The model of litter size reduction induces long‐term disruption of the gut‐brain axis: An explanation for the hyperphagia of Wistar rats of both sexes

Abstract

The gut microbiota affects the host's metabolic phenotype, impacting health and disease. The gut‐brain axis unites the intestine with the centers of hunger and satiety, affecting the eating behavior. Deregulation of this axis can lead to obesity onset. Litter size reduction is a well‐studied model for infant obesity because it causes overnutrition and programs for obesity. We hypothesize that animals raised in small litters (SL) have altered circuitry between the intestine and brain, causing hyperphagia. We investigated vagus nerve activity, the expression of c‐Fos, brain‐derived neurotrophic factor (BDNF), gastrointestinal (GI) hormone receptors, and content of bacterial phyla and short‐chain fatty acids (SCFAs) in the feces of adult male and female Wistar rats overfed during lactation. On the 3rd day after birth, litter size was reduced to 3 pups/litter (SL males or SL females) until weaning. Controls had normal litter size (10 pups/litter: 5 males and 5 females). The rats were killed at 5 months of age. The male and female offspring were analyzed separately. The SL group of both sexes showed higher food consumption and body adiposity than the respective controls. SL animals presented dysbiosis (increased Firmicutes , decreased Bacteroidetes ) and had increased vagus nerve activity. Only the SL males had decreased hypothalamic GLP‐1 receptor expression, while only the SL females had lower acetate and propionate in the feces and higher CCK receptor expression in the hypothalamus. Thus, overfeeding during lactation differentially changes the gut‐brain axis, contributing to hyperphagia of the offspring of both sexes.

Gut-derived peptide hormone receptor expression in the developing mouse hypothalamus

“…Interestingly, lower levels of fasting GLP-1 in adult overweight offspring exposed to maternal diabetes have also been reported [ 27 ]. In rodents, maternal overnutrition during lactation reduced GLP-1R expression in the hypothalamus of male offspring, while higher CCK-R expression in the hypothalamus of females was present [ 54 ], suggesting that the gut-brain axis might be disrupted by early postnatal overfeeding. Further, alterations in GLP1R expression are also linked with disrupted postnatal development of pancreatic beta cells, compounding the potential effects on offspring glucose homeostasis capacity [ 55 ].…”

Litter Size Reduction as a Model of Overfeeding during Lactation and Its Consequences for the Development of Metabolic Diseases in the Offspring

“…In adult SL males, the lower expression of the glucagon-like peptide 1 (GLP-1) receptor in the ARC may impair the satiety role of GLP-1. Despite the paradoxical CCK1-R overexpression in the ARC, the female SL offspring have lower acetate and propionate contents in their feces, which may impair PYY secretion [ 86 ]. These different changes may favor hyperphagic behavior in both sexes.…”

“…These different changes may favor hyperphagic behavior in both sexes. Additionally, male and female offspring exhibit dysbiosis (higher abundance of the phylum Firmicutes , lower abundance of Bacteroidetes ), which per se may impair energy metabolism [ 86 ], appearing before puberty [ 87 ] and being maintained until adult life [ 86 ].…”