Editors' ChoiceMetabolism

Tuning insulin sensitivity by exosome

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Sci. Signal.  17 Oct 2017:
Vol. 10, Issue 501, eaar2046
DOI: 10.1126/scisignal.aar2046

Adipose tissue macrophages release exosomes containing microRNAs that modulate insulin sensitivity.

Obesity often triggers insulin resistance, which can lead to type 2 diabetes, and is associated with the accumulation of proinflammatory macrophages in adipose tissue. Ying et al. found that adipose tissue macrophages (ATMs) regulated systemic insulin sensitivity through microRNA-containing exosomes. Coculturing experiments revealed that 3T3-L1 adipocytes took up exosomes containing myeloid cell–specific microRNAs that were released from ATMs. When injected into lean mice on a normal chow diet, ATM-derived exosomes from obese mice were taken up by muscle, liver, and adipose tissue. The lean mice developed glucose intolerance and insulin resistance and showed inhibited insulin signaling in a microRNA-dependent manner. Conversely, glucose and insulin tolerance were normalized in obese mice injected with ATM-derived exosomes from lean mice. Diet-induced obesity altered the abundance of various microRNAs in ATM-generated exosomes. In particular, it increased the abundance of miR-155, which is released by proinflammatory macrophages and targets peroxisome proliferator–activated receptor γ (PPARγ), a transcription factor that is involved in lipid and glucose metabolism. Overexpression of miR-155 diminished glucose uptake, blocked insulin signaling, and decreased PPARγ abundance in various cell types. Furthermore, miR-155 knockout mice developed glucose intolerance and insulin resistance to a lesser extent on a high-fat diet than did wild-type mice. This protection was reversed if irradiated miR-155 knockout mice were reconstituted with bone marrow cells from wild-type mice. These results suggest that ATMs release exosomes containing microRNAs that affect insulin sensitivity, and that miR-155 contributes to the insulin resistance that develops with obesity. However, the authors note that other exosomally released microRNAs in addition to miR-155 likely contribute to the modulation of insulin sensitivity.

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