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, Geoffrey Coxon, Roger Waigh, R. Tate, Alan Harvey, Brian Furman

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45 Citations (Scopus)

Abstract

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. 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. 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 acetyl-CoA 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. 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 - Apr 2008

Keywords

  • galegine
  • 3T3-L1 adipocytes
  • L6 myotubes
  • glucose uptake
  • acetyl CoA carboxylase
  • AMPK

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