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Mechanisms underlying the metabolic actions of galegine that contribute to weight loss in mice
Author(s) -
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
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.37
Subject(s) - acetyl coa carboxylase , ampk , endocrinology , lipolysis , medicine , 3t3 l1 , protein kinase a , adipocyte , fatty acid synthase , fatty acid synthesis , pyruvate carboxylase , amp activated protein kinase , beta oxidation , fatty acid , glucose uptake , biology , lipogenesis , myogenesis , chemistry , biochemistry , adipose tissue , metabolism , kinase , lipid metabolism , skeletal muscle , enzyme , insulin
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 μ M ‐3 m M ) stimulated glucose uptake. Galegine (1–300 μ M ) also reduced isoprenaline‐mediated lipolysis in 3T3‐L1 adipocytes and inhibited acetyl‐CoA carboxylase activity in 3T3‐L1 adipocytes and L6 myotubes. Galegine (500 μ M ) down‐regulated genes concerned with fatty acid synthesis, including fatty acid synthase and its upstream regulator SREBP. Galegine (10 μ M 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. British Journal of Pharmacology (2008) 153 , 1669–1677; doi: 10.1038/bjp.2008.37 ; published online 25 February 2008