An auto-regulatory module controls fat metabolism in "Caenorhabditis elegans"

Obesity and obesity-related diseases such as type-2 diabetes or metabolic syndrome are on the rise word-wide (Ng et al. 2014). The negative aspects of obesity on the health of individuals is accompanied by an increasing financial burden for the global economy. Excess adipose tissue is often perceived as an indication of poor dietary choices and a sedentary lifestyle. However, compelling evidence from diverse model organisms and humans suggest that genetic make-up influences most aspects of fat metabolism and therefore the likelihood to develop obesity (Min, Chiu, and Wang 2013; Yazdi, Clee, and Meyre 2015). Hence, careful dissection of the underlying genetic regulations of fat metabolism to identify new putative targets for treatment is essential.
We successfully used Caenorhabditis elegans as a model organism to uncover and describe a novel auto-regulatory module, which we found is essential for wild-type levels of body fat. Utilizing cold-sensitivity as readout, we identified a hitherto uncharacterized gene, C30F12.1, which we named rege-1 (REGnasE-1 homolog) after its mammalian homolog the PIN-domain endonuclease ZC3H12A/Regnase-1/MCPIP1. Regnase-1 negatively regulates pro-inflammatory cytokines via internal cleavage of their 3` untranslated region (3`UTR) (Iwasaki et al. 2011; Matsushita et al. 2009). Similarly, C. elegans REGE-1 targets the transcription factor ETS-4 and cleaves its mRNA within the first third of its 3`UTR. Knockout of rege-1 causes a strong loss in overall body fat, developmental delay and a transcriptional upregulation of fat metabolic and innate immunity genes, depending on ETS-4. We also provide evidence that ETS-4 transcriptionally activates (directly or indirectly) rege-1, thereby forming an auto-regulatory feedback loop. REGE-1::GFP is mainly localized in the first four cells of the intestine adjacent to the pharynx and the ETS-4/REGE-1 module is transcriptionally upregulated upon re-feeding following long-term starvation. This, together with the observation that metabolic and immunity genes are induced upon loss of rege-1 suggests that the ETS-4/REGE-1 module might have a role in bacteria clearance, nutrient uptake and/or defense against pathogens.