Perinatal high-fat diet induces systemic inflammation via altered tight junction complex organization during development and decreases expression of intestinal satiety peptides in male offspring.

Abstract

Objective Epidemiological evidence suggests that maternal obesity increases risk for offspring obesity and comorbidities, pointing to the significance of critical periods of development. Adverse metabolic effects of high fat (HF) diet consumption on the gut microbiome and inflammation have been well documented in obesity models. Emerging evidence demonstrates that the gut microbiome may play a role in transgenerational obesity, however, underlying mechanisms still need to be elucidated to identify intervention targets. Methods A rat model was used to demonstrate whether maternal HF diet during gestation and lactation results in gut-brain axis deficits in rat offspring. Gene expression of small intestinal satiety hormones and C-fiber innervation in the nucleus of the solitary tract (NTS) were measured in adult offspring. At weaning, circulating inflammatory mediators and colonic microbial metabolites were measured in offspring. Results In adulthood, HF males had reduced vagal innervation in the NTS and reduced small intestinal expression of CCK, GLP-1, and PYY. At weaning, HF offspring had elevated levels of CRP and IL-1{beta} and depleted levels of microbially produced colonic short chain fatty acids (SCFAs), which are critical for maintaining intestinal barrier function. HF males had reduced colocalization between tight junction proteins, Claudin-1 and ZO-1 at weaning, while HF females did not. Conclusion Disorganization of tight junction complexes in HF male offspring during development may play a role in the gut-brain axis deficits seen in HF males in adulthood. Together, these data demonstrate that inflammation-induced by HF diet can negatively impact gut-brain axis development and function.