMI levels only in the LH. GLP-1R extensively colocalized with the anorexigenic and antiobesogenic neuropeptide nucleobindin-2/nesfatin-1 but not with the astrocytic marker glial fibrillary acidic protein. These data suggest a potential role for GLP-1R in the regulation of energy balance in the human hypothalamus. In the LH, an appetite- and reward-related brain region, reduced GLP-1R immunoexpression may contribute to the dysregulation of homeostatic and/or hedonic feeding behavior. Possible effects of NUCB2/nesfatin-1 on central GLP-1R signaling require further investigation. Full article
(This article belongs to the Special Issue Stress-Response Pathways in Obesity and Metabolic Diseases)
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