The Future
What needs to be clarified
1. Is it an independently acting adiposity signal?
Where does Ghrelin fit into the Leptin controlled pathway (? downstream mediator or does it act independently?)
2. What is the difference between pulsatile and continuous infusion of Ghrelin?
3. Intracerebroventricular and SC administration (route) evokes different responses suggesting varying roles of these receptors and transfer across the BBB.... what is the implication in regulation and therapeutics?
4. Does Ghrelin cross the BBB? Initial studies have shown that human Ghrelin is transported bidirectional in a highly regulated fashion by saturable systems in the mice, while mouse Ghrelin is transferred mainly from brain to blood. Studies on Brain effects of Ghrelin are awaited to come out early 2004.
5. Long term safety and efficacy in humans is needed; not only of Ghrelin infusions but also of Ghrelin antagonism with Ghrelin antibodies or Ghrelin receptor blockers.
6. Delineation of the effect on receptors GHSR1a and 1b is needed. Both central and peripheral Ghrelin receptors have been described (peripheral receptor distribution outside the CNS is a bit controversial) with mRNA expression of both GHSR1a and GHSR1b being detected in peripheral tissues (almost ubiquitously in the case of 1b); but we need to know the specific action on stimulation/blockade of each separately which would be important in the development of an antagonist; t
7. Receptor number measurements would help explain varying Ghrelin effects in different circumstances: as up regulation or down regulation may explain decreased Ghrelin effects in pathological conditions suggesting Ghrelin resistance- anorexia nervosa, cardiac cachexia etc)
8. Better knowledge of factors influencing receptor expression (GHRH agonists and T4 increase expression) would help with pharmacologic modulation
9. Ghrelin and GHSr polymorphisms need to be elucidated which might explain variable Ghrelin binding and half life with influence on measured Ghrelin levels. Two polymorphisms have been described in humans. (Arg51Gln and Leu72Met) Obese patients with the Met72 allele became obese earlier than patients homozygous for the wild Leu72 allele. Int J Obes Relat Metab Disord. 2004 Mar;28(3):447-50 Severely obese subjects were noted to have a prevalence of the Arg41Gln mutation of 6.3%. J Clin Endocrinol Metab. 2001 Aug;86(8):3996-9.
10. What influences Ghrelin degradation with conversion of the acylated form to the des acylated form rendering it inactive? Is there a functional balance between acylated and unacylated Ghrelin forms that would play different actions?
11. Is there a sensor in the stomach locally that regulates Ghrelin secretion in response to food? Or is there only a central fat sensor that marks a set point that regulates Ghrelin secretion by the stomach? The fact that Ghrelin suppression does not occur after food in the obese suggests that probably the sensor is central with chronic regulation overriding acute regulation? Is there a substance secreted by fat that might regulate Ghrelin secretion? (TNF α or CRP ;) Is Ghrelin raised in other inflammatory states is a question that this hypothesis begs.
12. The stimulatory and inhibitory factors need to be defined whether it is- Dietary, intra luminal factors, other neuropeptides, and other gut or non-gut hormones: We need to know the specific dietary modulators of Ghrelin-
13. Are there other natural GHS-R ligands like Ghrelin and if so what is their role?
Problem with interpretationAre we measuring the true Ghrelin levels? Recently, acylated Ghrelin has been found to be bound to albumin and HDL whereas desacylated Ghrelin circulates as free peptide. So we need to use immunoassays specific to detect the active Ghrelin. (This might have contributed to some of the confusion in Ghrelin response in previous studies) A further study has tried to differentiate the defect in active and total Ghrelin: The Relationship between Active Ghrelin Levels and Human Obesity Involves Alterations in Resting Energy Expenditure The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 2 936-939
Rat studies have been different to human studies. In rats, insulin administration demonstrated increased gastric Ghrelin mRNA expression, but in humans insulin changes are reciprocal to Ghrelin levels
Various studies have been mutually contradictory especially with regard to the interrelationship of Leptin and Ghrelin. HyperLeptinaemic states in rodents which are lean have high Ghrelin levels. Also, humans with completely absent Leptin signalling with obesity have lower Ghrelin levels suggesting that Ghrelin levels respond or track fat mass and not Leptin, suggesting that it is probably working independent of Leptin and not in downstream signalling as proposed. Loss of body fat by caloric restriction is accompanied by decreased circulating Leptin levels, increased Ghrelin levels, and increased appetite. Further study to clarify their interrelationship would be to have calorie restricted weight loss with only physiologic Leptin restitution. A more recent study in six non-obese men, complete fasting for 3 days resulted in a low Leptin state without a major change in fat mass and abolished the meal-related secretory pattern of Ghrelin without increasing 24-h Ghrelin levels. Also, administration of recombinant human leptin in physiological and pharmacological doses did not regulate Ghrelin over several hours to a few days. [The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 1 335-343; Ghrelin Levels Are Not Regulated by Recombinant Leptin Administration and/or Three Days of Fasting in Healthy Subjects ]. These data suggest that probably circulating Ghrelin is not regulated by Leptin levels independent of changes in adiposity and suggest that the leptin and Ghrelin systems for energy homeostasis function independently of each other in healthy humans.
Hypothalamic Ghrelin measurement is difficult with current techniques of DNA hybridisation. There is a thought that CNS Ghrelin levels might be the major determinant than circulating Ghrelin
Further research?Ghrelin has been shown to be low in obese individuals with no suppression on food intake. It is postulated that a disordered regulation of Ghrelin maybe at work. Ghrelin levels rise on diet induced weight loss in the obese (17% weight loss inducing a 25% increase in AUC for 24 hour Ghrelin). Challenging these obese individuals with calories post weight loss to assess for restoration of Ghrelin response to feeding may tell us whether the abnormal response of Ghrelin to feeding in the obese is the cause or effect of adiposity per say. Essentially does weight loss improve only “secretory capacity” or improvement in regulatory mechanisms as well?
Lipodystrophic states and Ghrelin might be another area to be investigated.
Studies showing weight loss with blockade of endogenous Ghrelin is needed in humans
Studies with assessment of hypothalamic Ghrelin measurements are needed as these levels could be the major determinant of animal behaviour and not circulating Ghrelin
The autonomic nervous system is being evaluated for a causal effect in obesity. What would be the Ghrelin response in autonomic neuropathic states, especially with frank gastroparesis? A study in diabetics with autonomic neuropathy seems warranted.
1. Is it an independently acting adiposity signal?
Where does Ghrelin fit into the Leptin controlled pathway (? downstream mediator or does it act independently?)
2. What is the difference between pulsatile and continuous infusion of Ghrelin?
3. Intracerebroventricular and SC administration (route) evokes different responses suggesting varying roles of these receptors and transfer across the BBB.... what is the implication in regulation and therapeutics?
4. Does Ghrelin cross the BBB? Initial studies have shown that human Ghrelin is transported bidirectional in a highly regulated fashion by saturable systems in the mice, while mouse Ghrelin is transferred mainly from brain to blood. Studies on Brain effects of Ghrelin are awaited to come out early 2004.
5. Long term safety and efficacy in humans is needed; not only of Ghrelin infusions but also of Ghrelin antagonism with Ghrelin antibodies or Ghrelin receptor blockers.
6. Delineation of the effect on receptors GHSR1a and 1b is needed. Both central and peripheral Ghrelin receptors have been described (peripheral receptor distribution outside the CNS is a bit controversial) with mRNA expression of both GHSR1a and GHSR1b being detected in peripheral tissues (almost ubiquitously in the case of 1b); but we need to know the specific action on stimulation/blockade of each separately which would be important in the development of an antagonist; t
7. Receptor number measurements would help explain varying Ghrelin effects in different circumstances: as up regulation or down regulation may explain decreased Ghrelin effects in pathological conditions suggesting Ghrelin resistance- anorexia nervosa, cardiac cachexia etc)
8. Better knowledge of factors influencing receptor expression (GHRH agonists and T4 increase expression) would help with pharmacologic modulation
9. Ghrelin and GHSr polymorphisms need to be elucidated which might explain variable Ghrelin binding and half life with influence on measured Ghrelin levels. Two polymorphisms have been described in humans. (Arg51Gln and Leu72Met) Obese patients with the Met72 allele became obese earlier than patients homozygous for the wild Leu72 allele. Int J Obes Relat Metab Disord. 2004 Mar;28(3):447-50 Severely obese subjects were noted to have a prevalence of the Arg41Gln mutation of 6.3%. J Clin Endocrinol Metab. 2001 Aug;86(8):3996-9.
10. What influences Ghrelin degradation with conversion of the acylated form to the des acylated form rendering it inactive? Is there a functional balance between acylated and unacylated Ghrelin forms that would play different actions?
11. Is there a sensor in the stomach locally that regulates Ghrelin secretion in response to food? Or is there only a central fat sensor that marks a set point that regulates Ghrelin secretion by the stomach? The fact that Ghrelin suppression does not occur after food in the obese suggests that probably the sensor is central with chronic regulation overriding acute regulation? Is there a substance secreted by fat that might regulate Ghrelin secretion? (TNF α or CRP ;) Is Ghrelin raised in other inflammatory states is a question that this hypothesis begs.
12. The stimulatory and inhibitory factors need to be defined whether it is- Dietary, intra luminal factors, other neuropeptides, and other gut or non-gut hormones: We need to know the specific dietary modulators of Ghrelin-
13. Are there other natural GHS-R ligands like Ghrelin and if so what is their role?
Problem with interpretationAre we measuring the true Ghrelin levels? Recently, acylated Ghrelin has been found to be bound to albumin and HDL whereas desacylated Ghrelin circulates as free peptide. So we need to use immunoassays specific to detect the active Ghrelin. (This might have contributed to some of the confusion in Ghrelin response in previous studies) A further study has tried to differentiate the defect in active and total Ghrelin: The Relationship between Active Ghrelin Levels and Human Obesity Involves Alterations in Resting Energy Expenditure The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 2 936-939
Rat studies have been different to human studies. In rats, insulin administration demonstrated increased gastric Ghrelin mRNA expression, but in humans insulin changes are reciprocal to Ghrelin levels
Various studies have been mutually contradictory especially with regard to the interrelationship of Leptin and Ghrelin. HyperLeptinaemic states in rodents which are lean have high Ghrelin levels. Also, humans with completely absent Leptin signalling with obesity have lower Ghrelin levels suggesting that Ghrelin levels respond or track fat mass and not Leptin, suggesting that it is probably working independent of Leptin and not in downstream signalling as proposed. Loss of body fat by caloric restriction is accompanied by decreased circulating Leptin levels, increased Ghrelin levels, and increased appetite. Further study to clarify their interrelationship would be to have calorie restricted weight loss with only physiologic Leptin restitution. A more recent study in six non-obese men, complete fasting for 3 days resulted in a low Leptin state without a major change in fat mass and abolished the meal-related secretory pattern of Ghrelin without increasing 24-h Ghrelin levels. Also, administration of recombinant human leptin in physiological and pharmacological doses did not regulate Ghrelin over several hours to a few days. [The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 1 335-343; Ghrelin Levels Are Not Regulated by Recombinant Leptin Administration and/or Three Days of Fasting in Healthy Subjects ]. These data suggest that probably circulating Ghrelin is not regulated by Leptin levels independent of changes in adiposity and suggest that the leptin and Ghrelin systems for energy homeostasis function independently of each other in healthy humans.
Hypothalamic Ghrelin measurement is difficult with current techniques of DNA hybridisation. There is a thought that CNS Ghrelin levels might be the major determinant than circulating Ghrelin
Further research?Ghrelin has been shown to be low in obese individuals with no suppression on food intake. It is postulated that a disordered regulation of Ghrelin maybe at work. Ghrelin levels rise on diet induced weight loss in the obese (17% weight loss inducing a 25% increase in AUC for 24 hour Ghrelin). Challenging these obese individuals with calories post weight loss to assess for restoration of Ghrelin response to feeding may tell us whether the abnormal response of Ghrelin to feeding in the obese is the cause or effect of adiposity per say. Essentially does weight loss improve only “secretory capacity” or improvement in regulatory mechanisms as well?
Lipodystrophic states and Ghrelin might be another area to be investigated.
Studies showing weight loss with blockade of endogenous Ghrelin is needed in humans
Studies with assessment of hypothalamic Ghrelin measurements are needed as these levels could be the major determinant of animal behaviour and not circulating Ghrelin
The autonomic nervous system is being evaluated for a causal effect in obesity. What would be the Ghrelin response in autonomic neuropathic states, especially with frank gastroparesis? A study in diabetics with autonomic neuropathy seems warranted.