Combined Interleukin-6 and Interleukin-1 Deficiency Causes Obesity in Young Mice

Chida, Dai; Osaka, Toshimasa; Hashimoto, Ohiko; Iwakura, Yoichiro

doi:10.2337/diabetes.55.04.06.db05-1250

Cited by 80 publications

(79 citation statements)

References 44 publications

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“…We were unable to detect differences in food intake between the genotypes (data not shown). Overall, LT Ϫ/Ϫ mice did not show significant body weight or body fat gain over WT mice when fed a high-fat diet, and results are comparable with other mouse strains deficient in inflammatory mediators (8,46). Plasma total cholesterol levels were increased ϳ40% for HFHS-fed mice (120 mg/dl) compared with mice fed rodent chow (80 mg/dl), but no significant differences were seen between the genotypes.…”

Section: Lt Deficiency Results In Reduced Obesity Body Weights For Ltsupporting

confidence: 57%

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Deficiency of lymphotoxin-α does not exacerbate high-fat diet-induced obesity but does enhance inflammation in mice

Pamir

McMillen

Edgel

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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(LT␣) is secreted by lymphocytes and acts through tumor necrosis factor-␣ receptors and the LT␤ receptor. Our goals were to determine whether LT has a role in obesity and investigate whether LT contributes to the link between obesity and adipose tissue lymphocyte accumulation. LT deficient (LT Ϫ/Ϫ ) and wild-type (WT) mice were fed standard pelleted rodent chow or a high-fat/high-sucrose diet (HFHS) for 13 wk. Body weight, body composition, and food intake were measured. Glucose tolerance was assessed. Systemic and adipose tissue inflammatory statuses were evaluated by quantifying plasma adipokine levels and tissue macrophage and T cell-specific gene expression in abdominal fat. LT Ϫ/Ϫ mice were smaller (20%) and leaner (25%) than WT controls after 13 wk of HFHS diet feeding. LT Ϫ/Ϫ mice showed improved glucose tolerance, suggesting that, in WT mice, LT may impair glucose metabolism. Surprisingly, adipose tissue from rodent chow-and HFHS-fed LT Ϫ/Ϫ mice exhibited increased T lymphocyte and macrophage infiltration compared with WT mice. Despite the fact that LT Ϫ/Ϫ mice exhibited an enhanced inflammatory status at the systemic and tissue level even when fed rodent chow, they were protected from enhanced diet-induced obesity and insulin resistance. Thus, LT contributes to body weight and adiposity and is required to modulate the accumulation of immune cells in adipose tissue.

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Section: Lt Deficiency Results In Reduced Obesity Body Weights For Ltsupporting

confidence: 57%

“…To test the role of individual inflammatory proteins in obesity, genes have been ablated in mice and shown to induce obesity (8,16,39,46,54,55,68,73,86). Nearly all of these genes relate to monocyte tissue infiltration and/or macrophage activation and phenotypic switching.…”

mentioning

confidence: 99%

Deficiency of lymphotoxin-α does not exacerbate high-fat diet-induced obesity but does enhance inflammation in mice

Pamir

McMillen

Edgel

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…Considering the fact that Il1ra −/− mice on a HFD had increased body temperature, it is possible that the primary effect of Il1ra deficiency is to increase body temperature. However, we have previously demonstrated that Il1ra −/− Il-6 −/− mice on a normal diet show a lean phenotype comparable to Il1ra −/− mice [32]. Since IL-6 is essential for the IL-1-induced febrile response [37,38], it is not possible that the lean phenotype could be explained solely by the action of IL-1 as a pyrogen.…”

Section: Discussionmentioning

confidence: 99%

Increased fat:carbohydrate oxidation ratio in Il1ra −/− mice on a high-fat diet is associated with increased sympathetic tone

et al. 2008

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Aims/hypothesis Proinflammatory cytokines, including IL-1, exert pleiotropic effects on the neuro-immuno-endocrine system. Previously, we showed that mice with knockout of the gene encoding IL-1 receptor antagonist (Il1ra −/− , also known as Il1rn −/− ) have a lean phenotype. The present study was designed to analyse the mechanisms leading to this lean phenotype.Methods Il1ra −/− mice were fed a high-fat diet following weaning. Energy expenditure, body temperature, heart rate, blood parameters, urinary catecholamines and adipose tissue were analysed. Results Il1ra −/− mice exhibited resistance to obesity induced by a high-fat diet; this resistance was associated with increased energy expenditure and a decreased respiratory quotient, indicating that the ratio of fat:carbohydrate metabolism in Il1ra −/− mice is greater than in controls. Activity level in Il1ra −/− mice was significantly decreased and body temperature was significantly increased, compared with wild-type (WT) mice. Inguinal white adipose tissues in Il1ra −/− mice express increased levels of Ucp1 and mitochondrial respiratory chain genes compared with WT mice. Histological analysis of adipose tissue in Il1ra −/− mice revealed that brown adipose tissue is hyperactive and inguinal white adipose tissue contains smaller cells, which exhibit the distinctive multilocular appearance of brown adipocytes. Urinary epinephrine and norepinephrine excretion in Il1ra −/− mice was significantly increased compared with WT mice, suggesting that Il1ra −/− mice have increased sympathetic tone. Consistent with this, heart rate in Il1ra −/− mice was also significantly increased. Conclusions/interpretation Our results show that Il1ra −/− mice have increased energy expenditure, fat:carbohydrate oxidation ratio, body temperature, heart rate and catecholamine production. All of these observations are consistent with an enhanced sympathetic tone.

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“…Moreover, knockout of IL-RI, IL-6, and GM-CSF all result in mature-onset obesity, indicating that age-related cofactors are needed to obtain the obese phenotype (22,53). It has recently been reported that IL-1 receptor modulation also affects body fat in IL-6 knockout mice (54), but else there is little knowledge about the interactions between these three cytokines. Taken together, these results indicate interactions between several components of the immune system and body fat regulation.…”

Section: Discussionmentioning

confidence: 99%

Mature-Onset Obesity in Interleukin-1 Receptor I Knockout Mice

et al. 2006

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Interleukin-1 (IL-1) is a major mediator of inflammation that exerts its biological activities through the IL-1 type I receptor (IL-1RI). The body weights of IL-1RI؊/؊ mice of both sexes started to deviate from those of wild-type mice at 5-6 months of age and were 20% higher at 9 months of age. Visceral and subcutaneous fat mass, measured by dual-energy X-ray absorptiometry and magnetic resonance imaging, was markedly (1.5-to 2.5-fold) increased. Lean body mass and crown-rump length were also slightly (11 and 5%, respectively) increased, as was serum IGF-I. Obese IL-1RI؊/؊ mice were insulin resistant, as evidenced by hyperinsulinemia, decreased glucose tolerance, and insulin sensitivity. To elucidate the mechanisms for the development of obesity, young preobese IL-1RI ؊/؊ mice were investigated. They showed decreased suppression of body weight and food intake in response to systemic leptin treatment. The decreased leptin responsiveness was even more pronounced in older obese animals. Moreover, spontaneous locomotor activity and fat utilization, as measured by respiratory quotient, were decreased in preobese IL-1RI ؊/؊ mice. In conclusion, lack of IL-1RI-mediated biological activity causes mature-onset obesity. This obese phenotype is preceded by decreased leptin sensitivity, fat utilization, and locomotor activity. Diabetes 55: [1205][1206][1207][1208][1209][1210][1211][1212][1213] 2006 T he prevalence of obesity is growing rapidly in many parts of the world and reaching epidemic proportions in several developed countries (1). Overweight and obesity are associated with increased risk of metabolic disorders, such as type 2 diabetes and hyperlipidemia, and thereby increased risk of cardiovascular mortality. Although the regulation of body weight and body composition involves input from lifestyle and environment, compelling scientific evidence indicates that propensity to develop obesity is in large part attributable to genetic factors. Over the last decade, the study of different transgenic and knockout mouse models has contributed to the identification of new factors involved in the complex mechanisms regulating energy balance and to the clarification of the contribution of genetics to obesity (2,3). Moreover, a number of human genes have been identified in which major missense or nonsense mutations as well as genetic variations are associated with obesityrelated phenotypes. Many of these genetic variants have occurred in molecules identical or similar to those identified as a cause of obesity in rodents, supporting their involvement in the regulation of body weight homeostasis also in humans (4).Interleukin-1 (IL-1) is a major mediator of inflammation and exerts effects on the neuro-immuno-endocrine system (5). Infection, injury, and inflammation are associated with negative energy balance, characterized by reduced food intake, weight loss, increased thermogenesis, and fever. IL-1 could be of importance for these effects, as peripheral or central injection of IL-1 induces a marked rise in body temperature (f...

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Combined Interleukin-6 and Interleukin-1 Deficiency Causes Obesity in Young Mice

Cited by 80 publications

References 44 publications

Deficiency of lymphotoxin-α does not exacerbate high-fat diet-induced obesity but does enhance inflammation in mice

Deficiency of lymphotoxin-α does not exacerbate high-fat diet-induced obesity but does enhance inflammation in mice

Increased fat:carbohydrate oxidation ratio in Il1ra −/− mice on a high-fat diet is associated with increased sympathetic tone

Mature-Onset Obesity in Interleukin-1 Receptor I Knockout Mice

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