miR-137 regulates PTP61F, affecting insulin signaling, metabolic homeostasis, and starvation resistance in Drosophila
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:121 |
|---|---|
| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 121(2024), 5 vom: 30. Jan., Seite e2319475121 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Saedi, Hana [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 01.02.2024 Date Revised 04.02.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1073/pnas.2319475121 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM36743315X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM36743315X | ||
| 003 | DE-627 | ||
| 005 | 20240204232004.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240123s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1073/pnas.2319475121 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1280.xml |
| 035 | |a (DE-627)NLM36743315X | ||
| 035 | |a (NLM)38252824 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Saedi, Hana |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a miR-137 regulates PTP61F, affecting insulin signaling, metabolic homeostasis, and starvation resistance in Drosophila |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 01.02.2024 | ||
| 500 | |a Date Revised 04.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Drosophila | |
| 650 | 4 | |a metabolism | |
| 650 | 4 | |a miR-137 | |
| 650 | 7 | |a Insulin |2 NLM | |
| 650 | 7 | |a MicroRNAs |2 NLM | |
| 650 | 7 | |a Phosphoric Monoester Hydrolases |2 NLM | |
| 650 | 7 | |a EC 3.1.3.2 |2 NLM | |
| 650 | 7 | |a Triglycerides |2 NLM | |
| 650 | 7 | |a Ptp61F protein, Drosophila |2 NLM | |
| 650 | 7 | |a EC 3.1.3.48 |2 NLM | |
| 650 | 7 | |a Protein Tyrosine Phosphatases, Non-Receptor |2 NLM | |
| 650 | 7 | |a EC 3.1.3.48 |2 NLM | |
| 650 | 7 | |a Drosophila Proteins |2 NLM | |
| 700 | 1 | |a Waro, Girma |e verfasserin |4 aut | |
| 700 | 1 | |a Giacchetta, Lea |e verfasserin |4 aut | |
| 700 | 1 | |a Tsunoda, Susan |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Proceedings of the National Academy of Sciences of the United States of America |d 1915 |g 121(2024), 5 vom: 30. Jan., Seite e2319475121 |w (DE-627)NLM000008982 |x 1091-6490 |7 nnns |
| 773 | 1 | 8 | |g volume:121 |g year:2024 |g number:5 |g day:30 |g month:01 |g pages:e2319475121 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1073/pnas.2319475121 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 121 |j 2024 |e 5 |b 30 |c 01 |h e2319475121 | ||