The molecular and metabolic influence of long term agmatine consumption

J Biol Chem. 2014 Apr 4;289(14):9710-29. doi: 10.1074/jbc.M113.544726. Epub 2014 Feb 12.


Agmatine (AGM), a product of arginine decarboxylation, influences multiple physiologic and metabolic functions. However, the mechanism(s) of action, the impact on whole body gene expression and metabolic pathways, and the potential benefits and risks of long term AGM consumption are still a mystery. Here, we scrutinized the impact of AGM on whole body metabolic profiling and gene expression and assessed a plausible mechanism(s) of AGM action. Studies were performed in rats fed a high fat diet or standard chow. AGM was added to drinking water for 4 or 8 weeks. We used (13)C or (15)N tracers to assess metabolic reactions and fluxes and real time quantitative PCR to determine gene expression. The results demonstrate that AGM elevated the synthesis and tissue level of cAMP. Subsequently, AGM had a widespread impact on gene expression and metabolic profiling including (a) activation of peroxisomal proliferator-activated receptor-α and its coactivator, PGC1α, and (b) increased expression of peroxisomal proliferator-activated receptor-γ and genes regulating thermogenesis, gluconeogenesis, and carnitine biosynthesis and transport. The changes in gene expression were coupled with improved tissue and systemic levels of carnitine and short chain acylcarnitine, increased β-oxidation but diminished incomplete fatty acid oxidation, decreased fat but increased protein mass, and increased hepatic ureagenesis and gluconeogenesis but decreased glycolysis. These metabolic changes were coupled with reduced weight gain and a curtailment of the hormonal and metabolic derangements associated with high fat diet-induced obesity. The findings suggest that AGM elevated the synthesis and levels of cAMP, thereby mimicking the effects of caloric restriction with respect to metabolic reprogramming.

Keywords: Adenylate Cyclase (Adenylyl Cyclase); Carbohydrate Metabolism; Carnitine; Cyclic AMP (cAMP); Fatty Acid Oxidation; Insulin Resistance; Liver; Metabolic Syndrome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Agmatine / pharmacokinetics
  • Agmatine / pharmacology*
  • Animals
  • Biological Transport, Active / drug effects
  • Carnitine / analogs & derivatives
  • Carnitine / metabolism
  • Cyclic AMP / metabolism*
  • Dietary Fats / adverse effects
  • Dietary Fats / pharmacology
  • Fatty Acids / metabolism*
  • Gene Expression Regulation / drug effects
  • Gluconeogenesis / drug effects*
  • Humans
  • Liver / metabolism*
  • Male
  • Metabolome
  • Obesity / chemically induced
  • Obesity / drug therapy*
  • Obesity / metabolism
  • Oxidation-Reduction / drug effects
  • PPAR gamma / biosynthesis
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • Transcription Factors / biosynthesis


  • Dietary Fats
  • Fatty Acids
  • PPAR gamma
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, rat
  • Transcription Factors
  • acylcarnitine
  • Agmatine
  • Cyclic AMP
  • Carnitine