Ghrelin is a peptide hormone predominantly produced in the stomach  by post translational processing  after cleaving pre-pro-Ghrelin. Science. 2005 Nov 11;310(5750):996-9. Lower levels of Ghrelin expression has now been documented in various tissues including bowels, pancreas, kidneys, the immune system, placenta, testes, pituitary, hypothalamus Horm Res. 2003;59(3):109-17 and even chondrocytes  Endocrinology. 2004 Dec 2 Ghrelin ('Ghr' for growth; 'relin' for releasing) was discovered in 1999 by Kojima and colleagues Nature. 1999 Dec 9;402(6762):656-60  and described independently by Tomasetto from France as the motilin related peptide. Gastroenterology. 2000 Aug;119(2):395-405   It was initially thought to be involved in GH release alone via its action on the GHSr (Growth Hormone secretagogue receptor) but now thought possibly to have a role in long term satiety signaling. It was an year later since its discovery that the appetite stimulating effect of Ghrelin was demonstrated in 3 of 4 men tested. J Endocrinol Invest 23:493–495  Interestingly, synthetic GH secretagogues and Ghrelin receptors were identified much before the discovery of the endogenous growth-hormone secretagogue- Ghrelin. Science, Vol 273, Issue 5277, 974-977 , 16 August 1996. In fact, Hexarelin (GHRP-6) has been used as a diagnostic tool even before the isolation  of GHRH itself. Science. 1982 Nov 5;218(4572):585-7.
 

Ghrelin secretion is up-regulated under conditions of negative energy balance and down-regulated in the setting of positive energy balance. In fact, Ghrelin is unique among gut hormones in its increased secretion in the fasted state. Ghrelin levels rise pre-meals and are suppressed after feeding in lean humans. J Clin Endocrinol Metab. 2002 Jun;87(6):2984. Hence it is thought to be a meal initiator. This meal related rise and fall was demonstrable even in patients who had no time cues and hence no meal anticipation  Am J Physiol Endocrinol Metab. 2004 Mar 23.  Thus Ghrelin is the first gut hormone to have proven orexigenic properties, and the only gut hormone with orexigenic properties on peripheral administration. 

 Obese people have a low Ghrelin level in the fasting stage which was surprising, making the interpretation of its role more difficult. Ghrelin seems to correlate inversely with fat mass and insulin. The fact that Ghrelin levels fail to decrease in response to feeding in the obese might suggest a disordered control mechanism rather than a primary role for Ghrelin.  J Endocrinol Invest. 2003 Aug;26(8):723-7.   In pathologically lean people with anorexia nervosa, Ghrelin levels are raised as the fat mass is low, and fails to suppress with food, again suggesting chronic dysregulation resulting in lack of response to food ingestion. J Clin Endocrinol Metab. 2003 Apr;88(4):1678-82

 

 

Ghrelin characteristics

 

Ghrelin is an unusual peptide in that it has a side chain, which is mainly responsible for its actions. Two molecular forms are found in the stomach: a 28 amino acid form with n-octanoylated serine in position 3, as well as a 27 amino acid des-[Gln¹⁴] Ghrelin produced by alternative splicing of the Ghrelin gene. J Biol Chem. 2000 Jul 21;275(29):21995-2000   Octanoylation of the serine is crucial for activity of both forms of Ghrelin, with both forms stimulating GH release. Thus acylated and non-acylated (des-acyl Ghrelin) account for Ghrelin in circulation.  HDL has been proposed as a possible carrier particle for Ghrelin due to the positive correlation of Ghrelin levels with HDL levels. J Clin Endocrinol Metab. 2003 Dec;88(12):5747-52. Ghrelin clearance may primarily be effected via the kidneys as suggested by studies using I125 labeled Ghrelin in septic rats. Int J Mol Med. 2003 Nov;12(5):777-81 Acylated Ghrelin disappears more rapidly from plasma [t(1/2) of 9-13 minutes]  than total Ghrelin,  [t(1/2) 27-31 minutes]. Eur J Endocrinol. 2004 Apr;150(4):447-55   Women have higher levels of Ghrelin than men, which has been attributed to central obesity in cross sectional studies. J Clin Endocrinol Metab. 2004 Jan;89(1):335-43  Human Ghrelin is identical to rat ghrelin except for two residues.  Nature. 1999 Dec 9;402(6762):656-60
Ghrelin is expressed mainly in the stomach by neuroendocrine cells in the fundus. Endocrinology. 2000 Nov;141(11):4255-61   Gastrectomy thus reduces Ghrelin levels by up to 65%. J Clin Endocrinol Metab. 2001 Oct;86(10):4753-8. Ghrelin has also been described in small and large intestine, pituitary gland, arcuate nucleus of the hypothalamus, alpha Diabetes. 2002 Jan;51(1):124-9  and beta cells  J Clin Endocrinol Metab. 2002 Mar;87(3):1300-8  of the pancreatic islets,  kidney, testis, placenta Endocrinology. 2001 Feb;142(2):788-94.   and immune cells. Rat hypothalamus contains both n-octanoyl-modified and des-acyl Ghrelin, both of which decrease with fasting as well as selective blockade of carbohydrate metabolism with 2-deoxy-d-glucose (2-DG), in contrast to peripheral Ghrelin.  Endocrinology. 2005 Jun;146(6):2510-6. Bioactive acylated Ghrelin has been demonstrated to be present in saliva where it may have a role in proliferation of oral keratinocytes, along with other salivary growth factors. Clin Chem. 2005 Jun;51(6):997-1006

 

 

Ghrelin Administration
 

Rodent:

Short term infusions of Ghrelin in rats has increased food intake (as potently as NPY) with increased body weight. Pair fed studies in rats has demonstrated that fat deposition is increased independent of food intake. Ghrelin blockade in rats have produced decreased food intake and weight loss. Leptin infusion SC in rats has been found to negatively regulate Ghrelin. Short term infusions of Ghrelin intravenously, intracerebroventricularly and intraperitoneally increases appetite and food intake in rats, but its physiological role is yet to be ascertained fully.  Ghrelin inhibits the insulin secretion from rat islets in vitro in a dose and glucose-dependent manner.

Chronic central administration of Ghrelin (72 h) in rat significantly increased food intake and body weight. Chronic central administration of Ghrelin increased both Neuropeptide Y mRNA levels and AGRP mRNA levels  in the arcuate nucleus. Diabetes. 2001 Nov;50(11):2438-43.

Humans:

Injection of active acylated Ghrelin at differing doses(1 and 5 microg/kg)  in eighteen healthy humans demonstrated that both the low and high doses of Ghrelin strongly stimulated GH release and increased hunger in a dose-dependent manner. Eur J Endocrinol. 2004 Apr;150(4):447-55.  A difference in induction of insulin sensitivity has been noted depending on whether acylated or nonacylated or a combination of the two is administered. J Clin Endocrinol Metab. 2004 Oct;89(10):5035-42

 Acute intravenous Ghrelin administration (1.0 microg/kg) in nine obese women [BMI 36.3 +/- 2.3] and seven normal women (BMI 20.3 +/- 1.7 ) was studied. J Clin Endocrinol Metab. 2003 Nov;88(11):5478-83.  In Obese women and non obese women, Ghrelin significantly  increased  GH, PRL, ACTH, and cortisol levels. The GH response to Ghrelin in obese women was 55% lower  than in non obese women. In normal weight women, Ghrelin increased glucose but did not change insulin levels. In the obese women, Ghrelin increased glucose and reduced insulin (P < 0.05). Does this mean that it is not Ghrelin hypo secretion, but  a resistance to or decreased responsiveness to Ghrelin that produces the metabolic abnormalities of obesity?

Ghrelin infusion  in 7 healthy normal lean subjects induced transient decrease in spontaneous insulin secretion but not the insulin response to a glucose load. Also Ghrelin infusion raised basal glucose but not the glucose rise during OGTT. J Clin Endocrinol Metab. 2003 Sep;88(9):4268-72.

In a study quoted above involving acute intravenous Ghrelin administration (1.0 microg/kg) in nine obese women [BMI 36.3 +/- 2.3] and seven normal women (BMI 20.3 +/- 1.7),  Ghrelin increased glucose in the normal weight women, without a change in insulin levels. In the obese women, Ghrelin increased glucose and reduced insulin. J Clin Endocrinol Metab. 2003 Nov;88(11):5478-83. Ghrelin increases hunger and food intake in both lean and obese subjects. Int J Obes Relat Metab Disord. 2005 May 24