Abstract
Liver kinase B1 (Lkb1) plays crucial roles in development, metabolism and survival. As constitutive knockout of Lkb1 in mice leads to embryonic lethality, whether Lkb1 is required for the growth and survival of adult mice is unclear. Here we address this question using a tamoxifen-inducible Lkb1 knockout (KO) mouse model: Rosa26-CreER: Lkb1flox/flox (abbreviated as Rosa-Lkb1). The Rosa-Lkb1 mice exhibited body weight reduction and died within 6 weeks after tamoxifen induction. The body weight reduction was due to reduced weight of various tissues but the brown and white adipose tissues underwent much more pronounced weight reduction relative to the overall body weight reduction. Accordingly, the Rosa-Lkb1 mice had increased blood glucose levels and were intolerant to glucose challenge. Expression levels of adipogenic and lipogenic genes in adipose tissues were also dramatically reduced by Lkb1 deletion. Additionally, Lkb1 deletion reduced lipid deposition and increased expression of mitochondrial (Pgc1a, Cox5b and Cox7a) and hepatic gluconeogenesis related genes (Pepck) in liver. Finally, the Rosa-Lkb1 mice had much reduced oxygen consumption, carbon dioxide production, and energy expenditure. These results demonstrate that Lkb1 plays an important role in maintaining body weight, liver and adipose tissue function, blood glucose homeostasis and survival in adult mice.
Highlights
Liver kinase B1 (Lkb1) plays crucial roles in development, metabolism and survival
Upon examination of various tissues, we found that global deletion of Lkb[1] significantly decreased the weights of inguinal white adipose tissue (iWAT), brown adipose tissue (BAT), TA, EDL and Gas muscles, as well as various organs including spleen, kidney, liver and lung (Fig. 2C–E)
We found that global deletion of Lkb[1] in adult mice reduces body weight and leads to lethality within 6 weeks after TMX induction
Summary
Liver kinase B1 (Lkb1) plays crucial roles in development, metabolism and survival. As constitutive knockout of Lkb[1] in mice leads to embryonic lethality, whether Lkb[1] is required for the growth and survival of adult mice is unclear. We found several metabolic consequences in the Rosa-Lkb[1] mice that eventually lead to lethality within 6 weeks after TMX induced deletion of Lkb[1] in adult mice. The body weights of the Lkb1flox/flox and Rosa-Lkb[1] mice were similar before TMX injection, the body weight of the Rosa-Lkb[1] mice began to decrease from 2 weeks after TMX induction (Fig. 1E).
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