Loss of ADAMTS15 Promotes Browning in 3T3-L1 White Adipocytes via Activation of β3-adrenergic Receptor

Abstract

ADAMTSs belong to the superfamily of secreted metalloendopeptidases, some of which are reported to be closely associated with obesity. However, the role of ADAMTS15 is not well characterized in adipocytes. This study investigates the effect of Adamts15 deficiency on lipid metabolism in 3T3-L1 and HIB1B adipocytes, with a focus on the role of browning of white adipocytes. Quantitative real-time PCR, immunoblot analysis, immunofluorescence, and staining methods were applied to evaluate the effects of ADAMTS15 on other target proteins and genes involved in lipid metabolism, after silencing Adamts15 by applying the siRNA technique. Our results demonstrate that ADAMTS15 is expressed in both white and brown adipocytes, and the deficiency of Adamts15 promotes browning of white adipocytes by enhancing the expression of brown adipocyte-specific genes and proteins. In addition, silencing of Adamts15 activates brown adipocytes and also upregulates lipid metabolic activity in both white and brown adipocytes, by increasing mitochondrial biogenesis as well as the levels of lipolytic and fat oxidative marker proteins, and reducing adipogenic factors. Moreover, mechanistic studies revealed that depletion of Adamts15 induces browning via activation of the β3AR-PKA-CREB signaling pathway. Taken together, our data unveiled a previously unknown mechanism of ADAMTS15 in the regulation of lipids, and the significance of this protein as a pharmacotherapeutic target to treat obesity-related metabolic disorders.