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

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-3 mM) 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.

AMP-activated protein kinase is activated in adipose tissue of individuals with type 2 diabetes treated with metformin: a randomised glycaemia-controlled crossover study

“…Prolonged stimulation with metformin reduced the fold stimulation of glucose transport by insulin, yet this was likely to have occurred because of a non-significant increase in basal glucose transport rather than a decrease in insulin-stimulated glucose transport. A previous study also reported a modest tendency toward increased basal glucose transport in 3T3-L1 adipocytes stimulated with 0.3 mmol/l metformin for 24 h [41]. The data in the current study represent, to the authors' knowledge, the first report of the effect of metformin on insulin-stimulated glucose transport in 3T3-L1 adipocytes.…”

AMP-activated protein kinase—an energy sensor that regulates all aspects of cell function

“…AMPK is also activated by numerous drugs and xenobiotics. Some of these are in clinical use for the treatment of type 2 diabetes (e.g., metformin [Zhou et al 2001] and thiazolidinediones ), some are ''nutraceuticals'' (e.g., resveratrol from red wine [Baur et al 2006] and epigallocatechin gallate from green tea [Hwang et al 2007]), and some are plant products used in traditional herbal medicines in Europe (e.g., galegine, from which metformin was originally derived) (Mooney et al 2008) or Asia (e.g., berberine [Lee et al 2006] and hispidulin [Lin et al 2010]). One puzzling feature was how so many xenobiotics of very varied structure could all activate AMPK; it seemed unlikely that they would all bind directly to the kinase complex.…”

AMP-activated protein kinase pathway and bone metabolism

“…Many natural products derived from traditional medicine that were claimed to have beneficial effects in diabetes and cancer can also activate AMPK. They include resveratrol, epigallocathechin gallate, berberine, and quercitine (Mooney et al 2008, Turner et al 2008. Recent years have shown the development of novel pharmacological agents that can modulate AMPK directly with the hope that these compounds will be promising in the treatment of metabolic disorders.…”