Leptin actions on food intake and body temperature are mediated by IL-1

Luheshi, Giamal N.; Gardner, Jason; Rushforth, David; Loudon, A. S. I.; Rothwell, Nancy J.

doi:10.1073/pnas.96.12.7047

Cited by 332 publications

(260 citation statements)

References 44 publications

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“…21,36 The hypothalamic effects of leptin on food intake depend heavily on the action of IL-1b. 37 IL-1Ra binds to IL-1 receptors without inducing a cellular response, thereby antagonizing the effects of IL-1b, and central administration of IL-1Ra in rodents inhibits both leptin-induced suppression of food intake and increases in body temperature. 37 Similar mechanisms may be operative in obese humans, where elevated plasma IL-1Ra correlates with increased circulating leptin, and weight loss leads to a parallel reduction in IL-1Ra and leptin.…”

Section: Discussionmentioning

confidence: 99%

Stress-induced cytokine responses and central adiposity in young women

et al. 2007

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Background: Evidence suggests that people who are more responsive to psychological stress are at an increased risk of developing obesity. However, the biological mechanisms underlying this phenomenon are poorly understood. The cytokines leptin, interleukin-1 receptor antagonist (IL-1Ra) and interleukin-6 (IL-6) play a key role in fat metabolism and abnormal circulating levels of these proteins have been reported in obese people and in individuals subject to stress. Objective: This study investigated whether cytokine responses to acute mental stress are associated with adiposity in healthy young women. Design and Subjects: A laboratory study of 67 women, aged 18-25 years, recruited from University College London. Measurements: Height, weight and waist circumference were measured and body fat mass was estimated by bioelectrical impedance body composition analysis. Laboratory mental stress testing was carried out and blood pressure and heart rate were recorded at baseline, during two moderately challenging tasks (Stroop and speech) and during recovery 40-45 min post-stress. Blood samples taken at baseline, immediately post-stress and 45 min post-stress, were used for assessment of circulating cytokines. Saliva samples taken throughout the session were assessed for cortisol. Results: Women who had larger cytokine responses to stress were more abdominally obese than women with smaller cytokine stress responses. Specifically, there was a positive correlation between waist circumference and stress-induced increases in plasma levels of leptin (r ¼ 0.35, Po0.05) and IL-1Ra responses (r ¼ 0.29, Po0.05). There was also a significant positive correlation between prolonged diastolic blood pressure responses to stress and measures of total and abdominal obesity (r ¼ 0.28-0.33, Po0.05). Conclusion: Increased cytokine production could be a mechanism linking stress and abdominal obesity.

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Section: Discussionmentioning

confidence: 99%

Stress-induced cytokine responses and central adiposity in young women

et al. 2007

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“…Leptin, which is released from adipocytes, exerts an inhibitory feedback effect on fat masses by acting on hypothalamic nuclei, which express the cognate signal-transducing leptin receptor ObRb [2]. IL-1 production, which is induced by leptin, is involved in the leptin-induced suppression of feeding [3]. Another member of the IL-1 family, IL-1 receptor antagonist (IL1RA) binds to IL-1 receptors without exerting agonistic activity.…”

Section: Introductionmentioning

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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“…In addition, it has been recognized that POMC derived melanocortin peptides reduce food intake via the activation of the melanocortin 4-receptor, and that reduced POMC expression can lead to hyperphagia and obesity (67). Leptin has been widely demonstrated to have proinflammatory properties and has been shown to mediate the reduction in food intake following LPS (28,50,65). The attenuated increase in POMC and leptin at 2 h post-LPS, seen in the CR50% animals, may contribute to the CR animals' attenuated anorexia and weight loss.…”

Section: Cr Sickness Behavior and A Potential Mechanismmentioning

confidence: 99%

Calorie restriction attenuates LPS-induced sickness behavior and shifts hypothalamic signaling pathways to an anti-inflammatory bias

MacDonald

Radler

Paolini

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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MacDonald L, Radler M, Paolini AG, Kent S. Calorie restriction attenuates LPS-induced sickness behavior and shifts hypothalamic signaling pathways to an anti-inflammatory bias. Am J Physiol Regul Integr Comp Physiol 301: R172-R184, 2011. First published April 27, 2011 doi:10.1152/ajpregu.00057.2011 has been demonstrated to alter cytokine levels; however, its potential to modify sickness behavior (fever, anorexia, cachexia) has not. The effect of CR on sickness behavior was examined in male C57BL/6J mice fed ad libitum or restricted 25% (CR25%) or restricted 50% (CR50%) in food intake for 28 days and injected with 50 g/kg of LPS on day 29. Changes in body temperature, locomotor activity, body weight, and food intake were determined. A separate cohort of mice were fed ad libitum or CR50% for 28 days, and hypothalamic mRNA expression of inhibitory factor B-␣ (I B-␣), cyclooxygenase-2 (COX-2), prostaglandin E 2 (PGE2), suppressor of cytokine signaling 3 (SOCS3), IL-10, neuropeptide Y (NPY), leptin, proopiomelanocortin (POMC), and corticotrophin-releasing hormone (CRH) were determined at 0, 2, and 4 h post-LPS. CR50% mice did not develop fevers, whereas the CR25% mice displayed a fever shorter in duration but with the same peak as the controls. Both CR25% and CR50% mice showed no sign of anorexia and reduced cachexia after LPS administration. Hypothalamic mRNA expression of NPY and CRH were both increased by severalfold in CR50% animals preinjection compared with controls. The CR50% mice did not demonstrate the expected rise in hypothalamic mRNA expression of COX-2, microsomal prostaglandin E synthase-1, POMC, or CRH 2 h post-LPS, and leptin expression was decreased at this time point. Increases in SOCS3, IL-10, and I B-␣ expression in CR50% animals were enhanced compared with ad libitum-fed controls at 4 h post-LPS. CR results in a suppression of sickness behavior in a dose-dependent manner, which may be due to CR attenuating proinflammatory pathways and enhancing anti-inflammatory pathways. fever; suppressor of cytokine signaling 3; cyclooxygenase-2; microsomal prostaglandin E synthase-1; leptin CALORIE RESTRICTION (CR), a dietary regimen low in calories, while avoiding malnutrition, is the only manipulation that has consistently been shown to extend the mean and maximum life span in a range of species (2,42,71,76). In addition to an increase in life span, CR attenuates the normal immunosenscence seen with age (52), along with reducing the occurrence of other age-related diseases (14,39,43,53,54,79).It has been postulated that the mechanism by which CR extends the mean and maximum life span is by reducing oxidative stress caused by unregulated increases in reactive oxygen species (3,19,31,42,69), as well as by limiting the age-related increase in basal pro-inflammatory cytokine levels (73). One possible mechanism by which CR exerts its antiinflammatory effect are glucocorticoids, which are increased after CR (33, 47) and act to increase the transcription of anti-inflammatory cytokines and decrease the transcripti...

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Leptin actions on food intake and body temperature are mediated by IL-1

Cited by 332 publications

References 44 publications

Stress-induced cytokine responses and central adiposity in young women

Stress-induced cytokine responses and central adiposity in young women

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

Calorie restriction attenuates LPS-induced sickness behavior and shifts hypothalamic signaling pathways to an anti-inflammatory bias

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