Publication Date
10-1-2020
Journal
American Journal of Physiology-Endocrinology and Metabolism
DOI
10.1152/ajpendo.00045.2020
PMID
32799658
PMCID
PMC7864240
PubMedCentral® Posted Date
8-17-2020
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Adipocytes, Brown, Adipocytes, White, Animals, Blood Glucose, Cells, Cultured, Fatty Acid-Binding Proteins, Gene Regulatory Networks, Humans, Hypoglycemic Agents, Insulin Resistance, Metabolomics, Mice, MicroRNAs, Oligopeptides, Organelle Biogenesis, PPAR gamma, Rosiglitazone, etabolism, microRNA, mitochondria, PPARγ, subcutaneous adipocytes
Abstract
MicroRNA-30a (miR-30a) impacts adipocyte function, and its expression in white adipose tissue (WAT) correlates with insulin sensitivity in obesity. Bioinformatic analysis demonstrates that miR-30a expression contributes to 2% of all miRNA expression in human tissues. However, molecular mechanisms of miR-30a function in fat cells remain unclear. Here, we expanded our understanding of how miR-30a expression contributes to antidiabetic peroxisome proliferator-activated receptor-γ (PPARγ) agonist activity and metabolic functions in adipocytes. We found that WAT isolated from diabetic patients shows reduced miR-30a levels and diminished expression of the canonical PPARγ target genes ADIPOQ and FABP4 relative to lean counterparts. In human adipocytes, miR-30a required PPARγ for maximal expression, and the PPARγ agonist rosiglitazone robustly induced miR-30a but not other miR-30 family members. Transcriptional activity studies in human adipocytes also revealed that ectopic expression of miR-30a enhanced the activity of rosiglitazone coupled with higher expression of fatty acid and glucose metabolism markers. Diabetic mice that overexpress ectopic miR-30a in subcutaneous WAT display durable reductions in serum glucose and insulin levels for more than 30 days. In agreement with our in vitro findings, RNA-seq coupled with Gene Set Enrichment Analysis (GSEA) suggested that miR-30a enabled activation of the beige fat program in vivo, as evidenced by enhanced mitochondrial biogenesis and induction of UCP1 expression. Metabolomic and gene expression profiling established that the long-term effects of ectopic miR-30a expression enable accelerated glucose metabolism coupled with subcutaneous WAT hyperplasia. Together, we establish a putative role of miR-30a in mediating PPARγ activity and advancing metabolic programs of white to beige fat conversion.
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Biochemistry, Biophysics, and Structural Biology Commons, Endocrine System Diseases Commons, Endocrinology, Diabetes, and Metabolism Commons, Medical Cell Biology Commons, Medical Genetics Commons
