Combined nicotinamide N-methyltransferase inhibition and reduced-calorie diet normalizes body composition and enhances metabolic benefits in obese mice

Catherine M Sampson,Heather L Stevenson,Andrea L Dimet,Kehinde O Ogunseye,Stanley J Watowich,Harshini Neelakantan,Jonathan D Hommel

doi:10.1038/s41598-021-85051-6

Catherine M Sampson, Heather L Stevenson + Show 5 more

Open Access

https://doi.org/10.1038/s41598-021-85051-6

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Abstract

Obesity is a large and growing global health problem with few effective therapies. The present study investigated metabolic and physiological benefits of nicotinamide N-methyltransferase inhibitor (NNMTi) treatment combined with a lean diet substitution in diet-induced obese mice. NNMTi treatment combined with lean diet substitution accelerated and improved body weight and fat loss, increased whole-body lean mass to body weight ratio, reduced liver and epididymal white adipose tissue weights, decreased liver adiposity, and improved hepatic steatosis, relative to a lean diet substitution alone. Importantly, combined lean diet and NNMTi treatment normalized body composition and liver adiposity parameters to levels observed in age-matched lean diet control mice. NNMTi treatment produced a unique metabolomic signature in adipose tissue, with predominant increases in ketogenic amino acid abundance and alterations to metabolites linked to energy metabolic pathways. Taken together, NNMTi treatment’s modulation of body weight, adiposity, liver physiology, and the adipose tissue metabolome strongly support it as a promising therapeutic for obesity and obesity-driven comorbidities.

Highlights

The ever-increasing global incidence of obesity, a disorder characterized by excessive whole-body adiposity, is a major wellness, healthcare, and economic concern
Reduced calorie intake with the lean diet (LD) switch resulted in an initial body weight loss that plateaued with a slight weight regain thereafter in Western diet (WD)/LD-V mice
WD/LD-T mice exhibited accelerated body weight and fat loss that robustly persisted through the study that was statistically significant different compared to LD switch alone and nearly indistinguishable from the LD/LD-V group by body weight and whole-body fat mass levels (Fig. 1b,c; Supplementary Table S1)

Summary

Introduction

The ever-increasing global incidence of obesity, a disorder characterized by excessive whole-body adiposity, is a major wellness, healthcare, and economic concern. NNMT activity is dramatically increased in the WAT of diet-induced obese (DIO) m ice[22], and its mRNA expression is increased in both the omental and subcutaneous adipose tissues of individuals with T2D14. 5-amino-1-methylquinolinium is an NNMT-selective probe small molecule inhibitor compound with an IC50 ~ 1μM23; this NNMTi displays favorable drug-like characteristics including high aqueous solubility, amenable passive permeability and active transport, target engagement both in vitro (e.g., adipocytes) and in vivo (e.g., murine adipose tissue), cross-species liver metabolic stability, and substantial systemic exposure and pharmacokinetic profile[12,23]; the latter three are known in part from unpublished work. In the comprehensive study described we analyze the effect of NNMTi treatment combined with a reduced-calorie diet (lean diet, LD) on body weight, body composition, obesity-associated liver pathologies, and the WAT metabolomic profile in a mouse model of diet-induced obesity

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