Melanocortin Receptor Signaling Modulates Anti-Obesity and Hypoglycemic Effects of Hafnia alvei 4597 Probiotic Strain in Mice

Objective. The present study aimed to elucidate if the metabolic effects of probiotic bacterium Hafnia alvei 4597 depend on the melanocortin receptors (MCRs) signaling. Methods. The response to a 3-week intragastric treatment with the H. alvei bacterial suspension or total protein extract was compared between genetically similar mouse sub-strains but with different sensitivity of MCRs, KK and KK.Cg-Ay/a (KK-Ay), the latter overproducing agouti protein. Results. Treatment of KK mice with H. alvei protein extract stimulated energy expenditure and carbohydrate oxidation but reduced lipid oxidation, leptin level, pancreatic weight, and hypothalamic insulin and leptin receptor mRNA expression. Live bacteria in KK mice reduced food intake and stimulated hypothalamic mRNA expression of proopiomelanocortin, agouti-related peptide, and insulin receptors. In the sub-strain KK-Ay, probiotics had no effect on the aforementioned metabolic parameters. H. alvei-based probiotics improved glucose tolerance and deceased body fat and liver glycogen in both mouse sub-strains. Activation of MC4R by H. alvei protein extract was revealed by in vitro study showing of β-arrestin recruitment. Conclusion. These findings confirm beneficial effects of the H. alvei bacteria and show that, for several parameters, the bacterial protein extract may be a more efficacious than bacterial suspension. Differential responses to the treatment between the mouse sub-strains, particularly in energy metabolism, as well as in vitro data, indicate that the effects of H. alvei are mediated by MCRs signaling.