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Liver kinase b1 is required for white adipose tissue growth and differentiation.

ABSTRACT: White adipose tissue (WAT) is not only a lipogenic and fat storage tissue but also an important endocrine organ that regulates energy homeostasis, lipid metabolism, appetite, fertility, and immune and stress responses. Liver kinase B1 (LKB1), a tumor suppressor, is a key regulator in energy metabolism. However, the role of LKB1 in adipogenesis is unknown. The current study aimed to determine the contributions of LKB1 to adipogenesis in vivo. Using the Fabp4-Cre/loxP system, we generated adipose tissue-specific LKB1 knockout (LKB1(ad-/-)) mice. LKB1(ad-/-) mice exhibited a reduced amount of WAT, postnatal growth retardation, and early death before weaning. Further, LKB1 deletion markedly reduced the levels of insulin receptor substrate 1 (IRS1), peroxisome proliferator-activated receptor ?, CCAAT/enhancer-binding protein ?, and phosphorylated AMP-activated protein kinase (AMPK). Consistent with these results, overexpression of constitutively active AMPK partially ablated IRS1 degradation in LKB1-deficient cells. LKB1 deletion increased the levels of F-box/WD repeat-containing protein (Fbw) 8, the IRS1 ubiquitination E3 ligase. Silencing of Fbw8 increased IRS1 levels. Finally, promoter analysis and DNA chromatin immunoprecipitation analysis identified three sterol regulatory element (SRE) sites in the Fbw8 promoter, where SRE-binding protein 1c binds and induces the expression of Fbw8. Taken together, these data indicate that LKB1 controls IRS1-dependent adipogenesis via AMPK in WAT.

SUBMITTER: Zhang W

PROVIDER: S-EPMC3712073 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Liver kinase b1 is required for white adipose tissue growth and differentiation.

Zhang Wencheng W Wang Qilong Q Song Ping P Zou Ming-Hui MH

Diabetes 20130208 7

White adipose tissue (WAT) is not only a lipogenic and fat storage tissue but also an important endocrine organ that regulates energy homeostasis, lipid metabolism, appetite, fertility, and immune and stress responses. Liver kinase B1 (LKB1), a tumor suppressor, is a key regulator in energy metabolism. However, the role of LKB1 in adipogenesis is unknown. The current study aimed to determine the contributions of LKB1 to adipogenesis in vivo. Using the Fabp4-Cre/loxP system, we generated adipose ...[more]

PMID: 23396401

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Project description:ObjectiveThromboxane A2 receptor (TPr) has been reported to trigger vascular inflammation. Nuclear factor κ B (NF-κB) is a known transcription factor. The aims of the present study were to determine the contributions of NF-κB activation to TPr-triggered vascular inflammation and elucidate the mechanism(s) underlying TPr activation of NF-κB.Approach and resultsThe effects of TPr activators, [1S-[1 alpha,2 alpha(Z),3beta(1E,3S*), 4 alpha]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (I-BOP) and U46619, on NF-κB activation, phosphorylation of rhoA/rho-associated kinases and liver kinase B1, cell adhesion and migration, proliferation, and endothelium-dependent vasorelaxation were assayed in cultured human umbilical vein endothelial cells, human monocytes, or isolated mouse aortas. Exposure of human umbilical vein endothelial cells to TPr agonists I-BOP and U46619 induced dose-dependent and time-dependent phosphorylation of inhibitor of κB α in parallel with aberrant expression of inflammatory markers cyclooxygenase-2, inducible nitric oxide synthase, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. Inhibition of NF-κB by pharmacological or genetic means abolished TPr-triggered expression of inflammatory markers. Consistently, exposure of human umbilical vein endothelial cells to either I-BOP or U46619 significantly increased phosphorylation of inhibitor of κB α, I kappaB kinase, rhoA, rho-associated kinases, and liver kinase B1. Pretreatment of human umbilical vein endothelial cells with the TPr antagonist SQ29548 or rho-associated kinases inhibitor Y27632 or silencing of the LKB1 blocked TPr-enhanced phosphorylation of inhibitor of κB α and its upstream kinase, I kappaB kinase. Finally, exposure of isolated mouse aortas to either U46619 or I-BOP enhanced NF-κB activation and vascular inflammation in parallel with reduced endothelium-dependent relaxation in intact vessels.ConclusionsTPr stimulation instigates aberrant inflammation and endothelial dysfunction via rho-associated kinases/liver kinase B1/I kappaB kinase-dependent NF-κB activation in vascular endothelial cells.

Dataset Information

Liver kinase b1 is required for white adipose tissue growth and differentiation.

Publications

Liver kinase b1 is required for white adipose tissue growth and differentiation.

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