Molecular Mechanism and Regulation of Adipocyte Secretion

The adipose tissue is now recognized as an endocrine organ due to its active secretion of many important peptide hormones, collectively named adipokines, which regulate many physiological functions. Despite an increasing number of adipokines has been discovered in the past decades, the secretory mechanism of adipocytes remains poorly understood. Among these adipokines, leptin is secreted primarily by adipocytes to regulate energy balance and food intake. Adipocytes also secrete many chemokines including monocyte chemoattractant protein-1 (MCP-1), which can also be produced and secreted by other cell types such as immune cells. In obesity, hypertrophied adipocytes secrete more leptin and MCP-1. While leptin is required for negative feedback control of adiposity in obesity, elevated MCP-1 secretion leads to local inflammation, which has been linked to pathogenesis of obesity-associated chronic diseases such as insulin resistance, type II diabetes, and cardiovascular diseases. Therefore, if one can differentially control the secretion of these two adipokines, it is possible to manage the progress of diseases. N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are known to mediate exocytosis in many neuronal and endocrine systems. Using differentiated 3T3-L1 adipocytes as the model system, we identified certain SNARE proteins that mediate basal and insulin-stimulated leptin secretion. However the same SNARE proteins only play a minimal role in MCP-1 secretion, suggesting different secretory mechanisms for different adipokines. To explore possible secretory pathways that may be differentially utilized by different adipokines, pharmacological modulators of cellular trafficking were used. Interestingly, modulating protein kinase D (PKD), an emerging target known to control the trafficking from trans-Golgi network (TGN) to the plasma membrane, differentially regulates secretion of leptin and MCP-1 in adipocytes, suggesting that secretory pathways of leptin and MCP-1 may be different after exiting from TGN. Moreover, their post-TGN trafficking may be differentially regulated by PKD. Therefore, this grant proposal aims to address the following three questions: (1) to identify and characterize the SNARE complex mediating MCP-1 secretion, (2) to elucidate how PKD differentially regulates post-TGN secretory pathways of leptin and MCP-1, and finally (3) to understand how the SNARE complex and PKD regulates leptin and MCP-1 secretion in primary adipocytes, and if diet-induced obesity may affect the secretory mechanism in mice. This study will not only provide insight on the molecular mechanism controlling adipokine secretion under normal and pathological conditions, but will also provide new therapeutic methods in treating the diseases in the future.

Project ID:PC10301-0306
External Project ID:NSC102-2320-B182-022-MY3