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


METHODS
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.


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
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.
Mooney
M H
MH
Strathclyde Institute of Pharmacy & Biomedical Sciences University of Strathclyde, Glasgow, UK.
Fogarty
S
S
Stevenson
C
C
Gallagher
A M
AM
Palit
P
P
Hawley
S A
SA
Hardie
D G
DG
Coxon
G D
GD
Waigh
R D
RD
Tate
R J
RJ
Harvey
A L
AL
Furman
B L
BL
D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004435:Eating / Q000187:drug effects*; D005227:Fatty Acids / Q000378:metabolism; D029881:Galega / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009097:Multienzyme Complexes / Q000187:drug effects* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D015431:Weight Loss / Q000187:drug effects*
D005227:Fatty Acids; D006146:Guanidines; D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D005947:Glucose; C074315:galegine