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 4

Elevated fasting blood glucose level, glucose intolerance, and peripheral insulin resistance in HFD-fed KO mice.

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Elevated fasting blood glucose level, glucose intolerance, and periphera...
(A) Body weight growth curve in WT and KO mice (N = 10 mice per group). (B) Representative images of adipose tissue depots. (C–F) The weights of adipose and non-adipose tissues (N = 6–9 mice per group). (G) Intraperitoneal glucose tolerance test (GTT) of WT and KO mice after 18 weeks of the HFD (N = 9 mice per group). (H) Area under the curve (AUC) for GTT. (I) Intraperitoneal insulin tolerance (ITT) test of WT and KO mice after 18 weeks on the HFD (N = 9 mice per group). (J) Area under the curve (AUC) for ITT. (K) Glucose, (L) leptin, (M) adiponectin, (N) insulin, (O) NEFA, and (P) TG levels in WT and KO mice after 18 weeks on the HFD (N = 9 mice per group). (Q) Food intake (N = 9 mice per group). *P < 0.05, **P < 0.01 for KO vs. WT by Student’s t test.