Adipose tissue macrophage-derived exosomal miR-210-5p in modulating insulin sensitivity in rats born small for gestational age with catch-up growth

Hui Xiong; Wei Liu; Jie Song; Xia Gu; Shunchang Luo; Zhendong Lu; Hu Hao; Xin Xiao

doi:10.21037/tp-23-142

Adipose tissue macrophage-derived exosomal miR-210-5p in modulating insulin sensitivity in rats born small for gestational age with catch-up growth

Transl Pediatr. 2023 Apr 29;12(4):587-599. doi: 10.21037/tp-23-142. Epub 2023 Apr 26.

Authors

Hui Xiong^#¹, Wei Liu^#¹, Jie Song^#², Xia Gu¹, Shunchang Luo¹, Zhendong Lu¹, Hu Hao¹, Xin Xiao¹

Affiliations

¹ Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
² Department of Pediatrics, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.

^# Contributed equally.

Abstract

Background: Insulin resistance has been implicated in the pathogenesis of children born small for gestational age (SGA) with catch-up growth (CUG). Adipose tissue macrophages (ATMs) regulate insulin resistance by secreting exosomes containing microRNA (miRNA) cargo; however, their pathogenic roles and molecular mechanism are not fully understood. This study aimed to investigate the role of miR-210-5p in rats born SGA with CUG and insulin resistance.

Methods: The dietary needs of pregnant rats were restricted to ensure the birth of SGA rats. Transmission electron microscopy (TEM) and Western blot analysis were used to identify the exosomes from ATMs of CUG-SGA and adequate-for-gestational-age (AGA) rats. PKH-67 staining was performed to confirm the uptake of exosomes. miR-210-5p expression was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Glucose uptake and output were detected with glucose uptake and output assays, respectively. Insulin resistance was detected with glucose and insulin tolerance tests in vivo. The interaction between miR-210-5p and SID1 transmembrane family member 2 (SIDT2) was validated with dual-luciferase reporter assay.

Results: miR-210-5p was observed to be highly expressed in the exosomes derived from the ATMs of CUG-SGA rats. ATM-derived exosomes can serve as vehicles to deliver miR-210-5p into adipocytes, myocytes, and hepatocytes, where it can enhance cellular insulin resistance. SIDT2 was identified as a direct target gene of miR-210-5p. The miR-210-5p-induced insulin resistance was reversed by the restored SIDT2 expression. However, overexpression of SIDT2 abolished the inhibitory effect of CUG-SGA-ATM-exosomal miR-210-5p on insulin sensitivity in vivo.

Conclusions: ATM-derived exosomal miR-210-5p promoted insulin resistance in CUG-SGA rats by targeting SIDT2, which may act as a new potential therapeutic target for children born SGA with CUG.

Keywords: Insulin resistance; catch-up growth (CUG); macrophages; miR-210-5p; small-for-gestational-age.