Obese mice exhibit an altered behavioural and inflammatory response to lipopolysaccharide

Abstract

SUMMARYObesity is associated with an increase in the prevalence and severity of infections. Genetic animal models of obesity (ob/ob and db/db mice) display altered centrally-mediated sickness behaviour in response to acute inflammatory stimuli such as lipopolysaccharide (LPS). However, the effect of diet-induced obesity (DIO) on the anorectic and febrile response to LPS in mice is unknown. This study therefore determined how DIO and ob/ob mice respond to a systemic inflammatory challenge. C57BL/6 DIO and ob/ob mice, and their respective controls, were given an intraperitoneal (i.p.) injection of LPS. Compared with controls, DIO and ob/ob mice exhibited an altered febrile response to LPS (100 μg/kg) over 8 hours. LPS caused a greater and more prolonged anorexic effect in DIO compared with control mice and, in ob/ob mice, LPS induced a reduction in food intake and body weight earlier than it did in controls. These effects of LPS in obese mice were also seen after a fixed dose of LPS (5 μg). LPS (100 μg/kg) induced Fos protein expression in several brain nuclei of control mice, with fewer Fos-positive cells observed in the brains of obese mice. An altered inflammatory response to LPS was also observed in obese mice compared with controls: changes in cytokine expression and release were detected in the plasma, spleen, liver and peritoneal macrophages in obese mice. In summary, DIO and ob/ob mice displayed an altered behavioural response and cytokine release to systemic inflammatory challenge. These findings could help explain why obese humans show increased sensitivity to infections.

Exercise training promotes cardioprotection through oxygen-sparing action in high fat-fed mice

“…In a recent report by Pons and colleagues (37), decreased infarct size following treadmill running was demonstrated in a genetic model of severe obesity (ob/ob) mice that underwent in situ coronary artery occlusion followed by 24 h of reperfusion. However, it should be noted that this was an in vivo study using a model of genetic obesity lacking the gene encoding for leptin, a hormone shown to be proinflammatory and plays a role in the regulation of immunity (26,47).…”

Role of Adiposity-Driven Inflammation in Depressive Morbidity

“…Increased plasma levels of inflammatory cytokines (including interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, and C-reactive protein (CRP)) and activation of inflammatory signaling pathways have been reported in both obese individuals (Capuron et al, 2011b;Park et al, 2005;Visser et al, 1999) and animal models of obesity (Cani et al, 2008;De Souza et al, 2005;Dinel et al, 2011Dinel et al, , 2014Lawrence et al, 2012;Pistell et al, 2010;Xu et al, 2003).…”

Introductory Chapter: Obesity—“OMICS” and Endocrinology

“…An interest in the nutritional modulation of obesity, with or without concomitant diabetes, has increased due to the effects of feeding patterns on Sirt1 and p53, being involved in the reciprocal nuclear-mitochondrial interactions, emerging mutations, as well as apoptosis (cell death) and/or responses encompassing permanent cellular senescence [35][36][37][38][39][40][41]. Sirt1 and its posttranscriptional impact on p53 [42,43] is heavily involved in the differentiation of adipocytes, as well as lipid metabolism in general [44][45][46][47][48], with their implications for abnormal Sirt1 deacetylation of p53, linked to lipid metabolism with its characteristic transformation of adipocytes and ensuing liver disease. Interestingly, both Sirt1 and p53 knockout mice develop NAFLD [49][50][51][52], which alludes to a close connections between adipocyte phenotype "switch" involving Sirt 1 and/or p53 impact on mitochondrial functioning [53][54][55][56].…”

“…LPS has been shown to modulate SREBP expression in macrophages, while also subduing liver PGC1α expression [29,42,43], and thus being associated with an abnormal Sirt1-regulation of basal adipocyte cell functioning [27,44]. The LPS-facilitated "blockage" of the elimination of cholesterol from macrophages has been demonstrated to serve as an important factor in the cholesterol-rich lipoprotein intercommunication network [45][46][47], thus impacting on LPS neutralization in metabolic diseases, with focus on diabetes [48][49][50].…”

“…IFγ has also been shown to affect genes, like Sirt1 and p53 apoptosis coupled genes, whose role are being "dissociated" in dysfunctional stages of metabolism [45][46][47][48][49][50][51][52][53]. The impact of IFγ on chromatin modeling stimulates macrophages, controlling gene transcription, thus regulating inflammatory cytokine production in activated macrophages [46,47].…”