The availability of amino acid in the brown adipose tissue (BAT) has been shown to be altered under various conditions; however, little is known about the possible expression and pivotal role of amino acid transporters in BAT under physiological and pathological conditions. The present study comprehensively investigated whether amino acid transporters are regulated by obesogenic conditions in BAT in vivo. Moreover, we investigated the mechanism underlying the regulation of the expression of amino acid transporters by various stressors in brown adipocytes in vitro. The expression of solute carrier family 38 member 1 (Slc38a1; gene encoding sodium-coupled neutral amino acid transporter 1) was preferentially upregulated in the BAT of both genetic and acquired obesity mice in vivo. Moreover, the expression of Slc38a1 was induced by hypoxic stress through hypoxia-inducible factor-1α, which is a master transcription factor of the adaptive response to hypoxic stress, in brown adipocytes in vitro. These results indicate that Slc38a1 is an obesity-associated gene in BAT and a hypoxia-responsive gene in brown adipocytes.

1.
Rosen ED, Spiegelman BM: Adipocytes as regulators of energy balance and glucose homeostasis. Nature 2006;444:847-853.
2.
Cannon B, Nedergaard J: Brown adipose tissue: function and physiological significance. Physiol Rev 2004;84:277-359.
3.
Villarroya J, Cereijo R, Villarroya F: An endocrine role for brown adipose tissue? Am J Physiol Endocrinol Metab 2013;305:E567-E572.
4.
Hinoi E, Nakamura Y, Takada S, Fujita H, Iezaki T, Hashizume S, Takahashi S, Odaka Y, Watanabe T, Yoneda Y: Growth differentiation factor-5 promotes brown adipogenesis in systemic energy expenditure. Diabetes 2014;63:162-175.
5.
Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, Scimè A, Devarakonda S, Conroe HM, Erdjument-Bromage H, Tempst P, Rudnicki MA, Beier DR, Spiegelman BM: PRDM16 controls a brown fat/skeletal muscle switch. Nature 2008;454:961-967.
6.
Wang W, Seale P: Control of brown and beige fat development. Nat Rev Mol Cell Biol 2016;17:691-702.
7.
Jewell JL, Russell RC, Guan KL: Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol 2013;14:133-139.
8.
Castilho BA, Shanmugam R, Silva RC, Ramesh R, Himme BM, Sattlegger E: Keeping the eIF2 alpha kinase Gcn2 in check. Biochim Biophys Acta 2014;1843:1948-1968.
9.
Hyde R, Taylor PM, Hundal HS: Amino acid transporters: roles in amino acid sensing and signalling in animal cells. Biochem J 2003;373:1-18.
10.
Hundal HS, Taylor PM: Amino acid transceptors: gate keepers of nutrient exchange and regulators of nutrient signaling. Am J Physiol Endocrinol Metab 2009;296:E603-E613.
11.
Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ: Hypothalamic mTOR signaling regulates food intake. Science 2006;312:927-930.
12.
Herman MA, She P, Peroni OD, Lynch CJ, Kahn BB: Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels. J Biol Chem 2010;285:11348-11356.
13.
López-Soriano FJ, Alemany M: Effect of cold-temperature exposure and acclimation on amino acid pool changes and enzyme activities of rat brown adipose tissue. Biochim Biophys Acta 1987;925:265-271.
14.
López-Soriano FJ, Fernández-López JA, Mampel T, Villarroya F, Iglesias R, Alemany M: Amino acid and glucose uptake by rat brown adipose tissue. Effect of cold-exposure and acclimation. Biochem J 1988;252:843-849.
15.
Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, Tran TT, Suzuki R, Espinoza DO, Yamamoto Y, Ahrens MJ, Dudley AT, Norris AW, Kulkarni RN, Kahn CR: New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 2008;454:1000-1004.
16.
Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B: Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT. EMBO J 1998;17:5085-5094.
17.
Hinoi E, Ochi H, Takarada T, Nakatani E, Iezaki T, Nakajima H, Fujita H, Takahata Y, Hidano S, Kobayashi T, Takeda S, Yoneda Y: Positive regulation of osteoclastic differentiation by growth differentiation factor 15 upregulated in osteocytic cells under hypoxia. J Bone Miner Res 2012;27:938-949.
18.
Fujimori S, Hinoi E, Yoneda Y: Functional GABA(B) receptors expressed in cultured calvarial osteoblasts. Biochem Biophys Res Commun 2002;293:1445-1452.
19.
Iezaki T, Ozaki K, Fukasawa K, Inoue M, Kitajima S, Muneta T, Takeda S, Fujita H, Onishi Y, Horie T, Yoneda Y, Takarada T, Hinoi E: ATF3 deficiency in chondrocytes alleviates osteoarthritis development. J Pathol 2016;239:426-437.
20.
Fukasawa K, Park G, Iezaki T, Horie T, Kanayama T, Ozaki K, Onishi Y, Takahata Y, Yoneda Y, Takarada T, Kitajima S, Vacher J, Hinoi E: ATF3 controls proliferation of osteoclast precursor and bone remodeling. Sci Rep 2016;6:30918.
21.
Netzer N, Gatterer H, Faulhaber M, Burtscher M, Pramsohler S, Pesta D: Hypoxia, Oxidative Stress and Fat. Biomolecules 2015;5:1143-1150.
22.
Semenza GL: Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol 2014;9:47-71.
23.
Mackenzie B, Erickson JD: Sodium-coupled neutral amino acid (System N/A) transporters of the SLC38 gene family. Pflugers Arch 2004;447:784-795.
24.
Bröer S: The SLC38 family of sodium-amino acid co-transporters. Pflugers Arch 2014;466:155-172.
25.
Pugh CW, Ratcliffe PJ: Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 2003;9:677-684.
26.
Semenza GL: Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE 2007;2007:cm8.
27.
Trayhurn P: Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev 2013;93:1-21.
28.
Trayhurn P: Hypoxia and adipocyte physiology: implications for adipose tissue dysfunction in obesity. Annu Rev Nutr 2014;34:207-236.
29.
Shimizu I, Aprahamian T, Kikuchi R, Shimizu A, Papanicolaou KN, MacLauchlan S, Maruyama S, Walsh K: Vascular rarefaction mediates whitening of brown fat in obesity. J Clin Invest 2014;124:2099-2112.
30.
Zhang X, Lam KS, Ye H, Chung SK, Zhou M, Wang Y, Xu A: Adipose tissue-specific inhibition of hypoxia-inducible factor 1{alpha} induces obesity and glucose intolerance by impeding energy expenditure in mice. J Biol Chem 2010;285:32869-32877.
31.
Reimer RJ, Chaudhry FA, Gray AT, Edwards RH: Amino acid transport system A resembles system N in sequence but differs in mechanism. Proc Natl Acad Sci U S A 2000;97:7715-7720.
32.
Bröer S, Brookes N: Transfer of glutamine between astrocytes and neurons. J Neurochem 2001;77:705-719.
33.
Jewell JL, Kim YC, Russell RC, Yu FX, Park HW, Plouffe SW, Tagliabracci VS, Guan KL: Metabolism. Differential regulation of mTORC1 by leucine and glutamine. Science 2015;347:194-198.
34.
Altman BJ, Stine ZE, Dang CV: From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 2016;16:619-634.
35.
Bertran J, Magagnin S, Werner A, Markovich D, Biber J, Testar X, Zorzano A, Kühn LC, Palacin M, Murer H: Stimulation of system y(+)-like amino acid transport by the heavy chain of human 4F2 surface antigen in Xenopus laevis oocytes. Proc Natl Acad Sci U S A 1992;89:5606-5610.
36.
Mastroberardino L, Spindler B, Pfeiffer R, Skelly PJ, Loffing J, Shoemaker CB, Verrey F: Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature 1998;395:288-291.
37.
Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO: Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 2009;136:521-534.
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