Editors' ChoiceMetabolism

Metabolic Cues Converge on Transcriptional Coactivator

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Science's STKE  25 Oct 2005:
Vol. 2005, Issue 307, pp. tw374
DOI: 10.1126/stke.3072005tw374

As emphasized by the severe complications of diabetes, the maintenance of normal concentrations of glucose in the blood is a critical physiological function. Despite considerable attention, however, the regulatory mechanisms that accomplish such homeostasis are not particularly well understood. Koo et al. provide new insight through studies on a transcriptional coactivator known as TORC2 (for transducer of regulated CREB activity 2). [CREB is a transcription factor that is stimulated by the intracellular signaling molecule cAMP (adenosine 3′,5′-monophosphate).] Their findings indicate that TORC2 controls transcription of genes encoding enzymes that function in gluconeogenesis (synthesis of glucose from other metabolites) in the liver. Expression of such genes is enhanced under conditions in which an animal is fasting and blood glucose concentrations might otherwise be depleted. Such regulation, at the level of the whole organism, is mediated by hormones like glucagon and insulin. Activity of TORC2 is controlled by its phosphorylation, which determines whether TORC2 becomes localized in the nucleus. In livers of fasting mice, TORC2 became dephosphorylated and was translocated to the nucleus. Indeed, in mice in which TORC2 was depleted in hepatocytes by RNA interference, fasting caused abnormally low concentrations of glucose in the circulation. This systemic regulation of glucose is augmented by mechanisms that monitor cellular energy status. In this case, low cellular concentrations of adenosine triphosphate (indicative of low energy reserves) cause activation of the protein kinase AMPK (adenosine monophosphate-activated protein kinase), which inhibits the energy-intensive process of gluconeogenesis. Koo et al. find that this system also feeds into control of gluconeogenesis through TORC2. AMPK phosphorylated TORC2 in vitro, and stimuli that activated AMPK in cultured primary hepatocytes increased phosphorylation of TORC2 and inhibited its entry into the nucleus. Thus, TORC2 appears to represent a point of conversion of regulatory signals monitoring systemic and cellular energy status. As such, the authors propose, TORC2 may be a useful target for therapeutic intervention in metabolic disorders.

S.-H. Koo, L. Flechner, L. Qi, X. Zhang, R. A. Screaton, S. Jeffries, S. Hedrick, W. Xu, F. Boussouar, P. Brindle, H. Takemori, M. Montminy, The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109-1111 (2005). [PubMed]

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