Loss of neuronatin promotes browning of primary mouse adipocytes while reducing Glut1-mediated glucose disposal

Gburcik V, Cleasby ME, Timmons JA. Loss of neuronatin promotes browning of primary mouse adipocytes while reducing Glut1-mediated glucose disposal. Am J Physiol Endocrinol Metab 304: E885-E894, 2013. First published March 12, 2013; doi:10.1152/ajpendo.00463.2012.-Failure of white adipose tissue to appropriately store excess metabolic substrate seems to underpin obesity-associated type 2 diabetes. Encouraging browning of white adipose has been suggested as a therapeutic strategy to help dispose of excess stored lipid and ameliorate the resulting insulin resistance. Genetic variation at the DNA locus encoding the novel proteolipid neuronatin has been associated with obesity, and we recently observed that neuronatin expression is reduced in subcutaneous adipose tissue from obese humans. Thus, to explore the function of neuronatin further, we used RNAi to silence its expression in murine primary adipocyte cultures and examined the effects on adipocyte phenotype. We found that primary adipocytes express only the longer isoform of neuronatin. Loss of neuronatin led to increased mitochondrial biogenesis, indicated by greater intensity of MitoTracker Green staining. This was accompanied by increased expression of UCP1 and the key genes in mitochondrial oxidative phosphorylation, PGC-1 alpha, Cox8b, and Cox4 in primary subcutaneous white adipocytes, indicative of a browning effect. In addition, phosphorylation of AMPK and ACC was increased, suggestive of increased fatty acid utilization. Similar, but less pronounced, effects of neuronatin silencing were also noted in primary brown adipocytes. In contrast, loss of neuronatin caused a reduction in both basal and insulin-stimulated glucose uptake and glycogen synthesis, likely mediated by a reduction in Glut1 protein upon silencing of neuronatin. In contrast, loss of neuronatin had no effect on insulin signaling. In conclusion, neuronatin appears to be a novel regulator of browning and metabolic substrate disposal in white adipocytes.