PMID-29155147 – 5-Amino-1MQ Reverses High Fat Diet Obesity in Mice
Neelakantan H, Wang HY, Vance V, Hommel JD, McHardy SF, Watowich SJ. Structure-activity relationship for small molecule inhibitors of nicotinamide N-methyltransferase. J Med Chem… Biochem Pharmacol. 2018;147:141-152.
Quick Reference
| Property | Value |
|---|---|
| PMID | 29155147 |
| DOI | 10.1016/j.bcp.2017.11.007 |
| Year | 2018 |
| Journal | Biochemical Pharmacology |
| Study Type | Animal in vivo |
| Evidence Level | V |
| Sample | Diet-induced obese (DIO) C57BL/6 mice |
| Peptide(s) Studied | 5-Amino-1MQ |
Key Findings
- LANDMARK STUDY: First demonstration that 5-Amino-1MQ (a potent NNMT inhibitor) reverses diet-induced obesity in mice
- Treatment significantly reduced body weight and white adipose tissue (WAT) mass without affecting food intake
- Reduced plasma total cholesterol levels in treated animals
- Mechanism: NNMT inhibition reduced 1-methylnicotinamide (1-MNA) levels, increased intracellular NAD+ and S-adenosylmethionine (SAM) concentrations
- Downstream effects included suppression of de novo lipogenesis pathways
- 5-Amino-1MQ was identified as the most potent compound in a structure-activity relationship series of NNMT inhibitors
Study Design
C57BL/6 mice were fed a high-fat diet to induce obesity. After obesity establishment, mice received daily 5-Amino-1MQ treatment. Body weight, food intake, fat pad weights, plasma lipids, and intracellular metabolite levels (NAD+, SAM, 1-MNA) were measured. Structure-activity relationships were explored across a series of NNMT inhibitor analogs to identify the optimal compound.
Limitations
- Single mouse strain and obesity model (DIO) used
- Relatively short treatment duration
- No detailed toxicology or organ pathology assessment reported
- Pharmacokinetic profile not fully characterized in this study
- Mechanism was inferred from metabolite measurements rather than direct enzymatic assays in vivo
Clinical Relevance
This landmark study established 5-Amino-1MQ as a first-in-class NNMT inhibitor with anti-obesity effects. The mechanism is distinct from existing anti-obesity drugs — by modulating the NAD+/SAM/1-MNA axis, 5-Amino-1MQ addresses obesity at the metabolic programming level rather than through appetite suppression or nutrient malabsorption. The fact that weight loss occurred without reduced food intake is clinically attractive for patient compliance. This study provided the foundational rationale for 5-Amino-1MQ as a metabolic therapeutic.
Related
#research #animal-in-vivo #5-Amino-1MQ #evidence-level-V