Dissecting Mechanism Of Lipodystrophy Caused By Loss Of MED20 In Adipocytes

Lipodystrophy is a type of rare heterogeneous diseases,typically characterized by total or partial loss of adipose tissue.Loss of adipose tissue results in lipid failure to be stored in fat,leading to hyperlipidemia,insulin resistance,diabetes,non-alcoholic fatty liver disease(NAFLD),polycystic ovary syndrome(PCOS)and other metabolic and reproductive disorders.Although lipodystrophy is a rare disease,the latest research indicates that its prevalence is not low.Due to the heterogeneity of etiology and the diversity of clinical manifestations,as well as the lack of established diagnostic criteria and insufficient understanding of the disease,lipodystrophy is often missed or even misdiagnosed.Therefore,understanding the pathogenesis of the disease is very important for clinical diagnosis and treatment.Mediator complex is evolutionarily conserved from yeast to humans.It promotes transcriptional initiation of coding genes by structurally and functionally linking transcriptional activators to RNA polymerase II.Structurally,the Mediator complex can be divided into head,middle and tail module.In the classical model,the head and middle modules interact with the basic transcription machine,while the tail interacts with enhancer-linked transcriptional activators.Current studies have shown that Mediator complex subunits are involved in many processes including adipogenesis and lipid metabolism pathways.In our previous work,we found that Mediator complex MED20 subunit,which plays an important role in transcriptional activation,is the functional substrate of CUL4-DDB1-WDTC1 E3 ligase complex,and the Mediator subunit MED20 organizes the early adipogenic complex to promote adipogenesis and development of adipose tissues.We show that MED20 plays an important role in the differentiation of preadipocytes,but its function in mature adipocytes is not clear.To address this issue,we generated adipose-specific Med20 konckout mice(Med20-AKO).On chow diet,these mice exhibited insulin resistance,fatty liver,loss of adipose tissue,hyperlipidemia,hyperglycemia,lower leptin and other typical features of lipodystrophy.On high fat diet,Med20-AKO mice weighed lighter than control mice,and also show lipodystrophic phenotype.Mechanistically,loss of MED20 leads to necroptosis of adipocytes.Treatment with necroptosis inhibitor NEC-1 inhibited cell death and largely attenuated lipodystrophy in Med20-AKO mice.Further studies revelaed that MED20 control the transcription of two transcriptional repressors,Snai1 and Snai2.Loss of MED20 decreases the expression of Snai1 and Snai2,and thus increases the expression of FASN and PGC1α,which leads to increased ROS production due to increased de novo fatty acid synthesis and mitochondirial numbers.Treatment with FASN inhibitor and ROS chelating reagnent rescues necroptosis of adipocytes.Furthermore,treatment with ROS chelating reagent larged reversed the lipodystrophic phenotype in Med20-AKO mice.Our studies have thus uncovered a critical role of MED20 in regulating adipocyte survival and lipodystrophy,expanded current knowledges on the pathogenesis of lipodystrophy,and provided a new potential target for clinical diagnosis and treatment.