Desacetyl-α-MSH and α-MSH have sex specific interactions with diet to influence mouse gut morphology, metabolites and microbiota.

The melanocortin peptides have an important role in regulating body weight and appetite. Mice that lack the desacetyl-α-MSH and α-MSH peptides (Pomc) develop obesity. This effect is exacerbated by a high fat diet (HFD). However, development of obesity in female Pomc mice during chronic HFD conditions is not fully accounted for by the increased energy intake. We hypothesized that the protection against chronic HFD-induced obesity imparted by MSH peptides in females is mediated by sex-specific alterations in the gut structure and gut microbiota. We determined that female WT mice had reduced jejunum villus length and increased crypt depth in response to chronic HFD. WT males and Pomc mice lacked this adaptation to a chronic HFD. Both Pomc genotype and chronic HFD were significantly associated with gut microbiota composition. Sex-specific associations between Pomc genotype and gut microbiota were observed in the presence of a chronic HFD. Pomc females had significantly reduced fecal acetate and propionate concentrations when compared to WT females. We conclude that MSH peptides influence jejunum villus length, crypt depth and the structure of the gut microbiota. These effects favor reduced nutrient absorption and occur in addition to the recognized roles of desacetyl-α-MSH and α-MSH peptides in appetite control.