新たな肥満治療につながる発見/褐色脂肪細胞

 白色脂肪細胞を燃焼させて体熱に変える褐色脂肪細胞をどのように生成するかがわかり、新たな肥満治療への展開がはじまった。
 褐色脂肪細胞の特徴的な遺伝子のスイッチとなる1組の蛋白を使い、マウスや人の皮膚細胞を褐色脂肪細胞に変化させることができた。
 体温保持のため乳児は多くの褐色脂肪細胞を持っているが、2009年4月までは成人では褐色脂肪細胞は無くなってしまっていると思われていた。スウェーデンのイエーテボリ大のEnerbackらが、成人でも残っていて活性化させれば脂肪を燃焼させられる可能性を報告した。
画像 1994年にSpiegelman は白色脂肪細胞の制御機構を発見した。褐色脂肪細胞は白色脂肪細胞に由来するという仮説を立てた。(DNA螺旋の中に入り特定の遺伝子のスイッチを入れる)zinc finger と呼ばれる一種の蛋白が重要な鍵を握っていると考えた。褐色脂肪細胞の全てのzinc finger を不活性化すれば、前駆体である白色脂肪細胞になると思った。
 しかし結果は奇妙なことに、褐色脂肪細胞は白色脂肪細胞に変化するのではなく筋肉細胞になった。筋肉細胞が褐色脂肪細胞の前駆体だという発見は昨年なされた。zinc finger蛋白と筋肉細胞内で生成される2番目の蛋白質との組み合わせが褐色脂肪細胞へのマスタスイッチであり、皮膚細胞を褐色脂肪細胞へ改造するだろうという。
 褐色脂肪細胞は白色脂肪細胞の脂肪分解を促して脂肪酸として血液中に放出され、これが褐色脂肪細胞に取り込まれ多数存在するミトコンドリアにより通常細胞ならエネルギーの化学物質を生成するがその過程が阻害され発熱を生じる。ミトコンドリアは鉄を含むため褐色となる。
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カロリーを燃やす脂肪細胞
http://kurie.at.webry.info/200904/article_21.html
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Discovery May Help Treat Obesity
http://www.nytimes.com/2009/07/30/science/30fat.html
By NICHOLAS WADE
Published: July 29, 2009

A new approach to treating obesity has been opened up by a discovery about how the body creates brown fat, the cells that burn white fat and turn it into body heat.

Researchers led by Bruce M. Spiegelman of Harvard Medical School report their discovery in Thursday’s issue of the journal Nature. Their paper describes the natural system by which brown fat cells are generated from their precursors.

Dr. Spiegelman has used this system ― a pair of proteins that switch on the brown fat cell’s distinctive genes ― to convert both mouse and human skin cells into brown fat cells.

Brown fat cells have a very different role from the better-known white fat cells. The white cells store fat; the brown cells burn it off as heat.

Babies have lots of brown fat to help keep warm. Until April 2009, biologists believed that the brown fat quickly disappeared and was not found in adults. Dr. Sven Enerback of the University of Goteborg in Sweden and others then reported that some brown fat tissue persisted in adults, raising the possibility that if the cells could be made more active, a person might burn off more fat.

In a parallel line of research that has now converged with the brown fat discovery, Dr. Spiegelman has long been studying the body’s white fat cells and how they are controlled. In 1994 he found the body’s master regulator of white fat cells. Turning to brown fat cells, he followed the general assumption that they were derived from white fat cells.

A key element in making brown fat cells seemed to be a kind of protein called a zinc finger (because it reaches into the spiral of a DNA molecule to switch on particular genes). Dr. Spiegelman figured that if he inactivated all the relevant zinc finger proteins in brown fat cells, they should turn back into their precursors, the white fat cells.

The experiment worked. The brown fat cells did revert, but not into white fat cells. They turned into muscle cells.

“It was the most bizarre experiment my lab ever did,” Dr. Spiegelman said Wednesday.

His discovery that muscle cells are the natural precursors of brown fat cells was made last year. Dr. Spiegelman has now found that the zinc finger protein, in combination with a second protein produced in muscle cells, is the master switch for brown fat cells and will also convert skin cells into brown fat, even though this is not the process nature intended.

He has used this master switch to convert mouse skin cells to brown fat cells, which seem to work as expected when transplanted into normal mice. Now he is working on a second experiment, a crucial test for the possibility of therapy, to see what happens when brown fat cells are implanted into obese mice.

Asked if the mice were any thinner, Dr. Spiegelman said the results so far were encouraging. He declined to go further, saying journal editors would be unhappy if he gave away the findings before publication.

A similar procedure might be tried in people, he said, if the mouse experiments are promising. Further discoveries might produce the natural protein for turning on the zinc finger switch, and this protein might make a useful drug for converting skin cells into brown fat cells.

Dr. Enerback said Dr. Spiegelman had taken a “really important step” in elucidating the basic biology of brown fat cells. According to his calculations, Dr. Enerback said, inserting 50 to 100 grams of brown fat cells into a person would enable them to burn off more than 10 pounds of white fat tissue a year.

He said a cell therapy approach of this kind would allow a brown fat deposit of cells made from the patient’s skin cells to be made larger or smaller according to need. Such a therapy would be used not by itself but along with lifestyle changes and other interventions.

Brown fat cells induce the body’s white fat cells to break down their fat into fatty acids. These are released into the bloodstream and taken up by the brown fat cells. Brown fat cells contain large numbers of mitochondria, the chemical batteries of living cells.

The mitochondria (which originated long ago as bacteria enslaved in cells) usually generate a chemical form of energy. But in brown fat cells, this process is disrupted and the mitochondria produce heat instead.

Because the mitochondria contain iron, the cells adopt the brownish tinge that gives them their name.
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Nature advance online publication 29 July 2009 | doi:10.1038/nature08262; Received 1 June 2009; Accepted 13 July 2009; Published online 29 July 2009
Initiation of myoblast to brown fat switch by a PRDM16--C/EBP-bold beta transcriptional complex
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature08262.html
Shingo Kajimura1,2, Patrick Seale1,2, Kazuishi Kubota2, Elaine Lunsford3, John V. Frangioni3, Steven P. Gygi2 & Bruce M. Spiegelman1,2

1. Dana-Farber Cancer Institute,
2. Department of Cell Biology, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
3. Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA

Correspondence to: Bruce M. Spiegelman1,2 Correspondence and requests for materials should be addressed to B.M.S. (Email: bruce_spiegelman@dfci.harvard.edu.).

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Abstract

Brown adipose cells are specialized to dissipate chemical energy in the form of heat, as a physiological defence against cold and obesity1. PRDM16 (PR domain containing 16) is a 140 kDa zinc finger protein that robustly induces brown fat determination and differentiation2. Recent data suggests that brown fat cells arise in vivo from a Myf5-positive, myoblastic lineage by the action of PRDM16 (ref. 3); however, the molecular mechanisms responsible for this developmental switch is unclear. Here we show that PRDM16 forms a transcriptional complex with the active form of C/EBP-beta (also known as LAP), acting as a critical molecular unit that controls the cell fate switch from myoblastic precursors to brown fat cells. Forced expression of PRDM16 and C/EBP-beta is sufficient to induce a fully functional brown fat program in naive fibroblastic cells, including skin fibroblasts from mouse and man. Transplantation of fibroblasts expressing these two factors into mice gives rise to an ectopic fat pad with the morphological and biochemical characteristics of brown fat. Like endogenous brown fat, this synthetic brown fat tissue acts as a sink for glucose uptake, as determined by positron emission tomography with fluorodeoxyglucose. These data indicate that the PRDM16--C/EBP-beta complex initiates brown fat formation from myoblastic precursors, and may provide opportunities for the development of new therapeutics for obesity and type-2 diabetes.

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