Regulation of Obesity-Related Insulin Resistance with Gut Anti-inflammatory Agents

Abstract

Obesity has reached epidemic proportions, but little is known about its influence on the intestinal immune system. Here we show that the gut immune system is altered during high-fat diet (HFD) feeding and is a functional regulator of obesity-related insulin resistance (IR) that can be exploited therapeutically. Obesity induces a chronic phenotypic pro-inflammatory shift in bowel lamina propria immune cell populations. Reduction of the gut immune system, using beta7 integrin-deficient mice (Beta7(null)), decreases HFD-induced IR. Treatment of wild-type HFD C57BL/6 mice with the local gut anti-inflammatory, 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters. These beneficial effects are dependent on adaptive and gut immunity and are associated with reduced gut permeability and endotoxemia, decreased visceral adipose tissue inflammation, and improved antigen-specific tolerance to luminal antigens. Thus, the mucosal immune system affects multiple pathways associated with systemic IR and represents a novel therapeutic target in this disease.

Effect of anti-gut inflammatory agent on insulin resistance and lipid profile of mice fed different diets

“…Additionally, HFD+5-ASA-fed mice showed reduced liver steatosis when compared to HFD [9]. A similar downtrend in hepatic and plasma lipid levels in mice given 5-ASA+HFD, especially in mice fed HFC.…”

“…At the end of 12-weeks diet intervention, fat or lean mass was analyzed (the machine model is Bruker Minispec Whole Body Composition Analyzer). Fresh fecal samples were collected before treatment and after 3 weeks of diet intervention to conduct gut microbiome sequencing [9] .…”

“…Recently, a mice study suggested that targeting gut inflammation with 5-aminosalicylic acid (5-ASA) reversed intestinal inflammatory response and improved systemic IR [9], but no data on lipid profile was presented [9]. 5-Aminosalicylic acid (5-ASA) is a notable agent which exert its anti-inflammation function mainly in the gut.…”

“…To get more insight into this question in the present study, mice experiment was set up using the same diet composition as in the study by Luck et al did [9]. C57BL/6J mice were then used in our experiments, randomly assigned 6 groups of mice to LFD or HFD or HFC with or without 5-ASA supplementation at 1500 mg/kg/day for 12 weeks.…”

Cryopreserved Interleukin-4-Treated Macrophages Attenuate Murine Colitis in an Integrin β7-Dependent Manner

“…Observation of the anticolitic effect of M(IL-4)s in RAG1 -/-mice suggested that activity in the peritoneal cavity or the gut may be important to the inhibition of disease. The integrin α4β7 is important for homing to the gut via interaction with the mucosal addressin, MAdCAM (38,39), and αEβ7 interaction with E-cadherin in the gut mucosa can facilitate the retention of T cells (40). Use of M(IL-4)s differentiated from the bone marrow of Itgb7 knockout (KO) mice failed to suppress DNBS-induced colitis, identifying mucosal homing of M(IL-4)s as being critical to their ability to suppress inflammation in this model of colitis.…”