Impact of Gq signaling in the brown adipose tissue

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Two major types of fat can be distinguished in mammals: white adipose tissue (WAT) and brown adipose tissue (BAT). In contrast to WAT, which is the largest store of energy, BAT is specialized in dissipating energy, which is mediated by the brown adipocyte-specific mitochondrial protein UCP-1 (uncoupling protein-1). This process is also known as non-shivering thermogenesis and is essential for newborns to maintain body temperature in a cold environment. Importantly, recent studies using glucose tracers clearly showed that adults also possess metabolically active BAT and that BAT mass correlates with leanness in humans. Thus, BAT is a potential target for novel anti-obesity therapies, which are urgently needed since obesity has reached pandemic dimensions with nearly two billion people being overweight or obese. In addition to classical BAT, brown-like adipocytes (so called beige or brite (brown in white) cells) have been found in WAT. Brown and beige cells are activated by G protein coupled receptors (GPCRs) that are linked to Galphas and increase cyclic AMP (cAMP). cAMP activates protein kinase A, which in turn induces lipolysis and activates UCP-1 in brown and beige adipocytes. In contrast, Galphai-coupled receptors inhibit cAMP production and brown adipocyte activation. Apart from Galphas- and Galphai-linked receptors not much is known about other GPCRs and their role in BAT. Our preliminary data based on an unbiased screen of GPCRs present in brown adipocytes show that a considerable number of these GPCRs are linked with Galphaq. The Research Unit gives us the unique opportunity to identify the role of Galphaq signalling in brown and beige fat. We will study Galphaq function in human brown and beige fat cells as well as in murine BAT and WAT using the selective Galphaq inhibitor FR 900359 (a plant-derived molecule that is in the focus of this research initiative) and novel compounds generated in the RU as well as genetic tools including lentiviral vectors and transgenic animals.