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

M. H. Mooney, S. Fogarty, C. Stevenson, Alison Gallagher, P. Palit, S. A. Hawley, D. G. Hardie, G. D. Coxon, R. D. Waigh, R. J. Tate, A. L. Harvey, B. L. Furman

Research output: Contribution to journalArticle

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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.
LanguageEnglish
Pages1669-1677
JournalBritish Journal of Pharmacology
Volume153
Issue number8
DOIs
Publication statusPublished - Apr 2008

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Weight Loss
Adipocytes
Skeletal Muscle Fibers
Acetyl-CoA Carboxylase
AMP-Activated Protein Kinases
Fatty Acids
Body Weight
Glucose
Galega
Eating
3T3-L1 Cells
Biguanides
galegine
Fatty Acid Synthases
Lipolysis
Guanidine
Isoproterenol
Hepatocellular Carcinoma
Fats
Diet

Cite this

Mooney, M. H., Fogarty, S., Stevenson, C., Gallagher, A., Palit, P., Hawley, S. A., ... 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
Mooney, M. H. ; Fogarty, S. ; Stevenson, C. ; Gallagher, Alison ; Palit, P. ; Hawley, S. A. ; Hardie, D. G. ; Coxon, G. D. ; Waigh, R. D. ; Tate, R. J. ; Harvey, A. L. ; Furman, B. L. / Mechanisms underlying the metabolic actions of galegine that contribute to weight loss in mice. In: British Journal of Pharmacology. 2008 ; Vol. 153, No. 8. pp. 1669-1677.
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Mooney, MH, Fogarty, S, Stevenson, C, Gallagher, A, Palit, P, Hawley, SA, Hardie, DG, Coxon, GD, Waigh, RD, Tate, RJ, Harvey, AL & Furman, BL 2008, 'Mechanisms underlying the metabolic actions of galegine that contribute to weight loss in mice', British Journal of Pharmacology, vol. 153, no. 8, pp. 1669-1677. https://doi.org/10.1038/bjp.2008.37

Mechanisms underlying the metabolic actions of galegine that contribute to weight loss in mice. / Mooney, M. H.; Fogarty, S.; Stevenson, C.; Gallagher, Alison; Palit, P.; Hawley, S. A.; Hardie, D. G.; Coxon, G. D.; Waigh, R. D.; Tate, R. J.; Harvey, A. L.; Furman, B. L.

In: British Journal of Pharmacology, Vol. 153, No. 8, 04.2008, p. 1669-1677.

Research output: Contribution to journalArticle

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T1 - Mechanisms underlying the metabolic actions of galegine that contribute to weight loss in mice

AU - Mooney, M. H.

AU - Fogarty, S.

AU - Stevenson, C.

AU - Gallagher, Alison

AU - Palit, P.

AU - Hawley, S. A.

AU - Hardie, D. G.

AU - Coxon, G. D.

AU - Waigh, R. D.

AU - Tate, R. J.

AU - Harvey, A. L.

AU - Furman, B. L.

PY - 2008/4

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N2 - 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.

AB - 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.

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DO - 10.1038/bjp.2008.37

M3 - Article

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EP - 1677

JO - British Journal of Pharmacology

T2 - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

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