Primary Role of Interleukin-1α and Interleukin-1β in Lipopolysaccharide-Induced Hypoglycemia in Mice

Oguri, Senri; Motegi, Katsutoshi; Iwakura, Yoichiro; Endo, Yasuo

doi:10.1128/cdli.9.6.1307-1312.2002

Cited by 47 publications

(47 citation statements)

References 54 publications

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“…We also show that LPS caused a reduction in blood glucose in both db/ϩ and db/db mice. These findings confirm previous findings that LPS lowers blood glucose in animals and humans (35). Several mechanisms have been reported as to how LPS lowers blood glucose including enhanced systemic consumption of glucose (35), depletion of glycogen from liver and muscle (36), and impaired hepatic gluconeogenesis (37).…”

Section: Discussionsupporting

confidence: 81%

Augmented Lipopolysaccharide-Induced TNF-α Production by Peritoneal Macrophages in Type 2 Diabetic Mice Is Dependent on Elevated Glucose and Requires p38 MAPK

Sherry¹,

O’Connor²,

Kramer

et al. 2007

The Journal of Immunology

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Dysregulated inflammation is a complication of type 2 diabetes (T2D). In this study, we show that augmented LPS-induced TNF-α production by resident peritoneal macrophages (PerMφ) in type 2 diabetic (db/db) mice is dependent on elevated glucose and requires p38 MAPK. Intraperitoneal LPS administered to db/db and nondiabetic (db/+) mice induced 3- and 4-fold more TNF-α in the peritoneum and serum, respectively, of db/db mice as compared with db/+ mice. Examination of the TLR-4/MD2 complex and CD14 expression showed no difference between db/db and db/+ PerMφ. Ex vivo stimulation of PerMφ with LPS produced a similar 3-fold increase in TNF-α production in db/db PerMφ when compared with db/+ PerMφ. PerMφ isolated from db/+ mice incubated in high glucose (4 g/L) medium for 12 h produced nearly 2-fold more TNF-α in response to LPS than PerMφ incubated in normal glucose medium (1 g/L). LPS-dependent stimulation of PI3K activity, ERK1/2 activation, and p38 kinase activity was greater in PerMφ from db/db mice as compared with db/+ mice. Only inhibition of p38 kinase blocked LPS-induced TNF-α production in PerMφ from db/db mice. Taken together, these data indicate that augmented TNF-α production induced by LPS in macrophages during diabetes is due to hyperglycemia and increased LPS-dependent activation of p38 kinase.

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Section: Discussionsupporting

confidence: 81%

Augmented Lipopolysaccharide-Induced TNF-α Production by Peritoneal Macrophages in Type 2 Diabetic Mice Is Dependent on Elevated Glucose and Requires p38 MAPK

Sherry¹,

O’Connor²,

Kramer

et al. 2007

The Journal of Immunology

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“…These studies support the view that IL-1 resets glucose homeostasis at the level of the CNS. We have first established that endogenously produced IL-1 decreases glucose levels, results that are in line with those obtained in IL-1␣͞IL-1␤ knock out mice (27). We also show that, even after a glucose load, hypoglycemia lasted longer in IL-1-treated mice than in those that received regular insulin.…”

Section: Discussionsupporting

confidence: 65%

IL-1 resets glucose homeostasis at central levels

Rey

Roggero²,

Randolf³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Administration of IL-1␤ results in a profound and long-lasting hypoglycemia. Here, we show that this effect can be elicited by endogenous IL-1 and is related to not only the capacity of the cytokine to increase glucose uptake in peripheral tissues but also to mechanisms integrated in the brain. We show that (i) blockade of IL-1 receptors in the brain partially counteracted IL-1-induced hypoglycemia; (ii) peripheral administration or induction of IL-1 production resulted in IL-1␤ gene expression in the hypothalamus of normal and insulin-resistant, leptin receptor-deficient, diabetic db͞db mice; (iii) IL-1-treated normal and db͞db mice challenged with glucose did not return to their initial glucose levels but remained hypoglycemic for several hours. This effect was largely antagonized by blockade of IL-1 receptors in the brain; and (iv) when animals with an advanced Type II diabetes were treated with IL-1 and challenged with glucose, they died in hypoglycemia. However, when IL-1 receptors in the brains of these diabetic mice were blocked, they survived, and glucose blood levels approached those that these mice had before IL-1 administration. The prolonged hypoglycemic effect of IL-1 is insulin-independent and develops against increased levels of glucocorticoids, catecholamines, and glucagon. These findings, together with the present demonstration that this effect is integrated in the brain and is paralleled by IL-1␤ expression in the hypothalamus, indicate that this cytokine can reset glucose homeostasis at central levels. Such reset, along with the peripheral actions of the cytokine, would favor glucose uptake by immune cells during inflammatory͞ immune processes.T here is evidence that immune-derived cytokines can mediate metabolic alterations during the course of infective, inflammatory, autoimmune, and neoplastic processes (1-4), either by acting locally or by interacting with different endocrine mechanisms (2, 3, 5). Under physiological conditions, glucose is the principal and most readily available source of energy. When IL-1, a prototypic proinflammatory cytokine, is administered to mice, a profound and long-lasting hypoglycemia is observed. The hypoglycemic effect of IL-1 is not mediated by insulin, because it is clearly observed in insulin-resistant diabetic mice and rats; is not caused by glucose loss; and is independent from the anorexic effect of the cytokine (6-12). IL-1-induced hypoglycemia might be explained by the capacity of this cytokine to stimulate glucose uptake in vitro in a variety of tissues such as adipose cells (13), fibroblasts (14), articular chondrocytes (15), keratinocytes (16), intestinal macrophages (17), peritoneal mesothelial cells (18), and glial cells (19). Studies in vivo also show that overproduction of IL-1 results in increased 2-deoxyglucose uptake in all tissues tested, including lymphoid organs and the brain (20). Several of the mentioned in vitro studies on the effect of IL-1 on glucose transport have been performed by using human cells, and injection of very low doses of...

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“…On the other hand, IL-1 has been suggested to act as an antidiabetic agent, as treatment with IL-1 decreases blood glucose in both normal and genetically diabetic animals (13,14). However, there are few studies exploiting mouse knockout models to investigate the effects of endogenous IL-1 on glucose metabolism (15,16).…”

mentioning

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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Primary Role of Interleukin-1α and Interleukin-1β in Lipopolysaccharide-Induced Hypoglycemia in Mice

Cited by 47 publications

References 54 publications

Augmented Lipopolysaccharide-Induced TNF-α Production by Peritoneal Macrophages in Type 2 Diabetic Mice Is Dependent on Elevated Glucose and Requires p38 MAPK

Augmented Lipopolysaccharide-Induced TNF-α Production by Peritoneal Macrophages in Type 2 Diabetic Mice Is Dependent on Elevated Glucose and Requires p38 MAPK

IL-1 resets glucose homeostasis at central levels

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

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