The Effect of High-Fat Diet-Induced Pathophysiological Changes in the Gut on Obesity: What Should be the Ideal Treatment?

Abstract

Obesity is a metabolic disorder and fundamental cause of other fatal diseases including atherosclerosis and cancer. One of the main factor that contributes to the development of obesity is high-fat (HF) consumption. Lipid ingestion will initiate from the gut feedback mechanisms to regulate glucose and lipid metabolisms. But these lipid-sensing pathways are impaired in HF-induced insulin resistance, resulting in hyperglycemia. Besides that, duodenal lipid activates mucosal mast cells, leading to the disruption of the intestinal tight junction. Lipopolysaccharide that is co-transited with dietary fat postprandially, promotes the release of cytokines and the development of metabolic syndrome. HF-diet also alters microbiota composition and enhances fat storage. Although gut is protected by immune system and contains high level of antioxidants, obesity developed presumably when this protective mechanism is compromised by the presence of excessive fat. Several therapeutic approaches targeting different pathways have been proposed. There may be no one single most effective treatment, but all aimed to prevent obesity. This review will elaborate on the physiological and molecular changes in the gut that lead to obesity, and will provide a summary of potential treatments to manage these pathophysiological changes.

Figure 1

A multipronged mechanism that contributes to obesity development. (1) Luminal lipid activates gut lipid-sensing mechanisms to lower hepatic glucose production and maintain glucose homeostasis. These signaling pathways are suppressed by high-fat (HF) diet. (2) Interaction between microbiota and HF leads to the excessive release of adipocytokines, consequently obesity development. (3) As HF-diet increases 11β-HSD1 expression in the adipose tissues, which in turn promotes visceral obesity, it is likely that 11β-HSD1 enhances the release of adipocytokines, resulting in an effect similar to that observed between HF and microbiota. 11β-HSD1, 11β-hydroxysteroid dehydrogenase-1.