Abstract
Treatment with a nicotinamide N-methyltransferase inhibitor (NNMTi; 5-amino-1-methylquinolinium) combined with low-fat diet (LD) promoted dramatic whole-body adiposity and weight loss in diet-induced obese (DIO) mice, rapidly normalizing these measures to age-matched lean animals, while LD switch alone was unable to restore these measures to age-matched controls in the same time frame. Since mouse microbiome profiles often highly correlate with body weight and fat composition, this study was designed to test whether the cecal microbiomes of DIO mice treated with NNMTi and LD were comparable to the microbiomes of age-matched lean counterparts and distinct from microbiomes of DIO mice maintained on a high-fat Western diet (WD) or subjected to LD switch alone. There were minimal microbiome differences between lean and obese controls, suggesting that diet composition and adiposity had limited effects. However, DIO mice switched from an obesity-promoting WD to an LD (regardless of treatment status) displayed several genera and phyla differences compared to obese and lean controls. While alpha diversity measures did not significantly differ between groups, beta diversity principal coordinates analyses suggested that mice from the same treatment group were the most similar. K-means clustering analysis of amplicon sequence variants by animal demonstrated that NNMTi-treated DIO mice switched to LD had a distinct microbiome pattern that was highlighted by decreased Erysipelatoclostridium and increased Lactobacillus relative abundances compared to vehicle counterparts; these genera are tied to body weight and metabolic regulation. Additionally, Parasutterella relative abundance, which was increased in both the vehicle- and NNMTi-treated LD-switched groups relative to the controls, significantly correlated with several adipose tissue metabolites’ abundances. Collectively, these results provide a novel foundation for future investigations.
Highlights
Treatment with a nicotinamide N-methyltransferase inhibitor (NNMTi; 5-amino-1-methylquinolinium) combined with low-fat diet (LD) promoted dramatic whole-body adiposity and weight loss in diet-induced obese (DIO) mice, rapidly normalizing these measures to age-matched lean animals, while LD switch alone was unable to restore these measures to age-matched controls in the same time frame
LD alone, failed to improve obesity-linked liver pathologies[13]. Given that both diet composition and adiposity can each substantially impact the gut microflora in obese m ice[24], we conducted a secondary endpoint study using animals given the same series of diets to test the hypothesis that NNMTi treatment combined with LD, but not LD alone, shifts the cecal microbiome profile of obese animals to be similar to age-matched LD controls that were never given a high-fat diet
Obese mice had significantly higher body weights than mice continuously maintained on LD
Summary
Treatment with a nicotinamide N-methyltransferase inhibitor (NNMTi; 5-amino-1-methylquinolinium) combined with low-fat diet (LD) promoted dramatic whole-body adiposity and weight loss in diet-induced obese (DIO) mice, rapidly normalizing these measures to age-matched lean animals, while LD switch alone was unable to restore these measures to age-matched controls in the same time frame. Parasutterella relative abundance, which was increased in both the vehicle- and NNMTi-treated LD-switched groups relative to the controls, significantly correlated with several adipose tissue metabolites’ abundances These results provide a novel foundation for future investigations. LD alone, failed to improve obesity-linked liver pathologies[13] Given that both diet composition and adiposity can each substantially impact the gut microflora in obese m ice[24], we conducted a secondary endpoint study using animals given the same series of diets to test the hypothesis that NNMTi treatment combined with LD, but not LD alone, shifts the cecal microbiome profile of obese animals to be similar to age-matched LD controls that were never given a high-fat diet. This study used the NNMTi 5-amino-1-methylquinolinium (5A-M1Q), since our lab has set precedence using this probe molecule for proof-of-concept studies[8]
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