A continuous increase in obesity and obesity-related diseases, such as metabolic syndrome and type-II diabetes, has led to a global health crisis. Therefore, the understanding of molecular mechanism controlling fat metabolism is crucial to identify potential new therapeutic targets. Key transcription factors involved in lipid metabolism, such as SBP-1/SREBP, LPD-2/C/EBP and MDT-15, are conserved from nematodes to mammals, and C. elegans has proven to be a powerful model for obesity and metabolic research. The C. elegans RNase REGE-1 is closely related to the mammalian Regnase-1/MCPIP1/Zc3h12a, an extensively studied regulator of innate immunity. The loss of REGE-1 causes a dramatic decrease in overall body fat, accompanied by increased expression of lipid metabolic and innate immunity genes. Using Exon-Intron Split Analysis (EISA), we found that REGE-1 controls fat by targeting mRNA encoding a fat loss-promoting transcription factor, ETS-4, previously implicated in ageing. While REGE-1 degrades
ets-4 mRNA via an endonucleolytic cleavage within its 3UTR, ETS-4, in turn, promotes the transcription of
rege-1. Thus, ETS-4 and REGE-1 form an auto- regulatory module (ERM), affecting fat by controlling the transcriptional output of ETS-4. The ERM is a novel mechanistic paradigm in fat regulation. Posttranscriptional mechanisms are well suited to a rapid and reversible control of gene expression. Similarly, REGE-1-mediated mRNA degradation might be a way to rapidly re-wire lipid metabolism in response to environmental changes, including change of diet, temperature or exposure to pathogens.