Blocking obesity-associated protein stops dangerous fat formation

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! O: L- q( {4 I7 F脂肪位置决定肥胖疾病; ^+ X$ q$ o$ e: e, I+ V

6 B" s& j* i* f; l) H" D: U0 lOxford University和French Institute of Health and Medical research (INSERM) 的研究者们突变了小鼠的基因从而抑制了一个肥胖相关的蛋白，使用高热量饮食喂养的实验鼠的内脏器官没有形成大量脂肪的堆积。这一发现发表在Nature Medicine，他们在报道中还指出这些基因修饰的实验鼠及时体重增加仍然保持着对胰岛素的敏感性（正常情况下，肥胖会导致对胰岛素反应减低，耐受）。
1 P3 Q6 Y5 l1 ~内脏器官脂肪的堆积，尤其是胃部，会给健康带来很大的危害：导致胰岛素耐受，二型糖尿病以及心血管疾病。研究发现实验鼠改变了脂肪的沉积模式，由胃部周围到皮下，在这一过程中胰岛素敏感性一直保持，同时减低了二型糖尿病的发病率。
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之前的研究表面内脏堆积的脂肪会吸引 M1-type macrophages (免疫细胞，吞噬)，这些免疫细胞会产生有害的蛋白导致胰岛素耐受。3 L7 [, Y) {9 f' d6 e% y2 }4 [8 {- a
Professor Irina Udalova at the Kennedy Institute of Rheumatology at Oxford University指出：“我们之前的研究发现一个叫做 interferon regulatory factor-5 (IRF-5)的蛋白，它会促进温和型M2-type变为攻击型 M1-type。所以我们猜想敲除IRF-5是否会对肥胖症状有所改善。”为了验证这一猜想两个研究小组使用健康和高脂肪两种饲料喂养IRF-5缺陷的小鼠和正常小鼠，观察小鼠出现的差别症状。使用健康饲料喂养缺陷小鼠和野生型小鼠相比没有明显差异，使用高脂肪饲料喂养的两种小鼠体重都比健康饲料喂养的要重。但是突变鼠将脂肪储存在皮下，野生型小鼠堆积在内脏器官（胃部等）。突变鼠胃部脂肪细胞的尺寸也比较小（一般肥胖是脂肪数量不变，体积变大），因为存在大量的胶原蛋白（细胞支架）利于脂肪细胞的附着。2 g5 ]1 \9 ]" e6 @: b- ^0 ?
Professor Udalova说“虽然突变鼠的体重也在增加，但是脂肪堆积的位置和野生型小鼠是不同的。我们知道胃部有大量脂肪堆积的人群比大腿堆积脂肪的人群有更高的风险会得肥胖相关的基本，比如二型糖尿病。虽然我们现在在小鼠上的实验并不能复制到人上，即改变肥胖人群的体内脂肪分布，但是这一发现给我们提供了一些思路，是否改变脂肪的分布会改变肥胖相关疾病如二型糖尿病发生的条件。”研究者为了验证这一假设进行了一系列的实验，他们使用高糖的饮用水饲喂小鼠，检测胰岛素调控血糖的时间。肥胖会导致机体对胰岛素敏感性下降，这就需要更长的时间来使血液中的血糖下降,最终会导致二型糖尿病的发生。虽然突变鼠的体重升高，但是它们在血糖调控方面做的比野生型好。
5 [/ f, F% c. `! }* HINSERM的研究者也发现肥胖人群的IRF-5水平在脂肪组织中很高，尤其是内脏脂肪。对这组人群的研究还发现IRF-5表达水平提高的同时另一种macrophages产生的蛋白transforming growth factor beta (TGF beta)的表达降低。他们在试管中模拟了脂肪组织的环境，即人为提高瘦人中分离的细胞中的IRF-5表达水平，结果也导致TGF beta的表达降低，和肥胖者中观察到的现象相似。
5 C' _$ w% v7 v: Y研究者人为IRF-5的表达减低会导致一系列的变化，首先是TGFbeta表达提高，从而促进胶原蛋白的富集，导致腹部脂肪细胞的再分布，同时释放的其他化学成分维持了胰岛素的敏感性。
2 k! Z; ^& i1 }6 x: c+ FProfessor Udalova也表示“我们发现突变小鼠虽然会发胖，但整体还是健康的。存在一些副作用，比如容易产生过敏体质。所以还有很多的工作需要进行以了解是否改变IRF-5的表达水平在人类中适用。但是小鼠实验的结果很明显，脂肪堆积的位置是问题的关键。“
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http://www.ox.ac.uk/news/2015-05 ... ous-fat-formation-0) g0 v! u6 {0 y9 H4 T% c

2 J. ?4 K4 m: ]* h: U8 pBy changing mouse genes to block a protein associated with obesity, Oxford University scientists have prevented fat from forming around the animals' internal organs, even when the animals eat an unhealthy diet. The study in Nature Medicine found that these genetically engineered mice also retained their sensitivity to insulin (normally blunted by obesity), despite gaining weight., t7 J4 ~$ N0 r' Y
Visceral fat deposits around internal organs in the stomach are particularly harmful: they are associated with insulin resistance, type-2 diabetes and heart disease. The study, conducted in close collaboration with researchers at the at the French Institute of Health and Medical research (INSERM) in Paris, shows that changing the pattern of fat deposition from around the stomach to under the skin starts a chain of events which result in insulin sensitivity being maintained, reducing the chances of type-2 diabetes., V( E, Y0 B2 \$ S6 t
Researchers already know that visceral fat attracts special M1-type macrophages (immune cells that attack infections and damaged cells). These M1-type macrophages produce harmful proteins that promote insulin resistance. 'We've previously found that a protein called interferon regulatory factor-5 (IRF-5) seems to push macrophages to change from a more 'peaceful', M2-type to the more aggressive M1-type', said Professor Irina Udalova at the Kennedy Institute of Rheumatology at Oxford University, 'so we wondered if 'deleting' IRF-5 might have a beneficial effect'.2 a- L/ ^( X1 H2 j" g' s
To test this idea, the two research teams fed the mice that were lacking the gene coding for IRF-5 with a healthy diet or a high-fat one. The mice with genetic changes were no different from standard lab mice when both the groups ate the healthy diet. Both groups of mice gained weight when they ate the high-fat diet. However, the mice with the altered gene piled on the fat under the skin, rather than around the internal organs in their stomach. The size of the fat cells in the stomach was also smaller in these mice, because there was more collagen (a 'scaffolding' protein that provides the structure for many parts of the body) deposits, holding the fat cells in.
# y3 p+ l% ]: |: e2 I'The mice without IRF-5 still got fat, but what was different was where they deposited this fat. We know that people who put on fat around their belly have a higher risk of developing obesity-related illnesses such as type-2 diabetes, compared to people who put on weight around their thighs. But we can't change the pattern of fat deposition in people, which we can now do in these mice. So this turned out to be an excellent way of testing if changing the pattern of fat deposition actually changes the factors that lead to type-2 diabetes', said Professor Udalova.
$ Z( z  ]6 o8 i  Z3 x  d% wThe researchers tested this idea by giving the mice a very sweet drink, containing glucose. They then tracked how quickly the glucose was broken down by insulin. Obesity can make the body less sensitive to insulin, which means that it takes longer for the glucose to disappear from the blood stream. This loss of sensitivity can eventually lead to type-2 diabetes. Despite being fatter, the mice without IRF-5 did better than the standard mice on this glucose challenge test.7 l% j9 v- B' U4 R$ C  A
Researchers at INSERM also found that IRF-5 levels were elevated in fatty tissue from very obese people, especially in their visceral fat. A gene analysis of this group of people found that the higher the levels of IRF-5, the lower the levels of another protein produced by macrophages, transforming growth factor beta (TGFbeta). By mimicking the environment in fatty tissue in a test-tube, the researchers also found that artificially increasing the levels of IRF-5 in cells from thin people reduced the levels of TGFbeta, similar to what was found in the obese people. The researchers think that reducing IRF-5 levels sets off a chain of events, starting with increased TGFbeta levels. Increased TGFbeta in turn leads to more collagen being deposited, which results in 'remodelling' of abdominal fat deposits, and the release of other chemicals that maintain insulin sensitivity.
7 e4 r9 j/ h8 p& I" b) Q'We found that the mice without IRF-5 were essentially healthy, despite being significantly fatter. Blocking IRF-5's activity may however have other side-effects, such as increasing allergies. So more work is needed to understand if changing levels of IRF-5 (by using new drugs to target the protein) in humans would be a good way of treating the problem of obesity and obesity associated metabolic diseases. But the results show very clearly that where you get fat matters a lot', said Professor Udalova.+ M- h1 R! M# |. f) w3 P* Q' q$ T
                The paper, Irf5-deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity, is published in Nature Medicine.
7 n8 F  l& f6 F                About the Kennedy Institute of Rheumatology.
) ~! r! [: e+ |( Q" n: Y                About the French Institute of Health and Medical research (INSERM).