HDAC4 regulates fasting/feeding states

Many studies have shown that the control of lipid (fat) stores during fasting and feeding states is largely dependent on SIRT1 and FoxO activity. This latest study investigates the role of these proteins in obesity and adds another level of regulation to the mix.

Using a drosophila model, Wang et. al. (Cell 145:596-606) provide evidence that the serine/threonine salt-inducible kinase (SIK) 3 controls lipid storage or lipolysis in a HDAC4/FoxO dependent manner. During feeding, insulin activates SIK3 (its mammalian homolog is SIK2), phosphorylates HDAC4, which prevents its activation and subsequent movement to the nuclear compartment. This inhibits the deacetylation and activation of FoxO and ultimately increases lipid storage. Under fasting conditions, SIK3 activity is inhibited, HDAC4 remains in an active, dephosphorylated state where it can easily translocate to the nucleus. In the nucleus, HDAC4 deacetylates and activates FoxO to increase lipolysis as a mechanism to provide energy to the starving organism. When the organism re-feeds, FoxO is acetylated via the action of p300 and CBP and HDAC4 is re-phosphorylated. Therefore, HDAC4 activity is a critical regulator of fasting or feeding states.

This pathway is not limited to drosophila. Using a mouse hepatocyte cell line, Wang et. al. confirm their findings in mammals, suggesting a universality of this mechanism.

n3 science communications, llc

miRNAs strike again!

The ever-increasing number of articles documenting how miRNAs are key players in gene regulation, where overexpression or underexpression of a myriad of miRNAs results in disease states, continues to rise. Clearly, gene regulation is complex and control of transcription or translation is a key determinate in the development of disease. MicroRNAs are proving to be critical mediators of disease states and could potentially be therapeutic targets. Combined with other forms of regulation (epigenetic, transcriptional regulation, post-transcriptional modifications, and so on...) it will be possible to understand how cells specially fine-tune gene expression to maximize performance and prevent disease. Once a complete picture -- involving miRNAs, proteins, RNA, DNA, epigenetic mediators -- is fully realized, then real targeted therapy can be designed. But first, we must understand how each component works. Every new paper documenting how miRNAs control genes and disease is another step to understanding how to successfully target diseases with pharmacologic agents.