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Expression of Uncoupling Protein in Skeletal Muscle and White Fat of Obese Mice Treated with Thermogenic Beta 3-Adrenergic Agonist

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Expression of Uncoupling Protein in Skeletal Muscle and White Fat of Obese Mice Treated with Thermogenic Beta 3-Adrenergic Agonist Expression of uncoupling protein in skeletal muscle and white fat of obese mice treated with thermogenic beta 3-adrenergic agonist. I Nagase, … , T Kawada, M Saito J Clin Invest. 1996;97(12):2898-2904. https://doi.org/10.1172/JCI118748. Research Article The mitochondrial uncoupling protein (UCP) is usually expressed only in brown adipose tissue (BAT) and a key molecule for metabolic thermogenesis. The effects of a highly selective beta 3-adrenergic agonist, CL316,243 (CL), on UCP expression in skeletal muscle and adipose tissues were examined in mice. Daily injection of CL (0.1 mg/kg, sc) to obese yellow KK mice for two weeks caused a significant reduction of body weight, associated with a marked decrease of white fat pad weight and hypertrophy of the interscapular BAT with a sixfold increase in UCP content. Clear signals of UCP protein and mRNA were detected by Western and Northern blot analyses in inguinal, mesenteric and retroperitoneal white fat pads, and also in gastrocnemius and quadriceps muscles, whereas no signal in saline-treated mice. The presence of UCP mRNA in muscle tissues was also confirmed by reverse transcription-PCR analysis. Weaker UCP signals were also detected in control C57BL mice treated with CL, but only in inguinal and retroperitoneal fat pads. Immunohistochemical examinations revealed that UCP stains in the white fat pads were localized on multilocular cells quite similar to typical brown adipocyte, and those in the muscle tissues on myocytes. The mitochondrial localization of UCP in myocytes was confirmed by immunoelectron microscopy. In addition to UCP protein, UCP mRNA was also detected in myocytes by in situ hybridization […] Find the latest version: https://jci.me/118748/pdf Rapid Publication Expression of Uncoupling Protein in Skeletal Muscle and White Fat of Obese Mice Treated with Thermogenic ␤3-Adrenergic Agonist Itsuro Nagase,* Toshihide Yoshida,‡ Kenzo Kumamoto,§ Tsunekazu Umekawa,‡ Naoki Sakane,‡ Hideki Nikami,* Teruo Kawada,ʈ and Masayuki Saito* *Department of Biomedical Sciences, Laboratory of Biochemistry, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060, ‡First Department of Internal Medicine, Kyoto Prefectural University of Medicine, Kyoto 602, §Department of Anatomy, Meiji College of Oriental Medicine, Hiyoshi, 629-03 Kyoto, and ʈDepartment of Food Science and Technology, Faculty of Agriculture, Kyoto University, Kyoto 606, Japan Abstract Introduction The mitochondrial uncoupling protein (UCP) is usually ex- Heat production in brown adipose tissue (BAT)1 is a signifi- pressed only in brown adipose tissue (BAT) and a key mole- cant component of whole body energy expenditure, at least in cule for metabolic thermogenesis. The effects of a highly se- small rodents, and its dysfunction contributes to the develop- lective ␤3-adrenergic agonist, CL316,243 (CL), on UCP ment of obesity (1). BAT thermogenesis is directly controlled expression in skeletal muscle and adipose tissues were ex- by sympathetic nerves distributed to this tissue principally amined in mice. Daily injection of CL (0.1 mg/kg, sc) to through the ␤-adrenergic action of norepinephrine. It is now obese yellow KK mice for two weeks caused a significant re- established that there are three isoforms of ␤-adrenergic re- duction of body weight, associated with a marked decrease ceptor (AR) in brown adipocytes, ␤1-, ␤2-, and ␤3-ARs (2). of white fat pad weight and hypertrophy of the interscapu- Among them, recent interests have been concentrated mostly lar BAT with a sixfold increase in UCP content. Clear sig- on the ␤3-AR, because this isoform is expressed primarily, but nals of UCP protein and mRNA were detected by Western not exclusively, in brown and white adipocytes. The presence and Northern blot analyses in inguinal, mesenteric and ret- of ␤3-AR, different from the ␤1- and ␤2-ARs, was proposed roperitoneal white fat pads, and also in gastrocnemius and initially in pharmacological studies of lipolysis in white and quadriceps muscles, whereas no signal in saline-treated brown adipocytes (3). The recent cDNA cloning of this recep- mice. The presence of UCP mRNA in muscle tissues was tor from human, mouse and rat sources (4–6) has further pro- also confirmed by reverse transcription-PCR analysis. moted the development of agonists specific to the ␤3-AR, Weaker UCP signals were also detected in control C57BL which might be a selective stimulant of lipolysis and BAT ther- mice treated with CL, but only in inguinal and retroperito- mogenesis and be useful as an anti-obesity drug. neal fat pads. Immunohistochemical examinations revealed We previously (7) examined the effects of a highly selective that UCP stains in the white fat pads were localized on mul- ␤3-AR agonist, CL316,243 (CL), on energy metabolism and tilocular cells quite similar to typical brown adipocyte, and adiposity in one of the genetically obese and diabetic animal those in the muscle tissues on myocytes. The mitochondrial models, yellow KK mice, showing that chronic administration localization of UCP in myocytes was confirmed by immuno- of CL enhanced oxygen consumption, reduced adiposity, im- electron microscopy. In addition to UCP protein, UCP proved glucose tolerance, and increased GDP-binding to BAT mRNA was also detected in myocytes by in situ hybridiza- mitochondria, an index of the thermogenic activity of BAT. tion analysis. Thus, chronic stimulation of the ␤3-adrener- Similar thermogenic and anti-obesity effects of this drug were gic receptor induces ectopic expression of UCP in adipose also reported in rats (8). In contrast to rodents, humans have tissues conventionally considered as white fat and even in only minute amounts of BAT, and thereby the contribution of skeletal muscle, which probably contributes to the potent BAT to the regulation of energy balance has been claimed to anti-obesity effect of the ␤3-adrenergic agonist. (J. Clin. In- be much less or negligible in humans. However, this would not vest. 1996. 97:2898–2904.) Key words: brown adipose tissue always be the case, if the expression of uncoupling protein • immunohistochemistry • obesity • yellow KK mice (UCP), a key molecule for BAT thermogenesis, can be acti- vated in tissues other than BAT by some means. In this con- text, we have explored the possible expression of UCP in white fat and also in skeletal muscle. We report here, contradicting Address correspondence to Masayuki Saito, Ph.D., Department of the well-accepted view of exclusive expression of UCP in BAT Biomedical Sciences, Graduate School of Veterinary Medicine, Hok- (9, 10), that chronic treatment of yellow KK obese mice with kaido University, Sapporo 060, Japan. Phone: 11-706-5204; FAX: 11- CL induces UCP in various fat pads usually considered as 757-0703; E-mail: [email protected] white adipose tissue and even in skeletal muscle. Received for publication 16 October 1995 and accepted in revised form 29 March 1996. J. Clin. Invest. © The American Society for Clinical Investigation, Inc. 1. Abbreviations used in this paper: AR, adrenergic receptor; BAT, 0021-9738/96/06/2898/07 $2.00 brown adipose tissue; CL, CL316,243; UCP, uncoupling protein; Volume 97, Number 12, June 1996, 2898–2904 WAT, white adipose tissue. 2898 Nagase et al. Methods conventional ABC method. The sections were also counter-stained with hematoxylin and examined by a light microscope. Chemicals. CL316,243, disodium (R,R)-5([2-{3-chlorophenyl}-2- For electron microscopic observations, specimens of gastrocne- hydroxyethyl]-aminoproppyl)-1,3-benzodioxole-2,2-dicarboxylate (11), mius muscle fixed in 1% glutaraldehyde Ϫ0.1 M phosphate buffer was provided from American Cyanamid Co. (Pearl River, NY). (pH 7.4) were dehydrated in dimethylformamide, and embedded in Animals. Female yellow KK and C57BL mice (Charles River Ja- Lowicry K4M (Chemische Werke Lowi, Waldkaiburg, Germany) in pan, Osaka) were obtained at the age of 7 wk and housed in plastic gelatin capsules polymerized by ultraviolet irradiation. Ultrathin sec- cages at 22Ϯ2ЊC with 12 h light-dark cycle, and given free access to tions were mounted on nickel grids, immersed in 2% normal goat se- laboratory chow (CE-2; Clea Japan, Tokyo) and tap water. They rum in PBS for 1h, and treated with the rabbit antiserum against rat were given a subcutaneous injection of either CL 316,243 (0.1 mg/kg) UCP (ϫ100 diluted) in PBS containing 1% BSA overnight in a moist or saline once a day. After 2 wk, mice were killed by cervical disloca- chamber at 4ЊC. After being well washed with PBS, the sections were tion, and skeletal muscle (gastrocnemius), interscapular BAT, and treated with colloidal gold-labeled anti–rabbit IgG F(abЈ)2 (10 nm; subcutaneous (inguinal) WAT were rapidly removed in their entirety Bio Cell, Cardiff, UK) diluted at 1:15 in PBS containing 1% BSA for and frozen in liquid nitrogen for Western blot and RNA analyses. 2 h at room temperature, postfixed with 2.5% glutaraldehyde for 10 The animal care and procedure were approved by the Animal Care min, and stained with uranyl acetate for 15 min and lead citrate for 1 and Use Committee of Hokkaido University. min. In controls, non-immune rabbit serum was substituted for the Western blot analysis. Each tissue was homogenized in 5–10 vol- primary antiserum. umes of a solution containing 10 mM Tris-HCl, and 1 mM EDTA In situ hybridization. Tissue specimens obtained from mice trans- (pH 7.4) for 30 s with a Polytron. After centrifugation at 1,500 g for 5 cardially perfused with 4% paraformaldehyde-PBS were postfixed in min, the fat cake was discarded, and the infranant (fat-free extract) the same solution overnight, immersed in 20% sucrose–0.1 M phos- was used for Western blot analysis of UCP as described previously phate buffer (pH 7.4), frozen with dry ice, and cut into 12-␮m sec- (12, 13).
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