Abstract
Obesity is a chronic disease with rising worldwide prevalence and largely associated with several other comorbidities, such as cancer, non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome. Hepatic steatosis, a hallmark of NAFLD, is strongly correlated with obesity and has been correlated with changes in the gut microbiota, which can promote its development through the production of short-chain fatty acids (SCFAs) that regulate insulin resistance, bile acid, choline metabolism, and inflammation. Recent studies have suggested a controversial role for the inflammasome/caspase-1 in the development of obesity and non-alcoholic steatohepatitis (NASH). Here, we evaluated the role of inflammasome NLRP3 and caspases 1/11 in the establishment of obesity and hepatic steatosis in diet-induced obese mice, correlating them with the global lipid profile of the liver and gut microbiota diversity. After feeding wild-type, caspases 1/11, and NLRP3 knockout mice with a standard fat diet (SFD) or a high-fat diet (HFD), we found that the caspases 1/11 knockout mice, but not NLRP3 knockout mice, were more susceptible to HFD-induced obesity, and developed enhanced hepatic steatosis even under SFD conditions. Lipidomics analysis of the liver, assessed by MALDI-MS analysis, revealed that the HFD triggered a significant change in global lipid profile in the liver of WT mice compared to those fed an SFD, and this profile was modified by the lack of caspases 1/11 and NLRP3. The absence of caspases 1/11 was also correlated with an increased presence of triacylglycerol in the liver. Gut microbial diversity analysis, using 16S rRNA gene sequencing, showed that there was also an increase of Proteobacteria and a higher Firmicutes/Bacteroidetes ratio in the gut of caspases 1/11 knockout mice fed an HFD. Overall, mice without caspases 1/11 harbored gut bacterial phyla involved with weight gain, obesity, and hepatic steatosis. Taken together, our data suggest an important role for caspases 1/11 in the lipid composition of the liver and in the modulation of the gut microbial community composition. Our results further suggest that HFD-induced obesity and the absence of caspases 1/11 may regulate both lipid metabolism and gut microbial diversity, and therefore may be associated with NAFLD and obesity.
Highlights
Obesity has reached epidemic proportions globally according to the World Health Organization, since the number of obese individuals has been dramatically increasing worldwide
To investigate the influence of inflammasome components in inducing obesity in response to high-fat diet (HFD), C57/BL6 WT, Caspases 1/11−/−, and Nlrp3−/− mice were submitted to standard fat diet (SFD) or HFD for 3 months, with weekly monitoring of weight gain (Figure 1A)
Inflammation plays a fundamental role in the pathophysiology of obesity, and pro-inflammatory cytokines IL-1β and IL-18 have already been linked to this metabolic disorder
Summary
Obesity has reached epidemic proportions globally according to the World Health Organization, since the number of obese individuals has been dramatically increasing worldwide. Obesity is defined as abnormal or excessive fat accumulation that presents a significant danger to health, increasing the risk of type 2 diabetes, hypertension, and hyperlipidemia, among others. This metabolic disorder results from an imbalance in energy intake, energy expense, and fat aggregation [1]. Progression of obesity is followed by the development of a chronic inflammation promoted by the white adipose tissue and the influx of macrophages and T cells in this tissue. Among the several factors related to the progression and pathogenesis of obesity, many studies have speculated about the role of gut microbiota and non-alcoholic fatty liver disease (NAFLD). Alterations in gut microbial diversity, termed dysbiosis, have been associated with the development of obesity, and associated metabolic conditions
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