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Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue—brown especially—into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3′ UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine.

Context:HIV patients are at an increased risk for cardiometabolic disease secondary to depot-specific alterations in adipose function, but mechanisms remain poorly understood.Objective:The endoribonuclease Dicerhas been linked to the modulation of brown and white adipocyte differentiation. We previously demonstrated that Dicerknockout mice undergo transformation of brown adipose tissue to white adipose tissue and develop a lipodystrophic phenotype. We hypothesized reduced Dicerand brown adipose tissue gene expression from nonlipomatous sc fat among HIV patients with a lipodystrophic phenotype.Design:Eighteen HIV (nine with and without lipodystrophic changes in fat distribution, characterized by excess dorsocervical adipose tissue [DCAT]) and nine non-HIV subjects underwent punch biopsy of abdominal sc fat to determine expression of Dicerand other adipose-related genes.Results:HIV subjects with long-duration antiretroviral use demonstrated excess DCAT vs non-HIV subjects (9.8 ± 1.0 vs 6.6 ± 0.8 cm2, P= .02) with similar body mass index. Dicerexpression was decreased in abdominal sc fat of HIV vs non-HIV (4.88 [1.91, 11.93] vs 17.69 [10.72, 47.91], P= .01), as were PPARα, ZIC1, PRDM16, DIO2, and HSP60(all P≤ .03). Moreover, the expression of Dicer(2.49 [0.02, 4.88] vs 11.20 [4.83, 21.45], P= .006), brown fat (PPARα [P= .002], ZIC1[P= .004], LHX8[P= .03], PRDM16[P= .0008], PAT2[P= .008], P2RX5[P= .02]), beige fat (TMEM26[P= .004], CD137[P= .008]), and other genes (DIO2[P= .002], leptin[P= .003], HSP60[P= .0004]) was further decreased in abdominal sc fat comparing HIV subjects with vs without excess DCAT. Down-regulation of Dicerin the abdominal sc fat correlated with the down-regulation of all brown and beige fat genes (all P≤ .01).Conclusion:Our results demonstrate dysfunctional sc adipose tissue marked by reduced Dicerin relationship to the down-regulation of brown and beige fat-related genes in lipodystrophic HIV patients and may provide a novel mechanism for metabolic dysregulation. A strategy to increase browning of white adipose tissue may improve cardiometabolic health in HIV.

Exosomes/small extracellular vesicles (sEVs) can serve as multifactorial mediators of cell-to-cell communication through their miRNA and protein cargo. Quantitative proteomic analysis of five cell lines representing metabolically important tissues reveals that each cell type has a unique sEV proteome. While classical sEV markers such as CD9/CD63/CD81 vary markedly in abundance, we identify six sEV markers (ENO1, GPI, HSPA5, YWHAB, CSF1R, and CNTN1) that are similarly abundant in sEVs of all cell types. In addition, each cell type has specific sEV markers. Using fat-specific Dicer-knockout mice with decreased white adipose tissue and increased brown adipose tissue, we show that these cell-type-specific markers can predict the changing origin of the serum sEVs. These results provide a valuable resource for understanding the sEV proteome of the cells and tissues important in metabolic homeostasis, identify unique sEV markers, and demonstrate how these markers can help in predicting the tissue of origin of serum sEVs.

The cell surface markers ASC-1, PAT2, and P2RX5 can be used to mark and identify brown, beige, and white adipocytes in both rodents and humans.