Interplay between Hypoxia, Inflammation and Adipocyte Remodeling in the Metabolic Syndrome

Andrei, Ana Marina; Berbecaru-Iovan, Anca; Anghel, Felix Rareş Ioan Din; Stănciulescu, Camelia Elena; Berbecaru-Iovan, Sorin; Baniţă, IleanaMonica; Pisoschi, Cătălina Gabriela

doi:10.5772/65491

Cited by 8 publications

(5 citation statements)

References 113 publications

(202 reference statements)

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“…As a result, the dysregulated endothelial function leads to the excessive growth of fat and the pathological remodeling of AT in a cyclic manner [ 27 , 61 ] ( Figure 2 ). Such remodeling, similar to obesity but in a different fat depot, has also been hypothesized as the reason underlying the hypoxic conditions within lipedema AT, leading to necrosis, inflammation, and fibrosis [ 7 , 22 , 62 ].…”

Section: Mechanisms Implicated In the Pathogenesis Of Lipedemamentioning

confidence: 99%

Lipedema: Insights into Morphology, Pathophysiology, and Challenges

2022

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Lipedema is an adipofascial disorder that almost exclusively affects women. Lipedema leads to chronic pain, swelling, and other discomforts due to the bilateral and asymmetrical expansion of subcutaneous adipose tissue. Although various distinctive morphological characteristics, such as the hyperproliferation of fat cells, fibrosis, and inflammation, have been characterized in the progression of lipedema, the mechanisms underlying these changes have not yet been fully investigated. In addition, it is challenging to reduce the excessive fat in lipedema patients using conventional weight-loss techniques, such as lifestyle (diet and exercise) changes, bariatric surgery, and pharmacological interventions. Therefore, lipedema patients also go through additional psychosocial distress in the absence of permanent treatment. Research to understand the pathology of lipedema is still in its infancy, but promising markers derived from exosome, cytokine, lipidomic, and metabolomic profiling studies suggest a condition distinct from obesity and lymphedema. Although genetics seems to be a substantial cause of lipedema, due to the small number of patients involved in such studies, the extrapolation of data at a broader scale is challenging. With the current lack of etiology-guided treatments for lipedema, the discovery of new promising biomarkers could provide potential solutions to combat this complex disease. This review aims to address the morphological phenotype of lipedema fat, as well as its unclear pathophysiology, with a primary emphasis on excessive interstitial fluid, extracellular matrix remodeling, and lymphatic and vasculature dysfunction. The potential mechanisms, genetic implications, and proposed biomarkers for lipedema are further discussed in detail. Finally, we mention the challenges related to lipedema and emphasize the prospects of technological interventions to benefit the lipedema community in the future.

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Section: Mechanisms Implicated In the Pathogenesis Of Lipedemamentioning

confidence: 99%

Lipedema: Insights into Morphology, Pathophysiology, and Challenges

2022

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“…There is accumulating evidence that as adipose tissue mass expands, insufficient angiogenesis and cellular hypertrophy may limit oxygen availability to adipocytes, a concept that has been called ‘adipose tissue hypoxia’ [ 1 , 2 ]. Studies conducted in rodent models have shown that AT oxygenation is lower in rodent models with obesity compared to their lean counterparts [ 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

CYP1A1, VEGFA and Adipokine Responses of Human Adipocytes Co-exposed to PCB126 and Hypoxia

Amine

Mauger

Imbeault

2022

Cells

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It is increasingly recognized that hypoxia may develop in adipose tissue as its mass expands. Adipose tissue is also the main reservoir of lipophilic pollutants, including polychlorinated biphenyls (PCBs). Both hypoxia and PCBs have been shown to alter adipose tissue functions. The signaling pathways induced by hypoxia and pollutants may crosstalk, as they share a common transcription factor: aryl hydrocarbon receptor nuclear translocator (ARNT). Whether hypoxia and PCBs crosstalk and affect adipokine secretion in human adipocytes remains to be explored. Using primary human adipocytes acutely co-exposed to different levels of hypoxia (24 h) and PCB126 (48 h), we observed that hypoxia significantly inhibits the PCB126 induction of cytochrome P450 (CYP1A1) transcription in a dose-response manner, and that Acriflavine (ACF)—an HIF1α inhibitor—partially restores the PCB126 induction of CYP1A1 under hypoxia. On the other hand, exposure to PCB126 did not affect the transcription of the vascular endothelial growth factor-A (VEGFA) under hypoxia. Exposure to hypoxia increased leptin and interleukin-6 (IL-6), and decreased adiponectin levels dose-dependently, while PCB126 increased IL-6 and IL-8 secretion in a dose-dependent manner. Co-exposure to PCB126 and hypoxia did not alter the adipokine secretion pattern observed under hypoxia and PCB126 exposure alone. In conclusion, our results indicate that (1) hypoxia inhibits PCB126-induced CYP1A1 expression at least partly through ARNT-dependent means, suggesting that hypoxia could affect PCB metabolism and toxicity in adipose tissue, and (2) hypoxia and PCB126 affect leptin, adiponectin, IL-6 and IL-8 secretion differently, with no apparent crosstalk between the two factors.

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“…Hypoxia is a major trigger for adipose tissue dysfunctions, including adipocyte remodelling, inflammation, reactive oxygen species generation, and oxidative stress. 31 Therefore, we examined the expression of genes related to hypoxia in the PVAT and mPVAT of our experimental models. Strikingly, hypoxia-inducible factor 1-alpha ( Hif-1a ), the signature marker of hypoxia, and its downstream target vascular endothelial growth factor ( Vegf ) and ten-eleven translocation-1 ( Tet1 ) were significantly upregulated in both the aortic PVAT and mPVAT of A-NOS3 KO HFD mice compared to that of control HFD ( Figure 5 and Supplementary material online , Figure S3I and J ).…”

Section: Resultsmentioning

confidence: 99%

Deletion of adipocyte NOS3 potentiates high-fat diet-induced hypertension and vascular remodelling via chemerin

Man,

Zhou,

Reifenberg

et al. 2023

Cardiovascular Research

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Aims Obesity is an epidemic that is a critical contributor to hypertension and other cardiovascular diseases. Current paradigms suggest that endothelial nitric oxide synthase (eNOS/NOS3) in the vessel wall is the primary regulator of vascular function and blood pressure. However, recent studies have revealed the presence of eNOS/NOS3 in the adipocytes of white adipose tissues and perivascular adipose tissues (PVATs). The current understanding of the role of adipocyte NOS3 is based mainly on studies using global knockout models. The present study aimed to elucidate the functional significance of adipocyte NOS3 for vascular function and blood pressure control. Methods and Results We generated an adipocyte-specific NOS3 knockout mouse line using adiponectin promotor-specific Cre-induced gene inactivation. Control and adipocyte-specific NOS3 knockout (A-NOS3 KO) mice were fed a high-fat diet (HFD). Despite less weight gain, A-NOS3 KO mice exhibited a significant increase in blood pressure after HFD feeding, associated with exacerbated vascular dysfunction and remodeling. A-NOS3 KO mice also showed increased expression of signature markers of inflammation and hypoxia in the PVATs. Among the differentially expressed adipokines, we have observed an upregulation of a novel adipokine, chemerin, in A-NOS3 KO mice. Chemerin was recently reported to link obesity and vascular dysfunction. Treatment with chemerin neutralizing antibody normalized the expression of remodeling markers in the aorta segments cultured in serum from HFD-fed A-NOS3 KO mice ex vivo. Conclusions These data suggest that NOS3 in adipocytes is vital in maintaining vascular homeostasis; dysfunction of adipocyte NOS3 contributes to obesity-induced vascular remodeling and hypertension.

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Interplay between Hypoxia, Inflammation and Adipocyte Remodeling in the Metabolic Syndrome

Cited by 8 publications

References 113 publications

Lipedema: Insights into Morphology, Pathophysiology, and Challenges

Lipedema: Insights into Morphology, Pathophysiology, and Challenges

CYP1A1, VEGFA and Adipokine Responses of Human Adipocytes Co-exposed to PCB126 and Hypoxia

Deletion of adipocyte NOS3 potentiates high-fat diet-induced hypertension and vascular remodelling via chemerin

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