Lipoatrophy and metabolic disturbance in mice with adipose-specific deletion of kindlin-2

Gao, Huanqing; Guo, Yuxi; Yan, Qinnan; Wei, Yang; Li, Ruxuan; Lin, Simin; Bai, Xiaochun; Liu, Chuanju; Chen, Di; Cao, Huiling; Xiao, Guozhi

doi:10.1172/jci.insight.128405

Cited by 45 publications

(47 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is in line with a recent study showing that obesity-induced insulin resistance in mice can precede macrophage accumulation and inflammation in adipose tissue (Shimobayashi, Albert et al, 2018). Thus, integrin activity in mature white adipocytes appears to predominantly affect insulin action, which in some ways, is in contradiction to the conclusions drawn in a recent report on adipose selective knockout of Kindlin-2 (Gao et al, 2019). It is indeed difficult to conclude if the observed tissue fibrosis and apoptosis upon loss of Kindlin-2 are due to impaired integrin or insulin action, as both can mediate these processes.…”

Section: Discussionsupporting

confidence: 83%

“…1G and H). Both, adipose selective depletion of Kindlin-2 and FAK, bluntin inside-out and outside-in integrin signaling, respectively, resulted in increased adipocyte death and loss of Kindlin-2 was reported to impair adipogenesis (Gao et al, 2019, Luk et al, 2017. However, we did not observe differences in Pparg and Adiponectin gene expression measured in primary subcutaneous adipocytes, indicating that adipogenesis per se is not impaired (Fig.…”

Section: Expression Of 1 and 3 Integrins In Adipose Tissue Positivementioning

confidence: 55%

“…There are no data on the role of talins or integrins in adipose tissue, but adipose specific loss of Kindlin-2 (Gao, Guo et al, 2019), similar to the loss of the key outside-in signal mediator focal adhesion kinase (Luk, Shi et al, 2017), results in lipodystrophy due to adipocyte apoptosis.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Active integrins regulate white adipose tissue insulin sensitivity and brown fat thermogenesis

Ruiz‐Ojeda

Wang

Baecker

et al. 2020

Preprint

View full text Add to dashboard Cite

AbstractReorganization of the extracellular matrix is a prerequisite for healthy adipose tissue expansion, whereas fibrosis is a key feature of adipose dysfunction and inflammation. However, very little is known about the direct effects of impaired cell-matrix interaction in adipocyte function and insulin sensitivity. Using adipose selective deletion of β1 integrin (Itgb1adipo-cre) and Kindlin-2 (Kind2adipo-cre), we demonstrate here that active β1 and β3 integrins directly interact with the insulin receptor to regulate white adipocyte insulin action and systemic metabolism. Consequently, loss of adipose integrin activity, similar to loss of adipose insulin receptors, results in lipodystrophy and systemic insulin resistance. Conversely, we find that brown adipose tissue of Kind2adipo-cre and Itgb1adipo-cre mice is chronically hyperactivated, and has increased substrate delivery, reduced endothelial basement membrane thickness, and increased endothelial vesicular transport. Thus, we establish integrin-extracellular matrix interactions as key regulators of white and brown adipose tissue function and whole body metabolism.

show abstract

Section: Discussionsupporting

confidence: 83%

Section: Expression Of 1 and 3 Integrins In Adipose Tissue Positivementioning

confidence: 55%

See 1 more Smart Citation

Active integrins regulate white adipose tissue insulin sensitivity and brown fat thermogenesis

Ruiz‐Ojeda

Wang

Baecker

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The DNA sequences of primers used for qPCR are summarized in Supplemental Table 1 (supplemental material available online with this article; https://doi.org/10.1172/jci.insight.131692DS1). Western blot analysis was performed as previously described (53). Briefly, protein extracts were fractionated on a 10% SDS-PAGE gel and transferred onto nitrocellulose membranes (Schleicher & Schuell).…”

Section: Methodsmentioning

confidence: 99%

Focal adhesion proteins Pinch1 and Pinch2 regulate bone homeostasis in mice

Wang¹,

Yan²,

Zhao³

et al. 2019

JCI Insight

Self Cite

View full text Add to dashboard Cite

“…67 Quantitative real-time PCR (qRT-PCR) and western blot analysis RNA and protein isolation, qRT-PCR, and western blot analysis were performed as previously described. 68 The specific primers for gene expression analysis are listed in Supplementary Table 1. Primary antibody information is listed in Supplementary Table 2.…”

Section: Animal Studiesmentioning

confidence: 99%

LIM domain proteins Pinch1/2 regulate chondrogenesis and bone mass in mice

Lei

et al. 2020

Bone Res

Self Cite

View full text Add to dashboard Cite

The LIM domain-containing proteins Pinch1/2 regulate integrin activation and cell–extracellular matrix interaction and adhesion. Here, we report that deleting Pinch1 in limb mesenchymal stem cells (MSCs) and Pinch2 globally (double knockout; dKO) in mice causes severe chondrodysplasia, while single mutant mice do not display marked defects. Pinch deletion decreases chondrocyte proliferation, accelerates cell differentiation and disrupts column formation. Pinch loss drastically reduces Smad2/3 protein expression in proliferative zone (PZ) chondrocytes and increases Runx2 and Col10a1 expression in both PZ and hypertrophic zone (HZ) chondrocytes. Pinch loss increases sclerostin and Rankl expression in HZ chondrocytes, reduces bone formation, and increases bone resorption, leading to low bone mass. In vitro studies revealed that Pinch1 and Smad2/3 colocalize in the nuclei of chondrocytes. Through its C-terminal region, Pinch1 interacts with Smad2/3 proteins. Pinch loss increases Smad2/3 ubiquitination and degradation in primary bone marrow stromal cells (BMSCs). Pinch loss reduces TGF-β-induced Smad2/3 phosphorylation and nuclear localization in primary BMSCs. Interestingly, compared to those from single mutant mice, BMSCs from dKO mice express dramatically lower protein levels of β-catenin and Yap1/Taz and display reduced osteogenic but increased adipogenic differentiation capacity. Finally, ablating Pinch1 in chondrocytes and Pinch2 globally causes severe osteopenia with subtle limb shortening. Collectively, our findings demonstrate critical roles for Pinch1/2 and a functional redundancy of both factors in the control of chondrogenesis and bone mass through distinct mechanisms.

show abstract

Lipoatrophy and metabolic disturbance in mice with adipose-specific deletion of kindlin-2

Cited by 45 publications

References 53 publications

Active integrins regulate white adipose tissue insulin sensitivity and brown fat thermogenesis

Active integrins regulate white adipose tissue insulin sensitivity and brown fat thermogenesis

Focal adhesion proteins Pinch1 and Pinch2 regulate bone homeostasis in mice

LIM domain proteins Pinch1/2 regulate chondrogenesis and bone mass in mice

Contact Info

Product

Resources

About