Abstract
The hypothalamus regulates energy homeostasis by integrating environmental and internal signals to produce behavioral responses to start or stop eating. Many satiation signals are mediated by microbiota-derived metabolites coming from the gastrointestinal tract and acting also in the brain through a complex bidirectional communication system, the microbiota–gut–brain axis. In recent years, the intestinal microbiota has emerged as a critical regulator of hypothalamic appetite-related neuronal networks. Obesogenic high-fat diets (HFDs) enhance endocannabinoid levels, both in the brain and peripheral tissues. HFDs change the gut microbiota composition by altering the Firmicutes:Bacteroidetes ratio and causing endotoxemia mainly by rising the levels of lipopolysaccharide (LPS), the most potent immunogenic component of Gram-negative bacteria. Endotoxemia induces the collapse of the gut and brain barriers, interleukin 1β (IL1β)- and tumor necrosis factor α (TNFα)-mediated neuroinflammatory responses and gliosis, which alter the appetite-regulatory circuits of the brain mediobasal hypothalamic area delimited by the median eminence. This review summarizes the emerging state-of-the-art evidence on the function of the “expanded endocannabinoid (eCB) system” or endocannabinoidome at the crossroads between intestinal microbiota, gut-brain communication and host metabolism; and highlights the critical role of this intersection in the onset of obesity.
Highlights
Obesity is characterized by changes in gut microbiota, the onset of low-grade inflammation and increased endocannabinoid tone
In view of the above data, these results suggest that consumption of high-fat diets (HFDs) has a major repercussion on the cytoarchitecture of the hypothalamus in susceptible subjects, with changes that could lead to reactive gliosis (RG) partly due to activation of the M1 phenotype of microglia
Mounting evidence is revealing the effects of diet composition on the gut microbiota and microbiota-derived metabolites with consequent impact on brain function
Summary
Obesity is characterized by changes in gut microbiota, the onset of low-grade inflammation and increased endocannabinoid tone. Dysbiosis is typically featured by one or more of the following non-mutually exclusive aspects: loss of diversity, loss of commensals and bloom of pathobionts [14] It is usually characterized by a reduction in the Bacteroidetes/Firmicutes ratio and predominance in taxa causing enteric mucus degradation, thinning of the intestinal barrier and increased gut permeability or gut leakiness [7,9,10,14,15], associated with low-grade chronic inflammation of the intestinal mucosa. Seminal studies demonstrated that: (i) infusion of LPS had effects similar to those of a high-fat diet (HFD) at increasing fasting glycaemia, insulinemia and whole-body, hepatic and adipose tissue weight gain; (ii) LPS and endocannabinoid levels are positive correlated [16,17], because of the downregulation of gene expression of acid amide hydrolase (FAAH, the enzyme that degrades AEA) and N-acylethanolamines (NAEs, congeners of AEA) [18]; and (iii) gut dysbiosis and the eCB system are both involved in adipogenesis through a LPS-dependent neuroinflammatory mechanism under obesity-related conditions. These strategies include dietary manipulation, such as the use of prebiotics, probiotics or symbiotics, as well as the transplantation of intestinal/fecal microbial communities
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