Mechanisms underlying the metabolic actions of galegine that contribute to weight loss in mice.

Abstract

BACKGROUND AND PURPOSE:

Galegine and guanidine, originally isolated from Galega officinalis, led to the development of the biguanides. The weight-reducing effects of galegine have not previously been studied and the present investigation was undertaken to determine its mechanism(s) of action.

EXPERIMENTAL APPROACH:

Body weight and food intake were examined in mice. Glucose uptake and acetyl-CoA carboxylase activity were studied in 3T3-L1 adipocytes and L6 myotubes and AMP activated protein kinase (AMPK) activity was examined in cell lines. The gene expression of some enzymes involved in fat metabolism was examined in 3T3-L1 adipocytes.

KEY RESULTS:

Galegine administered in the diet reduced body weight in mice. Pair-feeding indicated that at least part of this effect was independent of reduced food intake. In 3T3-L1 adipocytes and L6 myotubes, galegine (50 microM-3 mM) stimulated glucose uptake. Galegine (1-300 microM) also reduced isoprenaline-mediated lipolysis in 3T3-L1 adipocytes and inhibited acetyl-CoA carboxylase activity in 3T3-L1 adipocytes and L6 myotubes. Galegine (500 microM) down-regulated genes concerned with fatty acid synthesis, including fatty acid synthase and its upstream regulator SREBP. Galegine (10 microM and above) produced a concentration-dependent activation of AMP activated protein kinase (AMPK) in H4IIE rat hepatoma, HEK293 human kidney cells, 3T3-L1 adipocytes and L6 myotubes.

CONCLUSIONS AND IMPLICATIONS:

Activation of AMPK can explain many of the effects of galegine, including enhanced glucose uptake and inhibition of acetyl-CoA carboxylase. Inhibition of acetyl-CoA carboxylase both inhibits fatty acid synthesis and stimulates fatty acid oxidation, and this may to contribute to the in vivo effect of galegine on body weight.

• Authors: M H Mooney, S Fogarty, C Stevenson, A M Gallagher, P Palit, S A Hawley, D G Hardie, G D Coxon, R D Waigh, R J Tate, A L Harvey, B L Furman
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 153 Issue 8 Pg. 1669-77 (Apr 2008) ISSN: 0007-1188 [Print] England
• PMID: 18297106 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fatty Acids
• Guanidines
• Multienzyme Complexes
• Protein Serine-Threonine Kinases
• AMP-Activated Protein Kinases
• Acetyl-CoA Carboxylase
• Glucose
• galegine

Topics

• AMP-Activated Protein Kinases
• Acetyl-CoA Carboxylase (antagonists & inhibitors, metabolism)
• Animals
• Cell Line
• Eating (drug effects)
• Fatty Acids (metabolism)
• Galega (chemistry)
• Gene Expression Regulation, Enzymologic (drug effects)
• Glucose (metabolism)
• Guanidines (pharmacology)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Multienzyme Complexes (drug effects, metabolism)
• Protein Serine-Threonine Kinases (drug effects, metabolism)
• Rats
• Weight Loss (drug effects)