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Molecular Mechanisms of Obesity and Metabolic Diseases

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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: 30 October 2025 | Viewed by 7958

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Dr. Liliya Mihaylova

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1. Department of Plant Cell Biotechnology, Center of Plant Systems Biology and Biotechnology, Plovdiv, Bulgaria
2. Laboratory of Metabolomics, Institute of Microbiology, Bulgarian Academy of Sciences, Plovdiv, Bulgaria
Interests: molecular pharmacology; the biological activity of natural products; crosstalk between the molecular mechanisms of obesity and metabolic disorders, pharmacological potential of plant-derived secondary metabolites for the management and prevention of metabolic diseases; preclinical models of obesity in human adipocytes and Caenorhabditis elegans; indentifcation of novel bioactive anti-obesogenic leads that target nutrient-sensing molecular signalling modulation; mitochondrial fatty acid oxidation

Special Issue Information

Dear Colleagues,

The rising global rates of chronic non-communicable diseases driven by disturbed metabolism, including obesity, type 2 diabetes, atherosclerosis, cardio-metabolic disorders and non-alcoholic fatty liver disease (NAFLD), constitute a concerning health challenge. The development of long-term metabolic complications is severely diminishing the quality of life of the affected individuals and is increasing the burden on public health care systems. In the realm of metabolic health preservation, scientific advancements that provide insights on the complex molecular mechanisms involved in these diseases are crucial. The detailed characterization of nutrient-sensing signaling pathways leads to the identification of novel biomarkers that identify the risk of metabolic complications or promising “druggable” molecular targets and therapeutic interventions that could answer the complex pathology of metabolic diseases.

This Special Issue, entitled “Molecular Mechanisms of Obesity and Metabolic Diseases”, aims to provide a platform for the presentation of studies related to pharmacology, molecular biology, mechanisms, multiomics, and any other issues associated with the disruption of molecular mechanisms during obesity, diabetes and NAFLD development. Original research articles and review articles that provide an overview of advancements in this field are welcome.

Dr. Liliya Mihaylova
Guest Editor

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Keywords

molecular pharmacology
molecular mechanisms
obesity
metabolic diseases
metabolic syndrome
type 2 diabetes
atherosclerosis
cardio-metabolic disorders
non-alcoholic fatty liver disease (NAFLD)

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Published Papers (7 papers)

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Research

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35 pages, 7691 KiB

Open AccessArticle

KLF14 and SREBF-1 Binding Site Associations with Orphan Receptor Promoters in Metabolic Syndrome

by Julio Jesús Garcia-Coste, Santiago Villafaña-Rauda, Karla Aidee Aguayo-Cerón, Cruz Vargas-De-León and Rodrigo Romero-Nava

Int. J. Mol. Sci. 2025, 26(7), 2849; https://doi.org/10.3390/ijms26072849 - 21 Mar 2025

Viewed by 315

Abstract

This study investigated the relationship between the transcription factors (TFs) KLF14 and SREBF-1 and orphan receptors (ORs) in the context of metabolic syndrome (MetS). A detailed bioinformatics analysis identified a significant association between the presence of binding sites (BS) for these TFs in the promoters of ORs genes and the total number of BS in the distal region. The results suggest that KLF14 and SREBF-1 can regulate the expression of some of these genes and, in turn, can modulate the development of MetS. Although a stronger association was observed with KLF14, both factors showed a significant contribution. Additionally, the sequence similarity of KLF14 also contributed to the quantity of BS in the gene’s distal region (DR). The statistical models used, such as Poisson and negative binomial regression, confirmed these associations and allowed for the appropriate adjustment of overdispersion present in the data. However, no significant differences in receptor groups (orphan G Protein-Coupled Rereptors (oGPCRs) and G Protein-Coupled Receptors associated with MetS (GPCRs-MetS)) regarding their relationship with TFs were found. In conclusion, this study provides strong evidence of the importance of KLF14 and SREBF-1 in regulating orphan receptors genes and their participation in the development of metabolic syndrome. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Obesity and Metabolic Diseases)

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14 pages, 3254 KiB

Open AccessArticle

Sestrin2 Suppression Promotes Endothelial–Mesenchymal Transition and Exacerbates Methylglyoxal-Induced Endothelial Dysfunction

by Shahenda Salah Abdelsalam, Muhammad Ammar Zahid, Sarah Khalaf Ghanem, Abbas Khan, Aijaz Parray and Abdelali Agouni

Int. J. Mol. Sci. 2024, 25(24), 13463; https://doi.org/10.3390/ijms252413463 - 16 Dec 2024

Viewed by 801

Abstract

Sestrin2 (SESN2) is a stress-inducible protein known for its cytoprotective functions, but its role in diabetic vascular complications remains unclear. This study investigated the impact of SESN2 on methylglyoxal (MGO)-induced endothelial–mesenchymal transition (EndMT). Human endothelial cells were transfected with SESN2 siRNA duplexes to silence SESN2 expression, followed by MGO treatment. SESN2 knockdown significantly exacerbated MGO-induced oxidative stress, as evidenced by the reduced expression of antioxidant markers. Furthermore, SESN2 silencing enhanced the inflammatory response to MGO, demonstrated by the increased levels of pro-inflammatory cytokines. Notably, SESN2 deficiency promoted EndMT, a key process in diabetes-induced cardiovascular complications, as shown by the increased expression of mesenchymal markers and the decreased expression of endothelial markers. These findings suggest that SESN2 plays a critical protective role in endothelial cells against MGO-induced damage. The study provides novel insights into the molecular mechanisms underlying diabetic cardiovascular complications and identifies SESN2 as a potential therapeutic target for preventing endothelial dysfunction in diabetes. Our results indicate that SESN2 downregulation may contribute to the pathogenesis of diabetic vascular complications by promoting EndMT, increased oxidative stress, and inflammation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Obesity and Metabolic Diseases)

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18 pages, 1918 KiB

Open AccessArticle

Feline Diabetes Is Associated with Deficits in Markers of Insulin Signaling in Peripheral Tissues

by Souvik Patra, Chantal J. McMillan, Elisabeth R. Snead, Amy L. Warren, Kevin Cosford and Prasanth K. Chelikani

Int. J. Mol. Sci. 2024, 25(23), 13195; https://doi.org/10.3390/ijms252313195 - 8 Dec 2024

Viewed by 1414

Abstract

Like humans, cats have a strong relationship between decreasing insulin sensitivity and the development of diabetes with obesity. However, the underlying molecular mechanisms of impaired insulin secretion and signaling in cats remain largely unknown. A total of 54 client-owned nondiabetic lean (n = 15), overweight (n = 15), and diabetic (n = 24) cats were included in the study. The pancreas, liver, and skeletal muscle were quantified for mRNA and protein abundances of insulin and incretin signaling markers. Diabetic cats showed increased liver and muscle adiposity. The pancreas of diabetic cats had decreased transcript abundances of insulin, insulin receptor, insulin-receptor substrate (IRS)-1, glucose transporters (GLUT), and protein abundance of mitogen-activated protein kinase. In treated diabetics, protein abundance of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide receptors, total and phosphorylated Akt, and GLUT-1 were increased in the pancreas, whereas untreated diabetics had downregulation of markers of insulin and incretin signaling. In the muscle and liver, diabetic cats had reduced mRNA abundances of insulin receptor, IRS-1/2, and phosphatidylinositol-3-kinase, and reduced protein abundances of GLUT-4 and phosphatidylinositol-3-kinase-p85α in muscle. We demonstrate that feline diabetes is associated with ectopic lipid deposition in the liver and skeletal muscle, deficits in insulin synthesis and incretin signaling in the pancreas, and impaired insulin signaling in the muscle and liver. These findings have implications for understanding the pathophysiological mechanisms of obesity and diabetes in humans and pets. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Obesity and Metabolic Diseases)

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11 pages, 1496 KiB

Open AccessArticle

Novel Expression of Apical Bile Acid Transport (ASBT) More Proximally Than Distal Ileum Contributing to Enhanced Intestinal Bile Acid Absorption in Obesity

by Shanmuga Sundaram, Arunkumar Jagadeesan, Raja Singh Paulraj, Uma Sundaram and Subha Arthur

Int. J. Mol. Sci. 2024, 25(21), 11452; https://doi.org/10.3390/ijms252111452 - 25 Oct 2024

Viewed by 1388

Abstract

Dietary lipid absorption is facilitated by bile acids. In the Zucker rat (ZR) model of obesity, bile acid absorption, mediated by the apical sodium bile acid transporter (ASBT), was increased in villus cells from the distal ileum. However, whether ASBT may be de novo expressed more proximally in the small intestine during obesity to facilitate additional bile acid absorption is not known. For this, starting from the end of the ileum to the mid jejunum, caudal-orally, five intestinal segments of equal length (S1–S5) were separated from lean and obese ZRs (LZR and OZR). Intestinal mucosa obtained from these segments were used for total RNA extraction, RT-qPCR and ³H-TCA uptake. The results showed that bile acid absorption along with the mRNA expression of ASBT and FXR progressively decreased caudal-orally in both LZRs and OZRs but was significantly higher in all small intestinal segments in OZRs. The expression of GATA4 was absent in the distal ileum (S1) in both LZRs and OZRs, but steadily increased along the proximal length in both. However, this steady increase was significantly reduced in the comparative obese proximal intestinal segments S2, S3, S4 and S5. The expressions of bile acid-activated G-protein-coupled bile acid receptor TGR5 and S1PR2 were unaltered in segments S1–S4 but were significantly increased in OZR S5. The paradigm changing observation of this study is that ASBT is expressed more proximally in the small intestine in obesity. This likely increases overall bile acid absorption and thereby lipid absorption in the proximal small intestine in obesity. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Obesity and Metabolic Diseases)

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17 pages, 5745 KiB

Open AccessArticle

Alkaline Mineral Complex Water Attenuates Transportation-Induced Hepatic Lipid Metabolism Dysregulation by AMPKα-SREBP-1c/PPARα Pathways

by Linli Gan, Hongrui Guo, Qiyuan Yang, Xueke Zhou, Yue Xie, Xiaoping Ma, Liping Gou, Jing Fang and Zhicai Zuo

Int. J. Mol. Sci. 2024, 25(21), 11373; https://doi.org/10.3390/ijms252111373 - 23 Oct 2024

Viewed by 1238

Abstract

Transportation, an unavoidable process in livestock farming, causes metabolic disorders in the body, which then lead to endocrine disruption, being immunocompromised, and growth suppression. Lipid metabolism dysregulation is a critical phenotype induced by transportation. The liver is a vital organ in lipid metabolism, with a role in both lipid synthesis and lipolysis. However, the specific mechanisms by which transportation affects hepatic lipid metabolism remain unclear. This study employed rats as a model to investigate the effects of transportation on hepatic lipid metabolism. Rats subjected to transportation showed altered serum lipid profiles, including decreased serum triglyceride (TG), low-density lipoprotein cholesterol (VLDL-C), and non-esterified fatty acid (NEFA) immediately after transportation (IAT) and serum total cholesterol (TC) on day 3, and increasing serum TG, TC, and low-density lipoprotein cholesterol (LDL-C) on day 10. Meanwhile, fatty droplets in the liver were also reduced at IAT and increased on days 3 and 10. Notably, transportation also affected hepatic-lipid-metabolism-related enzyme activities and signaling pathways, such as increased AMP-activated protein kinase alpha (AMPKα) phosphorylation and modulations in key proteins and genes related to lipid metabolism, decreased hepatic acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) activities at IAT, and increased carnitine palmitoyl transferase 1 alpha (CPT-1α) at IAT and ACC and CPT-1α activities on days 3 and 10. Supplementation with alkaline mineral complex water (AMC) before and after transportation mitigated the adverse effects on hepatic lipid metabolism by modulating the AMPKα-SREBP-1c/PPARα pathway, enhancing lipid synthesis, and reducing the oxidative catabolism of fatty acids. AMC inhibited the transportation-induced activation of AMPKα and restored the balance of lipid-metabolism-related enzymes and pathways. These findings highlight AMC’s potential as a therapeutic intervention to alleviate transportation-induced lipid metabolism disorders, offering significant implications for improving animal welfare and reducing economic losses in livestock farming. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Obesity and Metabolic Diseases)

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Review

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17 pages, 1143 KiB

Open AccessReview

New Perspectives on the Molecular Action of Metformin in the Context of Cellular Transduction and Adipogenesis

by Jorge Enrique González-Casanova, Mario Navarro-Marquez, Tamara Saez-Tamayo, Lissé Angarita, Samuel Durán-Agüero, Héctor Fuentes-Barría, Valmore Bermúdez and Diana Marcela Rojas-Gómez

Int. J. Mol. Sci. 2025, 26(8), 3690; https://doi.org/10.3390/ijms26083690 - 14 Apr 2025

Viewed by 544

Abstract

Metformin, a widely used antidiabetic drug, modulates the cellular physiology and metabolism of various body tissues, including adipose tissue. Adipogenesis, a complex process in which mesenchymal stem cells (MSC) differentiate into functional adipocytes, plays a key role in metabolic health and represents a potential therapeutic target for diverse metabolic disorders. Notably, recent evidence suggests that metformin modulates adipocyte differentiation. This narrative review explores the effects of metformin on cellular metabolism, with a particular focus on adipogenesis. The findings compiled in this review show that metformin regulates glucose and lipid metabolism in multiple tissues, including skeletal muscle, adipose tissue, liver, and intestine. Furthermore, metformin modulates adipogenesis through AMP-activated protein kinase (AMPK)-dependent and independent mechanisms in 3T3-L1 cells and adipose-derived stem cells. The review also emphasizes that metformin can promote or inhibit adipogenesis and lipid accumulation, depending on its concentration. Additionally, metformin attenuates inflammatory pathways by reducing the production of proinflammatory cytokines such as IL-6, MCP-1, and COX-2. Finally, evidence supports that vitamin D enhances the anti-inflammatory actions of metformin and promotes cell differentiation toward a beige adipocyte phenotype. In summary, this review examines the molecular actions of metformin to propose potential new therapeutic strategies for managing obesity and related metabolic diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Obesity and Metabolic Diseases)

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49 pages, 3293 KiB

Open AccessReview

Unraveling the Mystery of Insulin Resistance: From Principle Mechanistic Insights and Consequences to Therapeutic Interventions

by Mohammad Muzaffar Mir, Mohammed Jeelani, Muffarah Hamid Alharthi, Syeda Fatima Rizvi, Shahzada Khalid Sohail, Javed Iqbal Wani, Zia Ul Sabah, Waad Fuad BinAfif, Partha Nandi, Abdullah M. Alshahrani, Jaber Alfaifi, Adnan Jehangir and Rashid Mir

Int. J. Mol. Sci. 2025, 26(6), 2770; https://doi.org/10.3390/ijms26062770 - 19 Mar 2025

Viewed by 1517

Abstract

Insulin resistance (IR) is a significant factor in the development and progression of metabolic-related diseases like dyslipidemia, T2DM, hypertension, nonalcoholic fatty liver disease, cardiovascular and cerebrovascular disorders, and cancer. The pathogenesis of IR depends on multiple factors, including age, genetic predisposition, obesity, oxidative stress, among others. Abnormalities in the insulin-signaling cascade lead to IR in the host, including insulin receptor abnormalities, internal environment disturbances, and metabolic alterations in the muscle, liver, and cellular organelles. The complex and multifaceted characteristics of insulin signaling and insulin resistance envisage their thorough and comprehensive understanding at the cellular and molecular level. Therapeutic strategies for IR include exercise, dietary interventions, and pharmacotherapy. However, there are still gaps to be addressed, and more precise biomarkers for associated chronic diseases and lifestyle interventions are needed. Understanding these pathways is essential for developing effective treatments for IR, reducing healthcare costs, and improving quality of patient life. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Obesity and Metabolic Diseases)

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