The outbreak of a fat-enriched diet in Western countries is becoming a problem of the utmost importance.

Obesity is the result of a complex interaction between genetic and environmental factors.

Among the latter, changes in eating habits to increase fat intake are involved in the increased occurrence of metabolic diseases, such as obesity and diabetes, which are bearing features of the metabolic syndrome.

The major metabolic consequence of a high-fat diet is that insulin action and the regulatory mechanisms of body weight are impaired through a well-described lipotoxic effect (1).

In addition, it has been recently determined that obesity and insulin resistance are associated with low-grade chronic systemic inflammation (2).

In models of diet-induced and genetic obesity, the adipose tissue presents increased expression and content of proinflammatory cytokines such as tumor necrosis factor (TNF)-α (3,4), interleukin (IL)-1 (3,4), and IL-6 (4).

This cytokine production is then deleterious for muscle insulin action; for example, TNF-α has been shown to cause insulin resistance by increasing serine phosphorylation on insulin receptor substrate-1 (5), leading to its inactivation.

※insulin receptor substrate-1 (IRS-1): インスリン受容体基質-1。チロシンキナーゼであるインスリン受容体は、インスリンにより活性化されると、IRS-1の多数のチロシンをリン酸化する。TNF-αはIRS-1のセリンをリン酸化することでこの反応を阻害する

The consequent insulin resistance will favor hyperinsulinemia and excessive hepatic and adipose tissue lipid storage.

However, while extensive research is dedicated to the effects of an inflammatory reaction on energy metabolism, the triggering factor linking inflammation to high-fat diet-induced metabolic syndrome remains to be determined.

Recently, it has been shown that nutritional fatty acids activate toll-like receptor-4 (TLR4) signaling in adipocytes and macrophages and that the capacity of fatty acids to induce inflammatory signaling in adipose cells or tissue and macrophages is blunted in the absence of TLR4 (6).

Furthermore, adipose tissue lipolysis, from hypertrophied adipocytes, could serve as a naturally occurring ligand for TLR4 to induce inflammation (7).

※lipolysis: 脂肪分解、リポリーシス。中性脂肪(トリグリセリド)がホルモン感受性リパーゼにより加水分解されること。副腎皮質刺激ホルモン(ACTH)、糖質コルチコイド、グルカゴン、ノルアドレナリンにより脂肪細胞を刺激することによりリポリーシスが起き、遊離脂肪酸が生じる

※ligand: リガンド。受容体に結合するホルモンや分子

In addition, TLR4 mRNA concentration was induced during adipocyte differentiation, further enhancing free fatty acid-induced inflammation (8).

TLR4 mRNA concentration: 脂肪細胞が分化する間、脂肪組織でのTLR4発現が上昇する。さらに、TLR4の活性化(LPSおよび遊離脂肪酸による)は、NF-κBシグナルと炎症性サイトカイン遺伝子発現(TNF-αとIL-6)を刺激し、インスリン抵抗性を引き起こす

A very encouraging and innovative hypothesis has recently been proposed whereby the microbial ecology in humans could be an important factor affecting energy homeostasis (i.e., individuals predisposed to obesity may have gut microbial communities that would favor the occurrence of the metabolic diseases) (9-11).

Although the proposed mechanism was to promote a more efficient extraction and/or storage of energy from a given diet, the impact of microbiota on the occurrence of a low-tone inflammatory status was not determined.

However, another study recently showed that antibiotic treatment partially protects against type 1 diabetes in a diabetes-prone rat developing insulitis (12).

※insulitis: 膵島炎。膵臓ランゲルハンス島への単核球浸潤。浸潤する細胞はT、B、マクロファージなどで、膵島炎によりβ細胞が破壊されて1型糖尿病が発症する

The authors proposed that altering the gut microbiota composition by antibiotic treatment had reduced the antigenic load and hence the inflammatory reaction that had potently led to pancreatic β-cell destruction.

In that respect, we have been looking for a factor of microbial origin that would trigger and maintain a low-tone continuous inflammatory state when feeding on a high-fat diet.

※feed on: 餌にする、常食にする、<牛・馬が>食べる

We hypothesized that the bacterial lipopolysaccharide (LPS) from the Gram-negative intestinal microbiota would fulfill all the prerequisites to be eligible.

※prerequisite: pre + requisite 「必要なもの」。-iteはラテン語の過去分詞接尾辞-itusから

※eligible: 選ばれるに値する、適格な

Thus, endogenous LPS is

1) continuously produced in the gut by the death of Gram-negative bacteria and physiologically translocated into intestinal capillaries through a TLR4-dependent mechanism (13);
1) グラム陰性細菌が死ぬことにより腸で継続的に産生され、TLR4依存的な仕組みにより腸の毛細血管に生理的に移行する。

2) transported from the intestine toward target tissues by a mechanism facilitated by lipoproteins, notably chylomicrons freshly synthesized from epithelial intestinal cells in response to a high-fat diet (14);
2) 腸から標的の組織へと輸送され、その輸送メカニズムはリポタンパク質によって促進される。

and 3) triggers the secretion of proinflammatory cytokines when it binds to the complex of mCD14 and the TLR4 at the surface of innate immune cells (15,16).
3) 自然免疫細胞の表面でマウスCD14とTLR4の複合体に結合するとき、炎症性サイトカインの分泌を引き起こす。

※mCD14: murine CD14

Therefore, we aimed to demonstrate that LPS would be an early factor in the triggering of high-fat diet-induced metabolic diseases.

by travelair4000ext | 2013-03-06 14:22 | 翻訳  

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