Abstract
Obesity is characterized by chronic low-grade, systemic inflammation, altered gut microbiota, and gut barrier disruption. Additionally, obesity is associated with increased activity of endocannabinoid system (eCB). However, the clear connection between gut microbiota and the eCB system in the regulation of energy homeostasis and adipose tissue inflammation and metabolism, remains to be established. We investigated the effect of treatment of mice with a cannabinoid receptor 1 (CB1) antagonist on Diet-Induced Obesity (DIO), specifically whether such a treatment that blocks endocannabinoid activity can induce changes in gut microbiota and anti-inflammatory state in adipose tissue. Blockade of CB1 attenuated DIO, inflammatory cytokines and trafficking of M1 macrophages into adipose tissue. Decreased inflammatory tone was associated with a lower intestinal permeability and decreased metabolic endotoxemia as evidenced by reduced plasma LPS level, and improved hyperglycemia and insulin resistance. 16S rRNA metagenomics sequencing revealed that CB1 blockade dramatically increased relative abundance of Akkermansia muciniphila and decreased Lanchnospiraceae and Erysipelotrichaceae in the gut. Together, the current study suggests that blocking of CB1 ameliorates Diet-Induced Obesity and metabolic disorder by modulating macrophage inflammatory mediators, and that this effect is associated with alterations in gut microbiota and their metabolites.
Highlights
The gut microbiome is the key feature in maintaining the whole body energy balance by affecting the glucose metabolism and low-grade chronic inflammation associated with obesity
To assess the effect of SR141716A beyond its effect on weight loss and calorie intake, pair-feeding was conducted in diet intake-matched control (PFSR), and food intake was adjusted in body weight-matched (BWM) controls (Fig. 1a)
To maintain the same body weight in body weight-matched (BWM) group as SR141716A-treated Diet-Induced Obesity (DIO) group (HFD + SR), their food was restricted to even lower intake level than SR141716A-treated Diet-Induced Obesity (DIO) group (HFD + SR) (Fig. 1b)
Summary
The gut microbiome is the key feature in maintaining the whole body energy balance by affecting the glucose metabolism and low-grade chronic inflammation associated with obesity. The microbial community of the gut consists of symbionts (beneficial), neutral (commensals) as well as detrimental (pathobionts) microorganisms The homeostasis of these essential allies can modulate the host health and function[4]. Metabolic endotoxemia and inflammation in obese mice may result from the chronically higher levels of lipopolysaccharide (LPS) and pro-inflammatory cytokines[9]. Numerous studies have demonstrated that diet-induced obesity and associated-inflammatory disorders may result from dysregulation of endocannabinoid (eCB) system. Alterations in gut endocannabinoid (eCB) system are implicated in the dysregulation of lipopolysaccharide (LPS) level, gut integrity disruption, chronic inflammatory state of the gut, and dysbiosis of gut microflora[15]. Lipopolysaccharide (LPS) causes robust production of endogenous ligands of cannabinoid receptors, Anandamide (arachidonylethanolamide, AEA) in adipose tissue macrophages, which contributes to exacerbation of chronic inflammation in visceral fat, hyperglycemia and insulin resistance[16]
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