Mechanism Of HDAC6 Controls Fat- Induced Obesity By Regulating The Acetylation Of CIDEC

We are in the midst of a worldwide epidemic of obesity;a major factor in the development of type 2 diabetes,dyslipidemias,fatty liver,cardiovascular disease,and even some cancers.These affect human health and life quality a lot.Obesity development was a result of excess accumulation of fat.Fat storage is mainly in adipose tissue,an important endocrine organ not only serve to store energy but is also secreting hormones,cytokines,and proteins that affect the function of cells and tissues.Lipid droplet is one of the most important organelles in adipose tissue and its number and volume reflect fat accumulation.While,how intracellular signaling pathway sensing dietary fat to regulate lipid droplet,affect lipid storage and obesity is still unclear.Acetylation plays an important role in the regulation of transcription mainly through acetylating histones.Recent studies uncovered a large number of acetylated cytoplasm and mitochondria proteins to regulate metabolic pathways.However,the function of acetylation in adipose tissue has not been reported yet.CIDE family proteins include CIDEA,CIDEB and CIDEC(FSP 27);all are important lipid droplet associated proteins.CIDEC acetylation was regulated by fatty acid to promote its stability.However,the relationship between CIDEC acetylation and obesity was elusive.Here,we have observed that Class IIb histone deacetylase HDAC6 and HDAC10 are markedly reduced in adipose tissues of obese animals and humans.Mice with adipocyte specific depletion of Hdac6 exhibit increased fat accumulation and reduced insulin sensitivity.Conversely,transgenic mice with Hdac6 are resistant to diet-and genetic-induced obesity and insulin resistance.CIDEC acetylation was increased in adipose tissues of obese mice and human and it promotes lipid droplet fusion.The acetylation controlled by HDAC6,PCAF interaction with CIDEC induced by fatty acid happened on the endoplasmic reticulum,in that actual conversion of FA to triacylglycerol is required.We have thus revealed a HDAC function in obesity and may provide a promising therapeutic approach.