Understanding gut structure and function associated with melanocortin obesity

Abstract

Male and female C57BL/6J mice develop obesity when desacetyl-α-MSH and α-MSH are genetically removed (Pomctm1/tm1 mice). Chronic high-fat (HF) diet induced sexually dimorphic obesity in wild-type (WT) C57BL/6J, but not in Pomctm1/tm1 mice; female WT mice were protected from developing obesity. Both gut structure and gut microbiota are known to contribute to body weight and glucose metabolism regulation and these effects are sexually dimorphic. Therefore, in my study, I propose Pomctm1/tm1 obesity is associated with altered gut morphology and altered gut microbiota in a sexually dimorphic way. This is the first study to investigate associations between Pomctm1/tm1 genotype, gut structure and gut microbiota, in response to a chronic HF diet. Pomctm1/tm1 mice were fed either lowfat (LF) or HF diets from weaning for 23 weeks. The first aim was to test associations between Pomctm1/tm1 genotype, HF diet and intestinal morphology using gut histology, and Western blots to assess lysozyme and occludin protein expression. Sex-specific associations were observed between Pomctm1/tm1 genotype or HF diet and intestinal morphology. Reduced jejunum villus length and increased crypt depth were observed in female WT mice in response to HF diet, while Pomctm1/tm1 males had higher lysozyme expression compared with WT males, when mice were fed a LF diet. The second aim was to test associations between Pomctm1/tm1 genotype, HF diet and gut microbiota using 16S rRNA gene sequencing. Both Pomctm1/tm1 genotype and HF diet were significantly associated with gut microbiota composition; sex-specific associations between Pomctm1/tm1 genotype and gut microbiota were observed in the presence of a HF diet. Finally, associations between Pomctm1/tm1 genotype, HF diet and short chain fatty acids (SCFAs) and branched chain amino acids (BCAAs) were tested using gas chromatography-mass spectrometry detection. Pomctm1/tm1 females had significantly reduced faecal acetic acid and propionic acid compared with WT females. Taken together, this study identifies sex-specific effects for the Pomctm1/tm1 genotype associated with gut structure and function and identifies a new research direction for studying melanocortin obesity involving the gut.