Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor 4 mutation

doi:10.1016/j.bbrc.2006.12.190

Biochemical and Biophysical Research Communications

Volume 354, Issue 1, 2 March 2007, Pages 45-49

https://doi.org/10.1016/j.bbrc.2006.12.190 Get rights and content

Abstract

Obese adipose tissue is characterized by increased infiltration of macrophages, suggesting that they might represent an important source of inflammation. We have provided in vitro evidence that saturated fatty acids, which are released from hypertrophied adipocytes via the macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for Toll-like receptor 4 (TLR4) to induce the inflammatory changes in macrophages. Here we show the attenuation of adipose tissue inflammation in C3H/HeJ mice carrying a functional mutation in the TLR4 gene relative to control C3H/HeN mice during a 16-week high-fat diet. We also find that adiponectin mRNA expression is significantly reduced by co-culture of hypertrophied 3T3-L1 adipocytes and C3H/HeN peritoneal macrophages, which is reversed, when co-cultured with C3H/HeJ peritoneal macrophages. This study provides in vivo evidence that TLR4 plays a role in obesity-related adipose tissue inflammation and thus helps to identify the therapeutic targets that may reduce obesity-induced inflammation and the metabolic syndrome.

Section snippets

Materials and methods

Animals. Six-week-old male C3H/HeJ mice which have defective LPS signaling due to a missense mutation in the TLR4 gene and control C3H/HeN mice were purchased from CLEA Japan (Tokyo, Japan). The animals were housed in individual cages in a temperature-, humidity-, and light-controlled room (12 h light and 12 h dark cycle) and allowed free access to water and standard chow (Oriental MF; 362 kcal/100 g, 5.4% energy as fat) (Oriental Yeast, Co., Ltd., Tokyo, Japan), when otherwise noted. In the

Animal studies

We examined the effect of high-fat diet on the metabolic phenotypes of C3H/HeJ mice. Body weight gain was indistinguishable between C3H/HeJ and C3H/HeN mice during the 12-week standard diet and thereafter C3H/HeJ mice weighed slightly more than C3H/HeN mice (Fig. 1A). There was no marked difference in body weight between C3H/HeJ and C3H/HeN mice during a high-fat diet, although C3H/HeJ mice weighed more than C3H/HeN mice in response to 6- to 10-week high-fat diet. The weights of the epididymal

Acknowledgments

We thank Dr. Motohiro Takeya for rat monoclonal anti-mouse F4/80 antibody and the members of the Ogawa Laboratory for helpful discussions. This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Ministry of Health, Labour and Welfare of Japan, and research grants from Japan Diabetes Foundation, Mishima Kaiun Memorial Foundation, The Novo Nordisk Insulin Study Award, The SKYLARK Food Science

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Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor 4 mutation

Abstract

Section snippets

Materials and methods

Animal studies

Acknowledgments

J. Biol. Chem.

J. Biol. Chem.

Am. J. Pathol.

Biochem. Biophys. Res. Commun.

The perils of portliness: causes and consequences of visceral adiposity

Diabetes

Molecular mechanism of metabolic syndrome X: contribution of adipocytokines adipocyte-derived bioactive substances

Ann. N. Y. Acad. Sci.

Minireview: adiposity, inflammation, and atherogenesis

Endocrinology

Adipose tissue, inflammation, and cardiovascular disease

Circ. Res.

Obesity is associated with macrophage accumulation in adipose tissue

J. Clin. Invest.

Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance

J. Clin. Invest.