MICT1 function in thermogenesis

Obesity has become a global epidemic and is associated with type 2 diabetes and other chronic diseases. While white adipose tissue is the primary energy storage organ, brown adipose tissue (BAT) dissipates energy through non-shivering thermogenesis. Discovery of the presence of BAT/BAT-like tissues in human adults has generated a considerable interest in BAT biology to design strategies against obesity and insulin resistance. Recently, we have identified a new microprotein of 76 aa in length, highly expressed in BAT compared to other tissues, and is induced upon cold exposure. Microproteins in general function by affecting protein-protein interaction between signaling molecules. Our microprotein contains consensus docking motifs for Protein Phosphatase 2B. Our preliminary studies showed that overexpression of this microprotein in differentiated BAT cells increased oxygen consumption rate (OCR), while knockdown decreased OCR in basal and forskolin stimulated conditions. Moreover, we detected higher PKA activity without changes in cAMP levels upon overexpression of this microprotein in BAT cells. To document its physiological function, we have generated conditional knockout mice and transgenic mice overexpressing the microprotein in UCP1+ cells and in adipocytes. We propose that, our microprotein interacts with PP2B to regulate classic b-adrenergic downstream signaling and potentiates PKA activity for promotion of thermogenesis. Aim 1 is to study its effect on thermogenesis in differentiated brown adipocytes in culture. Aim 2 is to dissect the biochemical basis of its function in promoting thermogenesis. Finally, Aim 3 is to evaluate its in vivo function in thermogenesis by loss- and gain-of function studies in mice. This research may allow us to devise small molecule therapeutics to increase thermogenesis for preventing obesity and improving insulin sensitivity in the future.