<i>miR-137</i> regulates PTP61F, affecting insulin signaling, metabolic homeostasis, and starvation resistance in <i>Drosophila</i>.

Abstract

<i>miR-137</i> is a highly conserved brain-enriched microRNA (miRNA) that has been associated with neuronal function and proliferation. Here, we show that <i>Drosophila miR-137</i> null mutants display increased body weight with enhanced triglyceride content and decreased locomotor activity. In addition, when challenged by nutrient deprivation, <i>miR-137</i> mutants exhibit reduced motivation to feed and prolonged survival. We show through genetic epistasis and rescue experiments that this starvation resistance is due to a disruption in insulin signaling. Our studies further show that <i>miR-137</i> null mutants exhibit a drastic reduction in levels of the phosphorylated/activated insulin receptor, InR (InR-P). We investigated if this is due to the predicted <i>miR-137</i> target, Protein Tyrosine Phosphatase 61F (PTP61F), ortholog of mammalian TC-PTP/PTP1B, which are known to dephosphorylate InR-P. Indeed, levels of an endogenously tagged GFP-PTP61F are significantly elevated in <i>miR-137</i> null mutants, and we show that overexpression of <i>PTP61F</i> alone is sufficient to mimic many of the metabolic phenotypes of <i>miR-137</i> mutants. Finally, we knocked-down elevated levels of <i>PTP61F</i> in the <i>miR-137</i> null mutant background and show that this rescues levels of InR-P, restores normal body weight and triglyceride content, starvation sensitivity, as well as attenuates locomotor and starvation-induced feeding defects. Our study supports a model in which <i>miR-137</i> is critical for dampening levels of PTP61F, thereby maintaining normal insulin signaling and energy homeostasis.