GPS2-mediated regulation of the adipocyte secretome modulates adipose tissue remodeling at the onset of diet-induced obesity

English, Justin; Orofino, Joseph; Cederquist, Carly; Paul, Indranil; Li, Hao; Auwerx, Johan; Emili, Andrew; Belkina, Anna C.; Cardamone, Dafne; Perissi, Valentina

doi:10.1016/j.molmet.2023.101682

Cited by 5 publications

(4 citation statements)

References 177 publications

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“…One such modulator seems to be the multifunctional subunit Gps2. It exhibits extensive genomic and non-genomic functions, simultaneously modulating the transcription of Pparg, mitochondrial function and biogenesis, glucose uptake, and insulin signaling, which emerged as a critical factor in facilitating physiological adipose tissue adaptation to high-energy intake [33,46,47]. Gps2 is a well-known NCoR/SMRT transcriptional co-repressor complex component in mammalian cells, and its activation suppresses the transcription of Pparg.…”

Section: Discussionmentioning

confidence: 99%

“…They are recognized as the multifunctional factors of various intracellular metabolic pathways, potentially unlocking opposing physiological outcomes depending on the specific signaling interactions. Among them, the G-protein-coupled receptor 120 (Gpr120) [30,31] and the G protein pathway suppressor 2 (Gps2) [32,33] have emerged as prominent regulators in terms of determining the adaptive capacity of adipose tissue in response to high-energy intake. However, the precise role and underlying mechanisms through which DHA influences adipocyte metabolism and interacts with these factors remain poorly understood and warrant further investigation.…”

Section: Introductionmentioning

confidence: 99%

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DHA-Provoked Reduction in Adipogenesis and Glucose Uptake Could Be Mediated by Gps2 Upregulation in Immature 3T3-L1 Cells

Grigorova,

Ivanova,

Vachkova

et al. 2023

IJMS

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The signaling pathway of fatty acids in the context of obesity is an extensively explored topic, yet their primary mechanism of action remains incompletely understood. This study aims to examine the effect of docosahexaenoic acid (DHA) on some crucial aspects of adipogenesis in differentiating 3T3-L1 cells, using palmitic acid-treated (PA), standard differentiated, and undifferentiated adipocytes as controls. Employing 60 µM DHA or PA, 3T3-L1 preadipocytes were treated from the onset of adipogenesis, with negative and positive controls included. After eight days, we performed microscopic observations, cell viability assays, the determination of adiponectin concentration, intracellular lipid accumulation, and gene expression analysis. Our findings demonstrated that DHA inhibits adipogenesis, lipolysis, and glucose uptake by suppressing peroxisome proliferator-activated receptor gamma (Pparg) and G-protein coupled receptor 120 (Gpr120) gene expression. Cell cytotoxicity was ruled out as a causative factor, and β-oxidation involvement was suspected. These results challenge the conventional belief that omega-3 fatty acids, acting as Pparg and Gpr120 agonists, promote adipogenesis and enhance insulin-dependent glucose cell flux. Moreover, we propose a novel hypothesis suggesting the key role of the co-repressor G protein pathway suppressor 2 in mediating this process. Additional investigations are required to elucidate the molecular mechanisms driving DHA’s anti-adipogenic effect and its broader health implications.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DHA-Provoked Reduction in Adipogenesis and Glucose Uptake Could Be Mediated by Gps2 Upregulation in Immature 3T3-L1 Cells

Grigorova,

Ivanova,

Vachkova

et al. 2023

IJMS

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show abstract

“…A new body of evidence has focused on the decisive role of transcriptional coregulators in adipocyte biology. It has been especially pointed to the multifunctional protein Gps2 due to its ability to interact with numerous transcriptional factors involved in lipid metabolism, inflammation, mitochondrial biogenesis, and the insulin signaling pathway [57,60,61]. Although the physiological Gps2 action is still debatable, it is known to control the activity of master adipogenic regulators PPARγ and C/EBPs [62].…”

Section: Discussionmentioning

confidence: 99%

Antidiabetic and Hypolipidemic Properties of Newly Isolated Wild Lacticaseibacillus paracasei Strains in Mature Adipocytes

et al. 2023

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This study investigates the antidiabetic and hypolipidemic potential of newly isolated Lacticaseibacillus paracasei strains in mature adipocytes. Differentiated 3T3-L1 cells are treated with 10% cell-free supernatants (CFSs) from four autochthonous (wild) strains (M2.1, C8, C15, and P4) of Lacticaseibacillus paracasei. Glucose consumption, intracellular lipid deposition, lipolysis rates, and some gene expressions related to adipocyte insulin sensitivity are evaluated. The results show that all CFS-treated groups experienced a substantial increase in glucose uptake, indicating a promising potential for countering glucotoxicity and insulin resistance. The different strains had notable differences in metabolic pathway modulation. Generally, the P4 CFS supplementation seems to enhance insulin-dependent glucose inflow, while M2.1, C8, and C15 supernatants stimulate insulin-independent glucose consumption by mature adipocytes. M2.1 CFSs ameliorate the mature adipocyte buffer capacity by enhancing intracellular lipid accumulation and reducing the lipolysis rate—an advantageous therapeutic effect in overweight individuals subjected to substantial obesity-predisposing factors. Notably, C8 and C15 CFSs suppressed the gene expression of crucial adipocyte insulin sensitivity markers, indicating an unfavorable outcome risk with prolonged treatment. Overall, our findings suggest that M2.1 and P4 Lacticaseibacillus paracasei strains may be implemented as nutraceuticals to counteract glucotoxicity and insulin resistance, potentially easing the health status of obese individuals.

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“…These pathologies are associated with a low-grade inflammatory state that differentially affects the homeostasis and the secretome of specific AT depots. This leads to an alteration in the release of extracellular vesicles (EVs) in terms of both number and cargo, which is strictly dependent on the type and state of the cellular and tissue origin [ 6 , 7 ]. The role of epicardial adipose tissue (EAT) in this framework is of particular interest, as it has a significantly different transcriptome and secretome compared to other fat depots, and is in direct contact with the heart muscle [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Role of Epicardial Adipose Tissue Secretome on Cardiovascular Diseases

et al. 2023

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Obesity and insulin resistance are associated with the inflamed and defective adipose tissue (AT) phenotype, and are established risk factors for cardiovascular diseases (CVDs). Extracellular vesicles (EVs) are a heterogeneous group of cell-derived lipid membrane vesicles involved in the onset and development of many pathologies, including insulin resistance, diabetes, and CVDs. The inflammation associated with overweight and obesity triggers the transition of the AT secretome from healthy to pathological, with a consequent increased expression of pro-inflammatory mediators. Epicardial adipose tissue (EAT) is a specialized fat depot that surrounds the heart, in direct contact with the myocardium. Recently, the role of EAT in regulating the physiopathology of many heart diseases has been increasingly explored. In particular, the EAT phenotype and derived EVs have been associated with the onset and exacerbation of CVDs. In this review, we will focus on the role of the AT secretome in the case of CVDs, and will discuss the beneficial effects of EVs released by AT as promising therapeutic candidates.

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GPS2-mediated regulation of the adipocyte secretome modulates adipose tissue remodeling at the onset of diet-induced obesity

Cited by 5 publications

References 177 publications

DHA-Provoked Reduction in Adipogenesis and Glucose Uptake Could Be Mediated by Gps2 Upregulation in Immature 3T3-L1 Cells

DHA-Provoked Reduction in Adipogenesis and Glucose Uptake Could Be Mediated by Gps2 Upregulation in Immature 3T3-L1 Cells

Antidiabetic and Hypolipidemic Properties of Newly Isolated Wild Lacticaseibacillus paracasei Strains in Mature Adipocytes

Role of Epicardial Adipose Tissue Secretome on Cardiovascular Diseases

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