Feast or Famine - Are GLP-1 and Ghrelin Secretion Intertwined?

Throughout evolution the interplay between sensation of hunger and satiety has been an issue of survival in particular during times of famine and the fat depots have been recognized as by far being the largest caloric storage site [1].

In present time, however, it is clear that the mechanisms operating between hunger and satiety have failed in terms of survival of humans. In contrast, the prevalence of obesity as well as its many related diseases, e. g. type 2 diabetes mellitus, hypertension and cardiovascular diseases are growing exponentially and considered as a global epidemic which are utmost devastating to human health as well as to the national health care budgets.

This fact has urged our demands to gain insight into appetite regulation known to be located in the hypothalamus for half a century. Though our understanding of appetite regulation is far from complete, and in some areas may be even only rudimentary in this highly complex and dynamic research field, images are now emerging involving central as well as peripheral peptides. For detailed discussion regarding neuroanatomical sites for appetite regulation, various orexigenic signals as neuropeptide Y, galanin, opioid peptides, melanin-concentrating hormone, and amonoacids and the anorexigenic signals as the CRH family of peptides, neurotensin, melanocortin and agouti protein and the cocaine and amphetamine-regulated transcript the reader is referred to one of many excellent recent reviews [2] [3] [4].

The recent discovery of leptin and its role in relaying information on peripheral energy storage to the CNS has led to novel important insights into short and long term hypothalamic appetite control. Though the exact mechanisms of leptin action are still not known, it is widely accepted that leptin is a long-term regulator of fat storage. However, administration of leptin has taught us that one single peptide is not enough to control satiety and (lipid) metabolism. Not even in the few people characterized by leptin deficiency, does leptin administration deliver the full picture.

The incretin hormone, glucagon-like-peptide-1 (GLP-1) is a peptide derived from the intestinal L cells, which may offer a very promising new concept in terms of treatment of type 2 diabetes mellitus [5]. In addition to its effects on insulin secretion, beta-cell survival, glucagon secretion and gastric emptying it has a possibly clinical important effect on satiety though anoretic signalling [6]. Intraventricular injection of GLP-1 has been shown to inhibit food intake and microinjection experiments have identified the paraventricular nucleus to be essential for the anorectic actions of GLP-1 [7].

Recently another player among gut hormones influencing appetite has emerged, namely ghrelin. Ghrelin was recently isolated from rat stomach [8], and primary focus was put on its GH stimulating effects, but ghrelin production has also been detected in hypothalamic neurons [9]. In rodents, both intracerebroventricular and peripheral administration of ghrelin stimulates feeding, reduces fat utilization and increases body weight [10] [11] [12] [13]. Human ghrelin is homologous to rat ghrelin with the exception of two amino acid residues [8] and has similar orexigenic properties. Ghrelin operates in part via its action on receptors in the arcuate NPY neurons [14]. It has been hypothesized that elevated expression of ghrelin could contribute to obesity in humans, but fasting plasma ghrelin is reduced in obese compared to lean subjects [15], whereas weight loss in obese subjects is associated with a significant increase in circulating ghrelin levels [16]. However, the existence of a particular subset of obesity associated with hyperghrelinaemia due to distinct mutations in the ghrelin gene in humans has been reported [17]. Of notice, ghrelin has also been suggested to influence insulin secretion and independent of this glucose metabolism [18].

The close relationship between the gastrointestinal endocrine systems, and the gut-hypothalamic cross-talk in terms of appetite, made us hypothesize a coordinated regulation/secretion between these two hormones could exist and might be involved in control of hunger and satiety. We observed a clear-cut inverse relationship between circulation levels of ghrelin and GLP-1 (see p 411) which may indicate an interaction regarding regulation of the secretion of the two peptides in the prandial state. However, it is important to stress that the presence/relevance of this in our opinion intriguing regulatory pathway/interaction needs to be confirmed through intervention studies preferably in humans exposed to GLP-1 and ghrelin administration and in which other hormones are carefully controlled.

If the hypothesis about the interaction between ghrelin and GLP-1 secretion turns out to be confirmed another piece of information may be added to our “tip of the iceberg” insight into prevention and pharmacological treatment of obesity and cachexic disorders.

References

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