Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce

Li, Qian; Hagberg, Carolina E.; Cascales, Helena Silva; Lang, Simone; Hyvönen, Mervi T.; Salehzadeh, Firoozeh; Chen, Ping; Alexandersson, Ida; Terezaki, Eleni; Harms, Matthew; Kutschke, Maria; Arifen, Nahida; Krämer, Niels; Aouadi, Myriam; Knibbe, Carole; Boucher, Jérémie; Thorell, Anders; Spalding, Kirsty L.

doi:10.1038/s41591-021-01501-8

Cited by 107 publications

(106 citation statements)

References 80 publications

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“…The associations between AT cellular senescence and disease risk profile are also consistently shown in human studies, where an increased senescence burden in AT has been observed in patients with obesity, pre-diabetes/T2D and pre-frailty [ 13 , 145–147 ]. Importantly, subcutaneous adipocytes in participants with obesity and hyperinsulinemia, which are thought to be post-mitotic and hence less prone to be senescent, are capable of re-entering the cell cycle, evidenced by the expression of cell cycle markers cyclin A2/D1, and thereby proceeding towards senescence.…”

Section: Reprogramming By Cell Cycle Arrest and Senescencementioning

confidence: 71%

“…However, under chronic insulin signalling, these hypertrophic adipocytes fail to be functionally adaptative and acquire senescence phenotypes that pave the way for AT inflammation and metabolic dysfunction. Moreover, in contrast with the animal findings where senescence is often observed in the visceral depot, the authors reported that cellular senescence in humans has a minor role in reshaping the omental AT compared with the subcutaneous depot [ 13 ]. It is illuminating to observe how insulin may serve more of a mitotic stimulus than an anabolic signal during metabolic dysfunction, but questions remain on what triggers the adipocytes to respond to insulin by re-entering the cell cycle in a depot-specific manner and whether the downstream targets and signalling cascades of insulin have altered in the senescent cells.…”

Section: Reprogramming By Cell Cycle Arrest and Senescencementioning

confidence: 98%

“…Specifically, the plasticity of WAT allows it to be functionally reprogrammed in response to repeated episodes of feasting through the recruitment of immune cells, secretion of pro-inflammatory adipokines, and remodelling of extracellular matrix (ECM). As a consequence of the maladaptive reprogramming, the WAT develops an inflammatory and fibrotic phenotype associated with cellular senescence, escalating systemic low-grade inflammation and metabolic impairments [ 13–15 ].…”

Section: Introductionmentioning

confidence: 99%

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The shades of grey in adipose tissue reprogramming

Hui

2022

Bioscience Reports

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The adipose tissue (AT) has a major role in contributing to obesity-related pathologies through regulating systemic immuno-metabolism. The pathogenicity of the AT is underpinned by its remarkable plasticity to be reprogrammed under the condition of obesity, in the perspectives of tissue morphology, extracellular matrix (ECM) composition, angiogenesis, immuno-metabolic homeostasis and circadian rhythmicity. Dysregulation in these features escalates the pathogenesis conferred by this endo-metabolic organ. Intriguingly, the potential to be reprogrammed appears to be an Achilles' heel of the obese AT that can be targeted for the management of obesity and its associated comorbidities. Here, we provide an overview of the reprogramming processes of white AT (WAT), with a focus on their dynamics and pleiotropic actions over local and systemic homeostasis, followed by a discussion of potential strategies favouring therapeutic reprogramming. The potential involvement of AT remodelling in the pathogenesis of COVID-19 is also summarized and discussed.

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Section: Reprogramming By Cell Cycle Arrest and Senescencementioning

confidence: 71%

Section: Reprogramming By Cell Cycle Arrest and Senescencementioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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The shades of grey in adipose tissue reprogramming

Hui

2022

Bioscience Reports

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“…found that hyperinsulinemia prompts IL-6 and TNF - α gene expression in adipose tissue ( 58 ). Of note, a recent study showed that chronic hyperinsulinemia leads to premature adipocyte senescence and a pro-inflammatory secretory profile in vitro and in vivo ( 59 ).…”

Section: Adipose Tissue and Pancreatic Beta Cell Communication: A Com...mentioning

confidence: 99%

Role of the Gut Microbiome in Beta Cell and Adipose Tissue Crosstalk: A Review

et al. 2022

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In the last decades, obesity has reached epidemic proportions worldwide. Obesity is a chronic disease associated with a wide range of comorbidities, including insulin resistance and type 2 diabetes mellitus (T2D), which results in significant burden of disease and major consequences on health care systems. Of note, intricate interactions, including different signaling pathways, are necessary for the establishment and progression of these two closely related conditions. Altered cell-to-cell communication among the different players implicated in this equation leads to the perpetuation of a vicious circle associated with an increased risk for the development of obesity-related complications, such as T2D, which in turn contributes to the development of cardiovascular disease. In this regard, the dialogue between the adipocyte and pancreatic beta cells has been extensively studied, although some connections are yet to be fully elucidated. In this review, we explore the potential pathological mechanisms linking adipocyte dysfunction and pancreatic beta cell impairment/insulin resistance. In addition, we evaluate the role of emerging actors, such as the gut microbiome, in this complex crosstalk.

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“…Unlike most normal cells used for cell culture, adipocytes do not proliferate, they cannot be cryopreserved without breaking, they float and therefore do not attach to common culturing surfaces such as plastic, and they are incompatible with many standard cell biology techniques such as cell counting, flow cytometry, frozen sectioning, or upright microscopy. Some labs therefore use culturing models based on freshly isolated mature adipocytes, such as Membrane Mature Adipocyte Aggregate Cultures (MAAC), but because adipocytes cannot divide, these systems require a constant supply of fresh adipose tissue either from patient surgeries or mouse experiments, something not always readily available [ 6 , 7 ]. This has led the field to traditionally use adipocyte cultures based on adipose-derived progenitors or pre-adipocytes instead, which then are differentiated in vitro to become lipid-laden adherent cells (for a recent comprehensive overview please see Dufau et al, reference [ 8 ].…”

mentioning

confidence: 99%

Towards better models for studying human adipocytesin vitro

2022

Self Cite

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With obesity and its comorbidities continuing to rise, we urgently need to improve our understanding of what mechanisms trigger the white adipose tissue to become dysfunctional in response to over-feeding. The recent invent of 3D culturing models has produced several noteworthy protocols for differentiating unilocular adipocytes in vitro , promising to revolutionize the obesity research field by providing more representative adipose tissue models for such mechanistic studies. In parallel, these 3D models provide important insights to how profoundly the microenvironment influences adipocyte differentiation and morphology. This commentary highlights some of the most recent 3D models, including human unilocular vascularized adipocyte spheroids (HUVASs), developed by our lab. We discuss recent developments in the field, provide further insights to the importance of the microvasculature for adipocyte maturation, and summarize what challenges remain to be solved before we can achieve a culture model that fully recapitulates all aspects of human white adipocyte biology in vitro . Taken together, the commentary highlights important recent advances regarding 3D adipocyte culturing and underlines the many advantages these models provide over traditional 2D cultures, with the aim of convincing more laboratories to switch to 3D models.

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Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce

Cited by 107 publications

References 80 publications

The shades of grey in adipose tissue reprogramming

The shades of grey in adipose tissue reprogramming

Role of the Gut Microbiome in Beta Cell and Adipose Tissue Crosstalk: A Review

Towards better models for studying human adipocytesin vitro

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