Adipose Tissue, Obesity, and Metabolic Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Metabolism".

Deadline for manuscript submissions: closed (31 March 2025) | Viewed by 5681

Special Issue Editor


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Guest Editor
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba 305-8577, Japan
Interests: planetary health nutrition; synthetic biology; signaling dynamics; organelle morphology

Special Issue Information

Dear Colleagues,

Struggles against hunger represent a significant aspect of human history, but recent technological innovations are promising to end this. However, the widespread availability of high-fat diets due to advancements in animal husbandry and food processing has increased obesity and metabolic diseases, posing urgent global health challenges. Research in molecular biology, genetics, optics, and bioinformatics has shown that adipose tissue is not just a fat storage depot but plays a crucial role in energy balance, endocrine function, and lipotoxicity. These findings have highlighted the complex pathways governing adipose tissue dynamics and their relationships with multiple organs, impacting metabolic diseases. Despite these advances, much still remains to be discovered.

This Special Issue, “Adipose Tissue, Obesity, and Metabolic Diseases”, will collect relevant research to allow a deep understanding of the role of adipose tissue role in metabolic diseases, aiming to pave the way for innovative therapeutic strategies to combat obesity and its complications.

Dr. Takafumi Miyamoto
Guest Editor

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Keywords

  • adipose tissue
  • obesity
  • metabolic diseases
  • stress
  • inflammation
  • gut microbiota

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Published Papers (4 papers)

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Research

12 pages, 1509 KiB  
Article
Targeted Inhibition of GATA-3 by Pyrrothiogatain: Implications for Adipocyte Biology and Inflammatory Response
by Shamma Almuraikhy, Maha Alser, Khaled Naja, Aisha Al-Malki, Nayef A. Mazloum and Mohamed A. Elrayess
Cells 2025, 14(2), 100; https://doi.org/10.3390/cells14020100 - 10 Jan 2025
Viewed by 927
Abstract
GATA-3 is a master regulator of preadipocyte differentiation and function. Pharmacological or genetic targeting of GATA-3 will allow us to understand the function of GATA-3 in regulating metabolism, insulin signaling, and inflammation. Pyrrothiogatain, a novel small molecule inhibitor of GATA family proteins, has [...] Read more.
GATA-3 is a master regulator of preadipocyte differentiation and function. Pharmacological or genetic targeting of GATA-3 will allow us to understand the function of GATA-3 in regulating metabolism, insulin signaling, and inflammation. Pyrrothiogatain, a novel small molecule inhibitor of GATA family proteins, has emerged as a promising tool for modulating GATA-3 activity. This study aims to investigate the specificity of Pyrrothiogatain in regulating GATA-3-mediated preadipocyte differentiation and adipokine secretion under normal and pathological conditions. Wild-type and GATA-3 knockout 3T3-L1 cells were treated with different concentrations of Pyrrothiogatain in the presence and absence of 4-hydroxy-2-nonenal (4HNE), an inducer of oxidative stress and impairment of adipogenesis. As expected, GATA-3 knockout cells exhibited enhanced adipogenic capacity, characterized by increased cell and lipid droplet sizes, and upregulated expression of key adipogenic markers including CEBPβ, PPARγ, and PGC-1α. Pyrrothiogatain treatment reduced cell proliferation in both wild-type and GATA-3 knockout 3T3-L1 cells, but did not alter their adipogenic capacity. Furthermore, Pyrrothiogatain lowered secreted IL-6 levels and attenuated 4-HNE-induced TNF-α elevation in wild-type, but not in GATA-3 knockout cells. Co-treatment of 4-HNE and Pyrrothiogatain led to increased cell size, suggesting complex interactions between oxidative stress and GATA protein inhibition. This effect was similar to GATA-3 knockout cells, indicating Pyrrothiogatain’s potential to modulate cellular stress responses independently of GATA-3 inhibition. These results reveal that Pyrrothiogatain’s effects on adipocyte biology extend beyond simple GATA-3 inhibition. While GATA-3 knockout primarily affects adipogenesis, Pyrrothiogatain modulates inflammatory responses and potentially cellular stress mechanisms without directly impacting adipocyte differentiation. This study provides new insights into the multifaceted actions of Pyrrothiogatain and highlights its potential as a therapeutic agent for lowering inflammation and oxidative-stress-related aspects of metabolic disorders, distinct from the direct modulation of adipogenesis. Full article
(This article belongs to the Special Issue Adipose Tissue, Obesity, and Metabolic Diseases)
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30 pages, 10385 KiB  
Article
Second-Generation Antipsychotics Induce Metabolic Disruption in Adipose Tissue-Derived Mesenchymal Stem Cells Through an aPKC-Dependent Pathway
by Marco Varalda, Jacopo Venetucci, Herald Nikaj, Chaitanya Reddy Kankara, Giulia Garro, Nazanin Keivan, Valentina Bettio, Paolo Marzullo, Annamaria Antona, Guido Valente, Sergio Gentilli and Daniela Capello
Cells 2024, 13(24), 2084; https://doi.org/10.3390/cells13242084 - 17 Dec 2024
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Abstract
Metabolic syndrome (MetS) is a cluster of metabolic abnormalities, including visceral obesity, dyslipidemia, and insulin resistance. In this regard, visceral white adipose tissue (vWAT) plays a critical role, influencing energy metabolism, immunomodulation, and oxidative stress. Adipose-derived stem cells (ADSCs) are key players in [...] Read more.
Metabolic syndrome (MetS) is a cluster of metabolic abnormalities, including visceral obesity, dyslipidemia, and insulin resistance. In this regard, visceral white adipose tissue (vWAT) plays a critical role, influencing energy metabolism, immunomodulation, and oxidative stress. Adipose-derived stem cells (ADSCs) are key players in these processes within vWAT. While second-generation antipsychotics (SGAs) have significantly improved treatments for mental health disorders, their chronic use is associated with an increased risk of MetS. In this study, we explored the impact of SGAs on ADSCs to better understand their role in MetS and identify potential therapeutic targets. Our findings reveal that olanzapine disrupts lipid droplet formation during adipogenic differentiation, impairing insulin receptor endocytosis, turnover, and signaling. SGAs also alter the endolysosomal compartment, leading to acidic vesicle accumulation and increased lysosomal biogenesis through TFEB activation. PKCζ is crucial for the SGA-induced nuclear translocation of TFEB and acidic vesicle formation. Notably, inhibiting PKCζ restored insulin receptor tyrosine phosphorylation, normalized receptor turnover, and improved downstream signaling following olanzapine treatment. This activation of PKCζ by olanzapine is driven by increased phosphatidic acid synthesis via phospholipase D (PLD), following G protein-coupled receptor (GPCR) signaling activation. Overall, olanzapine and clozapine disrupt endolysosomal homeostasis and insulin signaling in a PKCζ-dependent manner. These findings highlight SGAs as valuable tools for uncovering cellular dysfunction in vWAT during MetS and may guide the development of new therapeutic strategies to mitigate the metabolic side effects of these drugs. Full article
(This article belongs to the Special Issue Adipose Tissue, Obesity, and Metabolic Diseases)
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17 pages, 3925 KiB  
Article
Adipose Tissue Macrophages of the Human Fetus
by Ádám Radványi, Katalin Gyurina, Emese Rácz, Ilona Kovács, Gábor Méhes and Tamás Röszer
Cells 2024, 13(21), 1787; https://doi.org/10.3390/cells13211787 - 28 Oct 2024
Viewed by 1129
Abstract
Prenatal adipose tissue development affects body composition and growth trajectory in early infancy, therefore it is a key determinant of adiposity in childhood. Childhood overweight and obesity increase the probability of being obese as an adult. After birth and in adulthood, adipose tissue [...] Read more.
Prenatal adipose tissue development affects body composition and growth trajectory in early infancy, therefore it is a key determinant of adiposity in childhood. Childhood overweight and obesity increase the probability of being obese as an adult. After birth and in adulthood, adipose tissue macrophages (ATMs) are relevant constituents of the fat depots, and they are necessary for physiological adipose tissue development and fat metabolism. In obesity, however, ATMs may induce chronic inflammation leading to insulin resistance, pancreatic beta cell damage and self-immunity. Despite being relevant regulators of adipose tissue development and functioning, it is unknown whether ATMs are present in the fetal adipose tissue, therefore it is elusive whether they may affect the prenatal establishment of fat depots. Here we studied the distribution of ATMs in the human fetus between gestational weeks 17 and 38 and labeled ATMs in the early postnatal life. We found that CD45+/CD14+/CD68+ ATMs infiltrated the fetal adipose tissue from the 17th week of gestation and remained persistent throughout the second and third trimesters. ATMs were phagocytic in the neonate and expressed interleukin-6, along with other pro-inflammatory gene products. These findings show that ATMs colonize the adipose tissue early in gestation, raising the possibility that intrauterine ATM–adipocyte communication may exist, eventually allowing ATMs to affect prenatal adipose tissue development. Full article
(This article belongs to the Special Issue Adipose Tissue, Obesity, and Metabolic Diseases)
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16 pages, 5929 KiB  
Article
Neddylation and Its Target Cullin 3 Are Essential for Adipocyte Differentiation
by Hongyi Zhou, Vijay Patel, Robert Rice, Richard Lee, Ha Won Kim, Neal L. Weintraub, Huabo Su and Weiqin Chen
Cells 2024, 13(19), 1654; https://doi.org/10.3390/cells13191654 - 5 Oct 2024
Cited by 1 | Viewed by 1814
Abstract
The ongoing obesity epidemic has raised awareness of the complex physiology of adipose tissue. Abnormal adipocyte differentiation results in the development of systemic metabolic disorders such as insulin resistance and diabetes. The conjugation of NEDD8 (neural precursor cell expressed, developmentally downregulated 8) to [...] Read more.
The ongoing obesity epidemic has raised awareness of the complex physiology of adipose tissue. Abnormal adipocyte differentiation results in the development of systemic metabolic disorders such as insulin resistance and diabetes. The conjugation of NEDD8 (neural precursor cell expressed, developmentally downregulated 8) to target protein, termed neddylation, has been shown to mediate adipogenesis. However, much remains unknown about its role in adipogenesis. Here, we demonstrated that neddylation and its targets, the cullin (CUL) family members, are differentially regulated during mouse and human adipogenesis. Inhibition of neddylation by MLN4924 significantly reduced adipogenesis of 3T3-L1 and human stromal vascular cells. Deletion of NAE1, a subunit of the only NEDD8 E1 enzyme, suppressed neddylation and impaired adipogenesis. Neddylation deficiency did not affect mitotic cell expansion. Instead, it disrupted CREB/CEBPβ/PPARγ signaling, essential for adipogenesis. Interestingly, among the neddylation-targeted CUL family members, deletion of CUL3, but not CUL1, CUL2, or CUL4A, largely replicated the adipogenic defects observed with neddylation deficiency. A PPARγ agonist minimally rescued the adipogenic defects caused by the deletion of NAE1 and CUL3. In conclusion, our study demonstrates that neddylation and its targeted CUL3 are crucial for adipogenesis. These findings provide potential targets for therapeutic intervention in obesity and metabolic disorders. Full article
(This article belongs to the Special Issue Adipose Tissue, Obesity, and Metabolic Diseases)
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