Calorie Restriction and Gastric Bypass Effects on FGF21
Objective To study the effect of different weight loss strategies on levels of the metabolic regulator FGF21 in morbidly obese females with normal glucose tolerance (NGT) or type 2 diabetes mellitus (T2DM).
Design Observational intervention trial.
Patients and measurements Weight reduction was achieved by Gastric Banding (GB,n = 11) or Roux-en-Y Gastric Bypass (RYGB,n = 16) in subjects with NGT, and by RYGB (n = 15) or a very-low-calorie diet (VLCD,n = 12) in type 2 diabetics. Fasted and/or postprandial levels of FGF21, FGF19 (an FGF21-related postprandial hormone) and bile salts (implicated in regulation of FGF21 and FGF19 expression) were measured before, and 3 and 12 weeks after intervention.
Results Fasted FGF21 levels were elevated in T2DM subjects. Calorie restriction by either GB or VLCD lowered bile salt and FGF21 levels. In contrast, RYGB surgery was associated with elevated bile salt and FGF21 levels.
Conclusions Calorie restriction and RYGB have opposite effects on serum bile salt and FGF21 levels. Calorie restriction results in FGF21 approaching nonobese control levels, suggesting that this intervention is effective in reducing the "nutritional crisis" that appears to underly FGF21 elevation in obesity. FGF21 elevation after RYGB may contribute to the beneficial effect of this procedure.
Fibroblast growth factors (FGF) 19 and 21 have been attributed diverse hormone-like metabolic functions. FGF21 has metabolic roles in both the fed and food-deprived state, with its expression regulated by both fasting (e.g. glucagon) and feeding (e.g. bile salts) signals. It is expressed mainly in the liver and white adipose tissue (WAT) where its transcription is regulated by peroxisome proliferator activating receptor (PPAR) alpha and PPARγ, respectively. In response to starvation, FGF21 mediates the effects of starvation-activated PPARα on hepatic lipid oxidation and ketogenesis, and inhibition of WAT lipolysis. In the fed state, FGF21 expression is induced in WAT where it regulates insulin-independent glucose uptake and mitochondrial oxidation. The regulation of FGF21 by fasting and feeding signals has led to the suggestion that FGF21 is a nutritional adaptation factor. FGF21 is elevated in obesity and type 2 diabetes mellitus (T2DM) but there is no consensus as to whether FGF21 levels rise or decline with weight loss and/or normalization of insulin levels.
FGF19 is expressed in the distal small intestine after postprandial activation of the bile salt-activated transcription factor farnesoid-X receptor (FXR). FGF19 stimulates hepatic protein and glycogen synthesis without inducing lipogenesis. Interestingly, FGF21 expression was recently demonstrated to be regulated by FXR as well, indicating that both endocrine FGFs may act as mediators of bile salt action. Circulating bile salts are correlated with insulin sensitivity, accordingly, dysfunction of the bile salt-FXR-FGF19/FGF21 axis may contribute to hyperglycaemia and hyperlipidemia.
Weight loss by calorie restriction or Roux-en-Y Gastric bypass surgery (RYGB) is a cornerstone in the current treatment for obesity and diabetes. The anatomical alterations after RYGB and peri-operative starvation likely affect endocrine FGFs in a direct manner, independent of the long-term effects of weight loss. The early effects of restrictive and metabolic weight loss strategies on (postprandial) bile salt, FGF19 and FGF21 levels have not been directly compared yet. Therefore, we investigated the sub-acute effects of RYGB as opposed to calorie restriction by very-low-calorie diet (VLCD) or gastric banding (GB) on these signalling molecules in obese subjects with normal glucose tolerance (NGT) or type 2 diabetes mellitus (T2DM). These different ways of calorie restriction (GB and VLCD) were chosen because of reluctance of surgeons to give T2DM subjects a gastric band, given the superior effects of RYGB. To elucidate whether RYGB exerts metabolic effects independent of weight loss, we examined subjects within 3 weeks after intervention when weight loss was relatively small and similar among the treatment groups. To address the effect of more pronounced weight loss, we also studied subjects 3 months after the interventions.
Abstract and Introduction
Abstract
Objective To study the effect of different weight loss strategies on levels of the metabolic regulator FGF21 in morbidly obese females with normal glucose tolerance (NGT) or type 2 diabetes mellitus (T2DM).
Design Observational intervention trial.
Patients and measurements Weight reduction was achieved by Gastric Banding (GB,n = 11) or Roux-en-Y Gastric Bypass (RYGB,n = 16) in subjects with NGT, and by RYGB (n = 15) or a very-low-calorie diet (VLCD,n = 12) in type 2 diabetics. Fasted and/or postprandial levels of FGF21, FGF19 (an FGF21-related postprandial hormone) and bile salts (implicated in regulation of FGF21 and FGF19 expression) were measured before, and 3 and 12 weeks after intervention.
Results Fasted FGF21 levels were elevated in T2DM subjects. Calorie restriction by either GB or VLCD lowered bile salt and FGF21 levels. In contrast, RYGB surgery was associated with elevated bile salt and FGF21 levels.
Conclusions Calorie restriction and RYGB have opposite effects on serum bile salt and FGF21 levels. Calorie restriction results in FGF21 approaching nonobese control levels, suggesting that this intervention is effective in reducing the "nutritional crisis" that appears to underly FGF21 elevation in obesity. FGF21 elevation after RYGB may contribute to the beneficial effect of this procedure.
Introduction
Fibroblast growth factors (FGF) 19 and 21 have been attributed diverse hormone-like metabolic functions. FGF21 has metabolic roles in both the fed and food-deprived state, with its expression regulated by both fasting (e.g. glucagon) and feeding (e.g. bile salts) signals. It is expressed mainly in the liver and white adipose tissue (WAT) where its transcription is regulated by peroxisome proliferator activating receptor (PPAR) alpha and PPARγ, respectively. In response to starvation, FGF21 mediates the effects of starvation-activated PPARα on hepatic lipid oxidation and ketogenesis, and inhibition of WAT lipolysis. In the fed state, FGF21 expression is induced in WAT where it regulates insulin-independent glucose uptake and mitochondrial oxidation. The regulation of FGF21 by fasting and feeding signals has led to the suggestion that FGF21 is a nutritional adaptation factor. FGF21 is elevated in obesity and type 2 diabetes mellitus (T2DM) but there is no consensus as to whether FGF21 levels rise or decline with weight loss and/or normalization of insulin levels.
FGF19 is expressed in the distal small intestine after postprandial activation of the bile salt-activated transcription factor farnesoid-X receptor (FXR). FGF19 stimulates hepatic protein and glycogen synthesis without inducing lipogenesis. Interestingly, FGF21 expression was recently demonstrated to be regulated by FXR as well, indicating that both endocrine FGFs may act as mediators of bile salt action. Circulating bile salts are correlated with insulin sensitivity, accordingly, dysfunction of the bile salt-FXR-FGF19/FGF21 axis may contribute to hyperglycaemia and hyperlipidemia.
Weight loss by calorie restriction or Roux-en-Y Gastric bypass surgery (RYGB) is a cornerstone in the current treatment for obesity and diabetes. The anatomical alterations after RYGB and peri-operative starvation likely affect endocrine FGFs in a direct manner, independent of the long-term effects of weight loss. The early effects of restrictive and metabolic weight loss strategies on (postprandial) bile salt, FGF19 and FGF21 levels have not been directly compared yet. Therefore, we investigated the sub-acute effects of RYGB as opposed to calorie restriction by very-low-calorie diet (VLCD) or gastric banding (GB) on these signalling molecules in obese subjects with normal glucose tolerance (NGT) or type 2 diabetes mellitus (T2DM). These different ways of calorie restriction (GB and VLCD) were chosen because of reluctance of surgeons to give T2DM subjects a gastric band, given the superior effects of RYGB. To elucidate whether RYGB exerts metabolic effects independent of weight loss, we examined subjects within 3 weeks after intervention when weight loss was relatively small and similar among the treatment groups. To address the effect of more pronounced weight loss, we also studied subjects 3 months after the interventions.
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