The interest in brown adipose tissue (BAT) as a target to combat metabolic disease has recently been renewed with the discovery of functional BAT in humans. In rodents, BAT can be activated by bile acids, which activate type 2 iodothyronine deiodinase (D2) in BAT via the G-coupled protein receptor TGR5, resulting in increased oxygen consumption and energy expenditure. Here we examined the effects of oral supplementation of the bile acid chenodeoxycholic acid (CDCA) on human BAT activity. Treatment of 12 healthy female subjects with CDCA for 2 days resulted in increased BAT activity. Whole-body energy expenditure was also increased upon CDCA treatment. In vitro treatment of primary human brown adipocytes derived with CDCA or specific TGR5 agonists increased mitochondrial uncoupling and D2 expression, an effect that was absent in human primary white adipocytes. These findings identify bile acids as a target to activate BAT in humans.

These results indicate that chronic endurance exercise is not associated with brown and beige adipocyte recruitment; in fact endurance training appears to be linked to lower the metabolic activity of BAT in humans.

Wiza C, Nascimento EB, Ouwens DM. Role of PRAS40 in Akt and mTOR signaling in health and disease. Am J Physiol Endocrinol Metab 302: E1453-E1460, 2012. First published February 21, 2012 doi:10.1152/ajpendo.00660.2011.-The proline-rich Akt substrate of 40 kDa (PRAS40) acts at the intersection of the Akt-and mammalian target of rapamycin (mTOR)-mediated signaling pathways. The protein kinase mTOR is the catalytic subunit of two distinct signaling complexes, mTOR complex 1 (mTORC1) and mTORC2, that link energy and nutrients to the regulation of cellular growth and energy metabolism. Activation of mTOR in response to nutrients and growth factors results in the phosphorylation of numerous substrates, including the phosphorylations of S6 kinase by mTORC1 and Akt by mTORC2. Alterations in Akt and mTOR activity have been linked to the progression of multiple diseases such as cancer and type 2 diabetes. Although PRAS40 was first reported as substrate for Akt, investigations toward mTOR-binding partners subsequently identified PRAS40 as both component and substrate of mTORC1. Phosphorylation of PRAS40 by Akt and by mTORC1 itself results in dissociation of PRAS40 from mTORC1 and may relieve an inhibitory constraint on mTORC1 activity. Adding to the complexity is that gene silencing studies indicate that PRAS40 is also necessary for the activity of the mTORC1 complex. This review summarizes the regulation and potential function(s) of PRAS40 in the complex Akt-and mTOR-signaling network in health and disease.proline-rich Akt substrate of 40 kDa; mammalian target of rapamycin PROLINE-RICH Akt SUBSTRATE OF 40 kDa (PRAS40) was first identified as a 14-3-3 binding protein in lysates from insulin-treated hepatoma cells (28) and is identical to the p39 protein that is phosphorylated in PC12 cells treated with nerve growth factor or epidermal growth factor (18) and the nuclear phosphoprotein Akt1 substrate 1 (AKT1S1) purified from Hela cells (3). Although originally described as substrate for Akt (28), analysis of mammalian target of rapamycin (mTOR) immunoprecipitates identified PRAS40 as a component and substrate of the mTOR complex 1 (mTORC1) (35,42,49,51).In addition to mTOR and PRAS40, the mTORC1 complex consists of regulatory-associated protein of mTOR (raptor), the mammalian ortholog of yeast lethal with Sec13 protein 8 (mLST8; also known as G␤L), and DEP domain-containing mTOR-interacting protein (deptor) (61). Within mTORC1, raptor functions as a scaffold through regulation of the assembly of the mTORC1 complex, the recruitment of substrates, and direction of the subcellular localization (61). Both PRAS40 and deptor exert an inhibitory action on mTORC1 activity (61). Activation of mTORC1, which occurs in response to nutrients and growth factors, results in phosphorylation of both PRAS40 and deptor by mTORC1 (33,61). This leads to dissociation of PRAS40 and deptor from the complex and relieves the inhibitory constraint on its activity (33, 61).

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