Abstract
MicroRNAs (miRNAs) are small non-protein coding RNAs and post-transcriptionally regulate cellular gene expression. In animal development, miRNAs play essential roles such as stem cell maintenance, organogenesis, and apoptosis. Using gain-of-function (GOF) screening with 160 miRNA lines in Drosophila melanogaster, we identified a set of miRNAs which regulates body fat contents and named them microCATs (microRNAs Controlling Adipose Tissue). Further examination of egg-to-adult developmental kinetics of selected miRNA lines showed a negative correlation between fat content and developmental time. Comparison of microCATs with loss-of-function miRNA screening data uncovered miR-969 as an essential regulator of adiposity. Subsequently, we demonstrated adipose tissue-specific knock-down of gustatory receptor 47b (Gr47b), a miR-969 target, greatly reduced the amount of body fat, recapitulating the miR-969 GOF phenotype.
Highlights
Obesity is one of the most prevalent public health problems and is rapidly escalating worldwide[1,2]
We set the fat content of control males to 100% and determined the body fat of each miRNA-expressing line compared to its control in the same batch (Fig 2A)
When we analyzed only the miRNA lines whose fat contents were below the mean of the total miRNA lines, we found a much stronger correlation between the fat contents and developmental time (DT) (r = - 0.744, p< 0.001) (Fig 3B)
Summary
Obesity is one of the most prevalent public health problems and is rapidly escalating worldwide[1,2]. In addition to social and psychological consequences, obesity is a significant risk factor for cardiovascular disease, type 2 diabetes, fatty liver, and cancer[3]. In the early 60s, James Neel introduced the ‘thrifty gene hypothesis’, which provides an evolution-based elegant explanation for the modern obesity epidemic[4,5]. Thrifty genes function efficiently to store energy (fat) to prepare for a famine. Modern industrialized societies have frequent feasts and rare famines. Based on a similar hypothesis, obese fruit flies were isolated from a natural population in Kaduna, Nigeria, and the responsible gene, adipose (adp), was later identified and cloned[6,7]. We hypothesized that “obesity genes” exist and exacerbate this obesity epidemic synergistically with behavior factors (too much high-calorie food consumption and little exercise)
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