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

Abstract

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.

Knock-Down of IL-1Ra in Obese Mice Decreases Liver Inflammation and Improves Insulin Sensitivity

“…Our energy expenditure data suggest that the leaner body weight is at least in part due to higher oxygen consumption, as well as a higher CBT. IL-1Ra knock-down in HFD-fed mice resembles the phenotype previously observed in IL-1Ra KO mice, whom display increased energy expenditure, increased oxygen consumption and higher CBT [22], [23], [42]. The reasons for these effects on energy expenditure could be due, in part, to the noted up-regulation of UCP1 in BAT in IL-1Ra-ASO treated HFD mice and the pyrogenic effects of IL-1β [43].…”

IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat

“…Interleukin-1 receptor 1 knockout (KO) mice paradoxically develop maturity-onset obesity (28), while IL-1Ra KO mice are lean and resist HFD-induced obesity (29,30). We envisage two explanations for this apparent discrepancy.…”

The intake of high-fat diets induces the acquisition of brown adipocyte gene expression features in white adipose tissue

“…High caloric intake and high fat diet independently of caloric intake are known to stimulate sympathetic nervous system activity [49][50][51] . Thus, as happens in BAT, increased UCP1 expression/browning could be expected in WAT in response to the intake of a HF diet.…”