We previously showed that visceral adipocyte-derived exosomal microRNA content is pathologically altered in obesity to impair insulin receptor signaling. However, why some obese youth (± insulin resistance) remain normoglycemic, while others progress to hyperglycemia, is not fully understood.
We hypothesize that compared to obese normoglycemic youth (ON), circulating adipocyte-derived exosomes from obese hyperglycemic youth (OH) are enriched for microRNAs targeting carbohydrate metabolism and this association is modified by the amount of visceral fat (VFAT).
We conducted a cross-sectional analysis of 55 obese pubertal adolescents (12-17 years), who underwent OGTT, whole body DXA, and serum adipocyte-derived exosomal microRNA assays. Univariate and regression analyses compared ON and OH groups. MicroRNA profiles were evaluated via ANCOVA and ANOVA.
ON (n=32) and OH (n=23) groups were similar for sex, age, race, pubertal stage, BMI, and fat mass (FM). However, OH had increased VFAT compared to ON (88.1±24.6cm2 vs. 71.4±21.6, p=0.01). Between OH and ON, 33 known mature human microRNAs were differentially expressed (p<0.01) in circulating adipocyte-derived exosomes. Once filtered for microRNAs with experimentally confirmed or highly conserved predicted targets, 14 microRNAs remained, which collectively putatively target 2331 mRNAs. These mRNAs were further filtered for association with VFAT (p<0.05), leaving 1304 mRNAs. These mRNAs were enriched for 179 canonical pathways (p<0.05). Notable carbohydrate metabolism targets include activation of PI3K/AKT (z=+1.4; 19/127 elements) and STAT3 signaling (z=+3.3; 21/132 elements).
Although similar to ON for BMI and FM, OH show changes in adipocyte-derived exosomal microRNAs targeting carbohydrate metabolism that are associated with increased VFAT. Circulating visceral adipocyte-derived exosomal microRNAs may help drive the transition from obese normoglycemia to hyperglycemia.
S.N. Magge: None. R.J. Freishtat: Stock/Shareholder; Self; Adipomics, Inc.
National Institutes of Health