Abstract
LKB1 plays important roles in governing energy homeostasis by regulating AMP-activated protein kinase (AMPK) and other AMPK-related kinases, including the salt-inducible kinases (SIKs). However, the roles and regulation of LKB1 in lipid metabolism are poorly understood. Here we show that Drosophila LKB1 mutants display decreased lipid storage and increased gene expression of brummer, the Drosophila homolog of adipose triglyceride lipase (ATGL). These phenotypes are consistent with those of SIK3 mutants and are rescued by expression of constitutively active SIK3 in the fat body, suggesting that SIK3 is a key downstream kinase of LKB1. Using genetic and biochemical analyses, we identify HDAC4, a class IIa histone deacetylase, as a lipolytic target of the LKB1-SIK3 pathway. Interestingly, we found that the LKB1-SIK3-HDAC4 signaling axis is modulated by dietary conditions. In short-term fasting, the adipokinetic hormone (AKH) pathway, related to the mammalian glucagon pathway, inhibits the kinase activity of LKB1 as shown by decreased SIK3 Thr196 phosphorylation, and consequently induces HDAC4 nuclear localization and brummer gene expression. However, under prolonged fasting conditions, AKH-independent signaling decreases the activity of the LKB1-SIK3 pathway to induce lipolytic responses. We also identify that the Drosophila insulin-like peptides (DILPs) pathway, related to mammalian insulin pathway, regulates SIK3 activity in feeding conditions independently of increasing LKB1 kinase activity. Overall, these data suggest that fasting stimuli specifically control the kinase activity of LKB1 and establish the LKB1-SIK3 pathway as a converging point between feeding and fasting signals to control lipid homeostasis in Drosophila.
Highlights
Perturbation of energy homeostasis either directly or indirectly causes human health problems such as obesity and type II diabetes [1]
Using the fruit fly as an in vivo model system, we reveal that Liver kinase B1 (LKB1) kinase activity is critical for lipid storage and controls the lipolysis pathway in the fat body, which is equivalent to mammalian adipose and liver tissue
We find that the lipolytic defects of LKB1 mutants are rescued by the expression of constitutively active salt-inducible kinase 3 (SIK3) in the fat body
Summary
Perturbation of energy homeostasis either directly or indirectly causes human health problems such as obesity and type II diabetes [1]. Dissecting the regulatory mechanisms of lipid homeostasis is essential to our understanding of how energy metabolism is maintained. Drosophila lipid reserves are mainly stored as triacylglycerol (TAG) in the fat body, the insect equivalent of mammalian adipose tissue. Bmm mutant flies are obese and display partial defects in lipid mobilization [3]. The primary role of AKH, the functional analogue of glucagon and β-adrenergic signaling in mammals [4,5], is to stimulate lipid mobilization by activating AKH receptor (AKHR) [6] and inducing cAMP/PKA signaling in the fat body [7]. A report demonstrated that AKH acts in parallel with Bmm to regulate lipolysis and that AKHR mutation leads to obesity phenotypes and defects in fat mobilization [7]. Bmm expression is hyperstimulated in starved AKHR mutants [7], implying the existence of an unknown regulatory mechanism between Bmm and AKHR in Drosophila
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