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

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 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.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.

SUBMITTER: Mooney MH

PROVIDER: S-EPMC2438274 | biostudies-other | 2008 Apr

REPOSITORIES: biostudies-other

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Project description:ObjectiveTo characterize the contributions of the loss of energy-expending tissues and metabolic adaptations to the reduction in resting metabolic rate (RMR) following weight loss.MethodsA secondary analysis was conducted on data from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy study. Changes in RMR, body composition, and metabolic hormones were examined over 12 months of calorie restriction in 109 individuals. The contribution of tissue losses to the decline in RMR was determined by weighing changes in the size of energy-expending tissues and organs (skeletal muscle, adipose tissue, bone, brain, inner organs, residual mass) assessed by dual-energy X-ray absorptiometry with their tissue-specific metabolic rates. Metabolic adaptations were quantified as the remaining reduction in RMR.ResultsRMR was reduced by 101 ± 12 kcal/d as participants lost 7.3 ± 0.2 kg (both p < 0.001). On average, 60% of the total reduction in RMR were explained by energy-expending tissues losses, while 40% were attributed to metabolic adaptations. The loss of skeletal muscle mass (1.0 ± 0.7 kg) was not significantly related to RMR changes (r = 0.14, p = 0.16), whereas adipose tissue losses (7.2 ± 3.0 kg) were positively associated with the reduction in RMR (r = 0.42, p < 0.001) and metabolic adaptations (r = 0.31, p < 0.001). Metabolic adaptations were correlated with declines in leptin (r = 0.27, p < 0.01), triiodothyronine (r = 0.19, p < 0.05), and insulin (r = 0.25, p < 0.05).ConclusionsDuring weight loss, tissue loss and metabolic adaptations both contribute to the reduction in RMR, albeit variably. Contrary to popularly belief, it is not skeletal muscle, but rather adipose tissue losses that seem to drive RMR reductions following weight loss. Future research should target personalized strategies addressing the predominant cause of RMR reduction for weight maintenance.

Project description:Dietary intervention is a common tactic employed to curtail the current obesity epidemic. Changes in nutritional status alter metabolic hormones such as insulin or leptin, as well as the insulin-like growth factor (IGF) system, but little is known about restoration of these parameters after weight loss in obese subjects and if this differs between the sexes, especially regarding the IGF system. Here male and female mice received a high fat diet (HFD) or chow for 8 weeks, then half of the HFD mice were changed to chow (HFDCH) for 4 weeks. Both sexes gained weight (p < 0.001) and increased their energy intake (p < 0.001) and basal glycemia (p < 0.5) on the HFD, with these parameters normalizing after switching to chow but at different rates in males and females. In both sexes HFD decreased hypothalamic NPY and AgRP (p < 0.001) and increased POMC (p < 0.001) mRNA levels, with all normalizing in HFDCH mice, whereas the HFD-induced decrease in ObR did not normalize (p < 0.05). All HFD mice had abnormal glucose tolerance tests (p < 0.001), with males clearly more affected, that normalized when returned to chow. HFD increased insulin levels and HOMA index (p < 0.01) in both sexes, but only HFDCH males normalized this parameter. Returning to chow normalized the HFD-induced increase in circulating leptin (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.001, only in females) and IGFBP3 (p < 0.001), whereas free IGF1 levels remained elevated (p < 0.01). In males IGFBP2 decreased with HFD and normalized with chow (p < 0.001), with no changes in females. Although returning to a healthy diet improved of most metabolic parameters analyzed, fIGF1 levels remained elevated and hypothalamic ObR decreased in both sexes. Moreover, there was sex differences in both the response to HFD and the switch to chow including circulating levels of IGF2 and IGFBP2, factors previously reported to be involved in glucose metabolism. Indeed, glucose metabolism was also differentially modified in males and females, suggesting that these observations could be related.

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

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