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

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

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    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 mM-3mM) stimulated glucose uptake. Galegine (1-300 mM) also reduced isoprenaline-mediated lipolysis in 3T3-L1 adipocytes and inhibited acetylCoA carboxylase activity in 3T3-L1 adipocytes and L6 myotubes. Galegine (500 mM) down-regulated genes concerned with fatty acid synthesis, including fatty acid synthase and its upstream regulator SREBP. Galegine (10 mM 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.

    Original languageEnglish
    Pages (from-to)1669-1677
    Number of pages9
    JournalBritish Journal of Pharmacology
    Volume153
    Issue number8
    DOIs
    Publication statusPublished - 2008

    Keywords

    • galegine
    • 3T3-L1 adipocytes
    • L6 myotubes
    • glucose uptake
    • acetyl CoA carboxylase
    • AMPK
    • ACTIVATED PROTEIN-KINASE
    • ACETYL-COA CARBOXYLASE
    • SKELETAL-MUSCLE
    • GLUCOSE-TRANSPORT
    • PHOSPHOINOSITIDE 3-KINASE
    • ARGININE DERIVATIVES
    • GLUT4 TRANSLOCATION
    • RESPIRATORY-CHAIN
    • AMPK ACTIVATION
    • ADIPOSE-TISSUE

    Cite this

    Mooney, M. H., Fogarty, S., Stevenson, C., Gallagher, A. M., Palit, P., Hawley, S. A., Hardie, D. G., Coxon, G. D., Waigh, R. D., Tate, R. J., Harvey, A. L., & Furman, B. L. (2008). Mechanisms underlying the metabolic actions of galegine that contribute to weight loss in mice. British Journal of Pharmacology, 153(8), 1669-1677. https://doi.org/10.1038/bjp.2008.37