Journal:
J Biol Chem.
Publication Date:
Fri, 2016-11-18
Institutions:
1From the Departments of Molecular and Cellular Biology and.
2the Department of Internal Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea.
3the Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, California 94143, and.
4Medicine, Division of Hematology and Oncology, Baylor College of Medicine, Houston, Texas 77030.
5the Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
6From the Departments of Molecular and Cellular Biology and [email protected].
Abstract:
The acquisition of beige adipocyte features by white fat cells corresponds to protection against obesity-induced metabolic diseases in humans and animal models of type 2 diabetes. In adipose tissue, expression of the E2 small ubiquitin-like modifier ligase ubiquitin carrier protein 9 (Ubc9) is positively correlated with markers of insulin resistance and corresponds with impaired browning of human white adipocytes. However, the molecular regulation of Ubc9 expression in adipocytes and other cells remains unclear. In this study, we demonstrate that the mRNA and protein expression of Ubc9 are regulated by the microRNA miRNA-30a (miR-30a) in human subcutaneous adipocytes. Ubc9 and miR-30a exhibit inverse expression in adipose tissue, with miR-30a robustly elevated in brown fat. Depletion of Ubc9 by siRNA or enforced expression of a miR-30a mimic augments mitochondrial volume and respiration in human white adipocytes, reflecting features of brown fat cells. Furthermore, Ubc9 depletion induces a brown fat gene program in human subcutaneous adipocytes. Induction of the beige-selective gene program corresponds to stabilization of the PR domain-containing 16 (PRDM16) protein, an obligate transcriptional regulator of the brown/beige fat metabolic program in white adipocytes that interacts with Ubc9. Taken together, our data demonstrate a previously unappreciated molecular axis that controls browning of human white adipocytes.