Affiliation:
1. Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523
Abstract
miR-137
is a highly conserved brain-enriched microRNA (miRNA) that has been associated with neuronal function and proliferation. Here, we show that
Drosophila miR-137
null mutants display increased body weight with enhanced triglyceride content and decreased locomotor activity. In addition, when challenged by nutrient deprivation,
miR-137
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
miR-137
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
miR-137
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
miR-137
null mutants, and we show that overexpression of
PTP61F
alone is sufficient to mimic many of the metabolic phenotypes of
miR-137
mutants. Finally, we knocked-down elevated levels of
PTP61F
in the
miR-137
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
miR-137
is critical for dampening levels of PTP61F, thereby maintaining normal insulin signaling and energy homeostasis.
Funder
Colorado State University
Publisher
Proceedings of the National Academy of Sciences