Curiosities About Ghrelin (Hunger Hormone)

Ghrelin is a hormone found in various organs. It plays an important role in increasing the feeling of hunger and regulating body weight. First discovered in studies on mice in 1999, this hormone interacts with the growth hormone secretagogue receptor.

Gene expression studies in humans and mice have revealed that ghrelin is active in many different organs. With this effect, ghrelin is a key factor in maintaining energy balance and regulating food intake.

The functions of ghrelin are intensely studied due to its broad effects on health and metabolism.

Molecular Structure and Variations of Ghrelin

Ghrelin exhibits homologous structures in various mammalian species. In humans, mice, and some other mammals, this hormone consists of 117 amino acids. This peptide, which triggers the feeling of hunger, has important features.
Especially, the N-terminal end is critical for the functionality of this hormone. Human ghrelin contains an octanoyl group attached to the serine amino acid. This structure forms the biologically active form of ghrelin.

• The ghrelin gene consists of five exons.
• The preproghrelin encoded by this gene is composed of 117 amino acids and weighs approximately 13 kDa.
• The ghrelin molecule is a structure of 28 amino acids, particularly coded by the second and third exons.
• The first exon does not participate in coding and is separated as a remnant part.
• Proghrelin is later divided into active ghrelin of 28 amino acids and a C-terminal piece of 66 amino acids.

This structural distinction allows the formation of two different forms of ghrelin: acylated ghrelin, the active form, and desacyl-ghrelin, which is not bound to fatty acid. Additionally, the C-terminal piece of 66 amino acids separated from the proghrelin molecule enables the synthesis of another peptide called obestatin.
This peptide acts as an antagonist of ghrelin and binds to one of the G protein-coupled receptors, GPR39. Ghrelin and its various forms play vital roles in regulating energy balance and controlling the feeling of hunger.

Pathways and Mechanisms of Ghrelin’s Effects

Ghrelin is known as the hunger hormone and has various biological functions. This hormone triggers the release of growth hormone-releasing hormone in the hypothalamus. Its activity occurs through two different types of growth hormone secretagogue receptors.
The functionally active GHS-R type 1a plays a critical role in signal transmission. On the other hand, GHS-R type 1b cannot directly bind ligands or transmit signals due to the lack of transmembrane domains. However, it is thought that ghrelin’s effects also occur indirectly through this receptor. The effects of ghrelin are observed through the following pathways:

• It reaches the hypothalamic arcuate nucleus via the bloodstream and stimulates the release of peptides that affect appetite.
• It is synthesized peripherally and activates vagal afferent nerve endings, which triggers GHS-R expression.
• It is synthesized locally in the hypothalamus and directly stimulates Neuropeptide Y/Agouti-Related Peptide cells.

These include:

• Melanin-concentrating hormone
• Orexins
• Agouti-related protein

These peptides play an important role in regulating appetite and contribute to maintaining energy balance. Ghrelin’s multifaceted interactions create a profound impact on metabolic processes and act as a fundamental factor in regulating eating behaviors.

Production and Distribution of Ghrelin

The ghrelin hormone is primarily synthesized in the stomach mucosa. The fundus region of the stomach is prominent in this process; it produces ghrelin at a higher rate compared to the pyloric region. Studies have confirmed the presence of ghrelin-positive cells in specific regions of the stomach mucosa. Besides the stomach, other organs where ghrelin is produced include:

• Small intestine
• Breast
• Salivary gland

Additionally, alpha and beta cells of the pancreas also produce ghrelin. A significant portion of the circulating amount of this hormone originates from the stomach. Ghrelin is synthesized in specific cell types in various organs, expanding its impact on the body.

For example, seven main types of endocrine cells have been identified in the human and rat stomach. Among these cells, X/A cells were discovered by Davis in 1954. This diversity in ghrelin synthesis explains the hormone’s versatile effects.

Studies by Kojima and his team have revealed the growth hormone-releasing properties of ghrelin and demonstrated that granules within X/A cells play a critical role in this process. Ghrelin has also been detected in the kidneys, chondrocytes, and saliva. This widespread distribution shows how ghrelin creates a network within the body and influences many different processes.

Various Systems Affected by Ghrelin

Ghrelin has significant effects on multiple systems. It functions as a growth hormone-releasing hormone in the body. By increasing appetite and the urge to eat, it directly affects energy intake. It also plays a regulatory role in carbohydrate metabolism and gastrointestinal functions.
Effective in the cardiovascular system, ghrelin lowers blood pressure and can increase heart volume. It promotes cell growth and proliferation, thus contributing to the body’s growth capability. The following items summarize the main systems affected by ghrelin:

• Growth hormone-releasing effect
• Increasing appetite and urge to eat
• Role in carbohydrate metabolism
• Regulating gastrointestinal system functions
• Impacting the cardiovascular system
• Supporting cell proliferation and growth capability

Ghrelin also affects the reproductive system by influencing the release of LH and FSH hormones in the hypothalamus and pituitary gland, thereby regulating the functions of the gonads. These effects show that ghrelin plays an important role in reproductive health in both males and females.
Ghrelin also contributes to managing energy stores and controlling body weight. Changes observed in serum levels before and after each meal reinforce this hormone’s regulatory properties on hunger and satiety. The effects of ghrelin are worth studying in detail due to their multifaceted impacts on health.

Conclusions and Future Research

The importance of ghrelin in scientific research is increasingly recognized. Considering its role in appetite regulation and energy balance, certain topics are prioritized in future studies. Here are the main topics to focus on:

• The effects of ghrelin on the digestive and reproductive systems should be examined in more detail.
• The potential role of ghrelin in combating obesity should be investigated.

While the effects and mechanisms of this hormone in the body are not yet fully understood, scientists hope to achieve more definitive results with the introduction of new technologies and methods. Especially studies on the GOAT enzyme, which helps ghrelin gain its active form, are among the promising aspects of this field.
The observation of ghrelin expression in every tissue indicates that it has a systemic effect, which attracts researchers’ attention. New findings will help us better understand the effects of ghrelin on the body and lead to potential therapeutic applications.