Adipose cell size changes are associated with a drastic actin remodeling

Hansson, Björn; Morén, Björn; Fryklund, Claes; Vliex, Lars M. M.; Wasserström, Sebastian; Albinsson, Sebastian; Berger, Karin; Stenkula, Karin G.

doi:10.1038/s41598-019-49418-0

Cited by 50 publications

(52 citation statements)

References 52 publications

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“…Treatment with Rosi partially reversed these morphological changes. Our results are consistent with a recent study that demonstrated correlations between adipocyte size, actin cytoskeletal complexity, and insulin resistance [ 65 ]. These results differ from another study, however, in which it was reported that larger adipocytes with functional declines had reduced actin polymerization [ 66 ].…”

Section: Discussionsupporting

confidence: 93%

Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling

Roh

Kumari

Taleb

et al. 2020

Molecular Metabolism

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Objective Obesity due to overnutrition causes adipose tissue dysfunction, which is a critical pathological step on the road to type 2 diabetes (T2D) and other metabolic disorders. In this study, we conducted an unbiased investigation into the fundamental molecular mechanisms by which adipocytes transition to an unhealthy state during obesity. Methods We used nuclear tagging and translating ribosome affinity purification (NuTRAP) reporter mice crossed with Adipoq-Cre mice to determine adipocyte-specific 1) transcriptional profiles (RNA-seq), 2) promoter and enhancer activity (H3K27ac ChIP-seq), 3) and PPAR γ cistrome (ChIP-seq) profiles in mice fed chow or a high-fat diet (HFD) for 10 weeks. We also assessed the impact of the PPAR γ agonist rosiglitazone (Rosi) on gene expression and cellular state of adipocytes from the HFD-fed mice. We integrated these data to determine the transcription factors underlying adipocyte responses to HFD and conducted functional studies using shRNA-mediated loss-of-function approaches in 3T3-L1 adipocytes. Results Adipocytes from the HFD-fed mice exhibited reduced expression of adipocyte markers and metabolic genes and enhanced expression of myofibroblast marker genes involved in cytoskeletal organization, accompanied by the formation of actin filament structures within the cell. PPAR γ binding was globally reduced in adipocytes after HFD feeding, and Rosi restored the molecular and cellular phenotypes of adipocytes associated with HFD feeding. We identified the TGFβ1 effector protein SMAD to be enriched at HFD-induced promoters and enhancers and associated with myofibroblast signature genes. TGFβ1 treatment of mature 3T3-L1 adipocytes induced gene expression and cellular changes similar to those seen after HFD in vivo , and knockdown of Smad3 blunted the effects of TGFβ1. Conclusions Our data demonstrate that adipocytes fail to maintain cellular identity after HFD feeding, acquiring characteristics of a myofibroblast-like cell type through reduced PPAR γ activity and elevated TGFβ-SMAD signaling. This cellular identity crisis may be a fundamental mechanism that drives functional decline of adipose tissues during obesity.

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Section: Discussionsupporting

confidence: 93%

Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling

Roh

Kumari

Taleb

et al. 2020

Molecular Metabolism

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“…Hasson et al show that in C57BL/6J mice treated with high-fat diet for 2 weeks, Factin increased 4-fold in VAT compared with chow-fat group in response to the intact interaction between IQGAP1 and IRS-1. Reversed feeding correspondingly restored cell size, insulin response, expression of F-actin, and its regulatory proteins [143]. Although this study indicated the critical role of actin in adipocyte remodeling, the effect of cytoskeleton on the structure of adipocytes is quite contrary to the findings in other articles [138,144].…”

Section: Development Of "Supersized" Lipid Dropletcontrasting

confidence: 81%

Adipose Morphology: a Critical Factor in Regulation of Human Metabolic Diseases and Adipose Tissue Dysfunction

Liu

Wang

et al. 2020

OBES SURG

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Emerging evidence highlights that dysfunction of adipose tissue contributes to impaired insulin sensitivity and systemic metabolic deterioration in obese state. Of note, adipocyte hypertrophy serves as a critical event which associates closely with adipose dysfunction. An increase in cell size exacerbates hypoxia and inflammation as well as excessive collagen deposition, finally leading to metabolic dysregulation. Specific mechanisms of adipocyte hypertrophy include dysregulated differentiation and maturation of preadipocytes, enlargement of lipid droplets, and abnormal adipocyte osmolarity sensors. Also, weight loss therapies exert profound influence on adipocyte size. Here, we summarize the critical role of adipocyte hypertrophy in the development of metabolic disturbances. Future studies are required to establish a standard criterion of size measurement to better clarify the impact of adipocyte hypertrophy on changes in metabolic homeostasis.

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“…In this study, we have characterized the presence of small surface-associated lipid droplets, rarely recognized before, distinct from the large central droplet which accounts for and determines the cellular volume [30]. Based on microscopy analyses, we propose that these droplet clusters represent an intermediate stage of lipid transport in primary adipocytes.…”

Section: Discussionmentioning

confidence: 80%

Surface-associated lipid droplets: an intermediate site for lipid transport in human adipocytes?

2020

Self Cite

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Adipose tissue plays a major role in regulating whole-body energy metabolism. While the biochemical processes regulating storage and release of excess energy are well known, the temporal organization of these events is much less defined. In this study, we have characterized the presence of small surface-associated lipid droplets, distinct from the central droplet, in primary human adipocytes. Based on microscopy analyses, we illustrate the distribution of mitochondria, endoplasmic reticulum and lysosomes in the vicinity of these specialized lipid droplets. Ultrastructure analysis confirmed the presence of small droplets in intact adipose tissue. Further, CIDEC, known to bind and regulate lipid droplet expansion, clearly localized at these lipid droplets. Neither acute or prolonged stimulation with insulin or isoprenaline, or pharmacologic intervention to suppress lipid flux, affected the presence of these lipid droplets. Still, phosphorylated perilipin and hormone-sensitive lipase accumulated at these droplets following adrenergic stimuli, which supports metabolic activity at these locations. Altogether, we propose these lipid droplet clusters represent an intermediate site involved in lipid transport in primary adipocytes.

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Adipose cell size changes are associated with a drastic actin remodeling

Cited by 50 publications

References 52 publications

Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling

Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling

Adipose Morphology: a Critical Factor in Regulation of Human Metabolic Diseases and Adipose Tissue Dysfunction

Surface-associated lipid droplets: an intermediate site for lipid transport in human adipocytes?

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