# Intestinal Epithelial-Derived Exosomes Under Cold Stimulation Promote Adipose Thermogenesis

## TL;DR

Cold-stimulated intestinal cells release exosomes that boost fat tissue's ability to generate heat, potentially aiding in obesity treatment.

## Contribution

The study reveals that intestinal exosomes under cold conditions enhance adipose thermogenesis via miR-674-3p transfer.

## Key findings

- Cold IEC-Exo significantly enhance adipose thermogenesis compared to room temperature IEC-Exo.
- miR-674-3p in Cold IEC-Exo increases Ucp1 expression and fatty acid utilization in adipocytes.
- AAV-mediated miR-674-3p overexpression in BAT and sWAT improves thermogenesis and glucose intolerance.

## Abstract

Background: Whether intestinal epithelial cells can regulate distant adipose tissue remains a mystery. Methods: Cold-stimulated intestinal epithelial cell-derived exosomes (Cold IEC-Exo) play a pivotal role in enhancing adipose thermogenesis and metabolic homeostasis, as demonstrated in this study. Results: IEC-Exo can accumulate in adipose tissue. Compared with IEC-Exo derived from room temperature mice (RT IEC-Exo), Cold IEC-Exo significantly enhanced the thermogenesis of adipose. In vitro, Cold IEC-Exo directly stimulated thermogenesis in primary adipocytes by elevating oxygen consumption rate, proton leak, and fatty acid uptake, with no effect on glucose uptake. Small RNA sequencing identified miR-674-3p as a key mediator enriched in Cold IEC-Exo. miR-674-3p mimicry replicated Cold IEC-Exo effects, augmenting Ucp1 expression, mitochondrial uncoupling, and fatty acid utilization in adipocytes. Local overexpression of miR-674-3p in BAT and sWAT via AAV in vivo enhanced thermogenesis and attenuated diet-induced glucose intolerance. Conclusions: These findings establish that Cold IEC-Exo, via miR-674-3p transfer, drive adipose thermogenic activation and mitigate metabolic dysfunction, highlighting their therapeutic potential in obesity-related disorders.