Lipoatrophy and metabolic disturbance in mice with adipose-specific deletion of kindlin-2
Huanqing Gao, Yuxi Guo, Qinnan Yan, Wei Yang, Ruxuan Li, Simin Lin, Xiaochun Bai, Chuanju Liu, Di Chen, Huiling Cao, Guozhi Xiao
Huanqing Gao, Yuxi Guo, Qinnan Yan, Wei Yang, Ruxuan Li, Simin Lin, Xiaochun Bai, Chuanju Liu, Di Chen, Huiling Cao, Guozhi Xiao
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Research Article Metabolism

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

Abstract

Kindlin-2 regulates integrin-mediated cell adhesion to and migration on the extracellular matrix. Our recent studies demonstrate important roles of kindlin-2 in regulation of mesenchymal stem cell differentiation and skeletal development. In this study, we generated adipose tissue–specific conditional knockout of kindlin-2 in mice by using Adipoq-Cre BAC–transgenic mice. The results showed that deleting kindlin-2 expression in adipocytes in mice caused a severe lipodystrophy with drastically reduced adipose tissue mass. Kindlin-2 ablation elevated the blood levels of nonesterified fatty acids and triglycerides, resulting in massive fatty livers in the mutant mice fed with high-fat diet (HFD). Furthermore, HFD-fed mutant mice displayed type II diabetes–like phenotypes, including elevated levels of fasting blood glucose, glucose intolerance, and peripheral insulin resistance. Kindlin-2 loss dramatically reduced the expression levels of multiple key factors, including PPARγ, mTOR, AKT, and β-catenin proteins, and suppressed adipocyte gene expression and differentiation. Finally, kindlin-2 loss drastically reduced leptin production and caused a high bone mass phenotype. Collectively, these studies establish a critical role of kindlin-2 in control of adipogenesis and lipid metabolism as well as bone homeostasis.

Authors

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

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Figure 5

Deregulated lipid metabolism in HFD-fed KO mice.

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Deregulated lipid metabolism in HFD-fed KO mice. (A and B) Quantitative ...
(A and B) Quantitative real-time reverse transcriptase PCR (qPCR) analyses of gene expression in iWAT and BAT of HFD-fed WT and KO mice (N = 6 mice per group). (C) Representative H&E staining of BAT, eWAT, iWAT, and BAT of WT and KO mice after 18 weeks of HFD feeding (original magnification, ×200). (D) Adipocyte size in adipose tissue. (E) Distribution of eWAT adipocyte size as determined by histomorphometric analyses (N = 4–7 mice per group). (F) Relationship between calculated mean adipocyte volume and calculated total adipocyte number in the eWAT based on H&E staining in C. (G) H&E staining of livers from WT and KO mice after 18 weeks of HFD feeding (original magnification, ×200). (H) Immunohistochemical staining of F4/80 in iWAT from WT and KO mice after 18 weeks of HFD feeding (original magnification, ×200). *P < 0.05, **P < 0.01 for KO vs. WT by Student’s t test.