Adipose tissue, metabolic and inflammatory responses to stroke are altered in obese mice

Abstract

Obesity is an independent risk factor for stroke, although several clinical studies have reported that obesity improves stroke outcome. Obesity is hypothesised to aid recovery by protecting against post-stroke catabolism. We therefore assessed whether obese mice had an altered metabolic and inflammatory response to stroke. Obese ob/ob mice underwent a 20-min middle cerebral artery occlusion and 24-h reperfusion. Lipid metabolism and expression of inflammatory cytokines were assessed in the plasma, liver and adipose tissue. The obese-specific metabolic response to stroke was assessed in plasma using non-targeted ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) metabolomics coupled with univariate and multivariate analysis. Obesity had no effect on the extent of weight loss 24 h after stroke but affected the metabolic and inflammatory responses to stroke, predominantly affecting lipid metabolism. Specifically, obese mice had increases in plasma free fatty acids and expression of adipose lipolytic enzymes. Metabolomics identified several classes of metabolites affected by stroke in obese mice, including fatty acids and membrane lipids (glycerophospholipids, lysophospholipids and sphingolipids). Obesity also featured increases in inflammatory cytokines in the plasma and adipose tissue. Overall, these results demonstrate that obesity affected the acute metabolic and inflammatory response to stroke and suggest a potential role for adipose tissue in this effect. These findings could have implications for longer-term recovery and also further highlight the importance of considering comorbidities in preclinical stroke research, especially when identifying biomarkers for stroke. However, further work is required to assess whether these changes translate into long-term effects on recovery.

Stroke Induces Prolonged Changes in Lipid Metabolism, the Liver and Body Composition in Mice

“…In addition, healthy weight loss is typically associated with a reduction in plasma free fatty acids and triglycerides. Experimental stroke has been previously shown to acutely affect peripheral lipid metabolism, potentially through the release of inflammatory mediators that can promote a catabolic state [18], and can also exacerbate atherosclerosis [61]. Together, these findings of lipid and adipokine disturbance here suggest that experimental stroke in non-obese mice resulted in long-lasting changes in metabolism, potentially originating in the adipose tissue.…”

“…The reason for this dramatic and prolonged weight loss after stroke is unclear and could involve several mechanisms, including reduced food intake and/or raised energy expenditure, possibly via the action of inflammatory mediators. Acute weight loss after experimental stroke can correlate positively with ischaemic damage [30,58], although this correlation is not always observed [18]. Here, the degree of weight loss over 49 days did not directly correlate with initial damage at 48 h, suggesting that post-stroke weight loss may be caused by factors secondary to the initial injury, and develop during recovery.…”

“…Liver damage is also reported in other experimental models of injury including heart failure [68]. Within in the first 24 h after stroke in rodents, an increase in chemokine and cytokine expression is observed in the liver, which is accompanied by infiltration of neutrophils that could potentially initiate damage [18,25,67,69]. An increase in liver triglyceride content is also seen 24 h after stroke in mice [18].…”

“…Increases in liver triglycerides have previously been reported 24 h after stroke in mice [18]. Livers were therefore taken at day 60 and assessed histologically.…”

LC-MS Method for Determining Amiodarone and Desethylaminodarone in Rat Plasma Used in Endogenous Overdosing Conditions Following Lipolysis

“…In weight-loss diets (obese patients with increased cardiovascular risk at which gradual weight loss is recommended), or in case of forced weight-loss (parenteral nutrition in patients unable to receive a balanced nutritional and caloric intake after myocardial infarction or stroke) by modifying the insulin/glucagon ratio in favor of glucagon, gluconeogenesis from amino acids and lipolysis is induced, the released fatty acids being used to maintain energy cell homeostasis [13]. In this case, AMI and DEA accumulated in the adipose tissue would be mobilized, raising problems both during chronic treatment, by increased plasma levels and toxicity, but also in case of discontinuation of treatment, complete elimination from the body requiers a longer period of time.…”