The kinase complex mTORC2 is the key regulator for adrenoceptor-stimulated glucose uptake in brown adipocytes, Olsen et al. reveal.
Brown adipose tissue can take up large amounts of glucose from the bloodstream to use as a fuel source to generate body heat. The sympathetic nervous system stimulates glucose uptake by activating the β3-adrenoceptor, but the signaling pathway leading to GLUT1-dependent glucose import is largely unknown.
Insulin induces glucose uptake by activating the kinases PI3K and Akt, but Olsen et al. found that inhibiting these kinases had no effect on β3-adrenoceptor–stimulated glucose import. In contrast, inhibiting the mTOR kinase—a key regulator of cell metabolism—blocked glucose uptake in both mouse and human adipocytes in response to β3-adrenoceptor activation. mTOR inhibitors had no effect on cAMP-dependent GLUT1 expression but impaired the transporter’s subsequent delivery to the plasma membrane.
mTOR operates in two complexes, known as mTORC1 and mTORC2. Olsen et al. found that the latter complex was required for glucose uptake by brown adipocytes, and they think that it promotes GLUT1 translocation by regulating the actin cytoskeleton.
Because brown adipose tissue can take up so much glucose from the bloodstream, stimulating this pathway could have both acute and long-term effects on glucose homeostasis in rodents and, perhaps, humans. It could therefore be an effective treatment for both type II diabetes and obesity. Senior author Tore Bengtsson now wants to investigate this possibility in mice.
Text by Ben Short