Introduction

The feelings of appetite and satiety involve complex interactions between hormones from the gastrointestinal (GI) tract to the hypothalamus and subsequent feedback. Within the hypothalamus are specific regions where hormones interact to produce sensations of appetite and satiety, leading to food consumption or a feeling of fullness. Through the interactions of ghrelin and leptin, the hypothalamus can regulate the sensation of hunger and satiety, leading to energy homeostasis. Ghrelin, termed the "hunger hormone," was initially discovered through its receptor, the growth hormone secretagogue receptor (GHS-R), before explaining its role as a growth-hormone-releasing peptide.[1] 

Leptin was discovered primarily as a signal in regulating body weight.[2] However, the roles of these hormones in regulating appetite and satiety were not explicitly known until research showed a correlation between a rise in plasma levels of ghrelin before meals and a subsequent decrease in plasma levels of ghrelin after meals and a subsequent change in plasma leptin levels.[3] Together, ghrelin and leptin signals regulate our sensations of hunger and satiety by sending signals to different nuclei within the hypothalamus for food intake. An imbalance or dysregulation of these hormones may drastically affect the body's energy homeostasis. 

Issues of Concern

Knowing the actions of ghrelin and leptin has led to many therapeutic advances. With the rise of obesity in the past 50 years, researchers have attempted to find methods to treat and prevent this public health problem associated with many secondary diseases.[4] Research into the applications of leptin has been ongoing in an attempt to treat obesity and associated disorders such as lipodystrophy.[5] Similarly, research has explored the effects of ghrelin in helping those with eating and growth disorders.[6] 

Understanding the roles of these hormones and the hypothalamic nuclei where they act has been crucial in developing potential treatments for multiple disorders. An imbalance or decreased sensitivity to ghrelin or leptin can lead to problems with anorexia or excessive eating. Specific pathophysiologies (discussed in a later section) can arise due to an imbalance of these two hormones. Therefore maintaining appropriate levels of ghrelin and leptin is critical in maintaining homeostasis. As the worldwide health problem of obesity increases, potentially leading to secondary diseases, therapeutic effects such as managing leptin levels are under investigation.[7]

Cellular Level

Researchers have explored the effects of ghrelin and leptin since their discovery. From knowing that ghrelin was a growth hormone and leptin's effects in regulating body weight, many studies have explored their subsequent actions and effects. Studies have shown that their primary action lies in the various nuclei of the hypothalamus in regulating appetite and satiety.

Ghrelin is a 28-amino acid peptide synthesized from the human ghrelin gene, GHRL, on chromosome 3.[8] X/A-like cells are the primary synthesizing ghrelin cells contained in these dense granules.[8] The mRNA of ghrelin mainly exists in gastric tissue, functioning in regulating energy homeostasis in communication with the hypothalamus. From preproghrelin to proghrelin, ghrelin becomes activated through a series of post-transcriptional enzymes. In circulating blood, ghrelin exists in two forms: a non-acylated form of ghrelin and acylated ghrelin, with non-acylated ghrelin in far higher levels in the bloodstream.[9] The primary receptor of ghrelin is the growth hormone secretagogue receptor type 1a (GHS-R1a), a seven-transmembrane domain GPCR. GHS-R1a is expressed throughout the body, such as the hypothalamus, and aids in coordinating and maintaining energy homeostasis.[10]

The obese (ob) gene, located on chromosome 7, produces leptin, which is primarily found in adipose tissues. Leptin is an adipocyte-derived hormone existing as a 167 amino acid peptide with a highly preserved form across species.[11] It is released into the bloodstream as a function of adipose storage, signaling the brain to regulate homeostasis. Leptin's primary receptor is LepR, with many subtypes expressed in many different nuclei within the hypothalamus. LepR is expressed in the hypothalamus, where leptin can cross the blood-brain barrier through a transport system and signal the status of bodily energy stores. Leptin's different actions on the arcuate nucleus, ventromedial nucleus, and lateral hypothalamus owe to its stimulatory effects of satiety and its inhibitory effects of hunger in coordinating the body's energy homeostasis. Furthermore, LepRb, a leptin receptor subtype, further induces signaling cascades like JAK2/ERK and STAT3, among others.[12]

Subjects with a higher BMI and corresponding percent of body fat have demonstrated a marked increase of leptin in the circulating blood plasma. Besides regulating energy storage levels, leptin release also depends on factors such as food intake, gender, age, exercise, and circulating glucose.[7]

Development

Maintaining homeostatic balance in appetite and satiety control via hormones such as ghrelin and leptin would not be possible without the hypothalamus coordinating the various hormonal inputs. The three zones of the hypothalamus divide into periventricular, medial, and lateral. The majority of the hypothalamic nuclei are located in the medial region leading to further subdivisions such as the preoptic area, anterior (supraoptic) region, the middle (tuberal) region, and the posterior (mamillary) region.[13] In regulating neurohormonal appetite and satiety, the lateral hypothalamus, arcuate nucleus, and ventromedial hypothalamus within the middle (tuberal) region are crucial in balancing our sensations.[14]

The development of the hypothalamus and its regions is critical in maintaining homeostasis. Morphogens such as Wnt8 are responsible for the anterior-posterior patterning of the induced neural plate.[15] Inhibition of Wnt is required for anterior patterning of the neural plate, eventually giving rise to the hypothalamus. Many different regulators contribute to the many parts of the hypothalamus, owing to their specific functions in each region. The ventromedial hypothalamus derives from the expressions of Rax and Nkx2.1. Although not much is known in determining the cell fate of the lateral hypothalamus, Foxb1 is expressed in progenitors giving rise to the lateral hypothalamus.[15] While ongoing research continues, much has yet to be discovered regarding the regulatory factors and the development stage of the hypothalamus.

Organ Systems Involved

Signals from the gut and adipose tissue are important in regulating sensations of appetite and satiety, respectively. The gut produces ghrelin, while leptin derives from adipose tissue. The hypothalamus integrates the signals from these two locations to regulate the body's energy homeostasis—circulating ghrelin and leptin act on the hypothalamus, allowing the body to adapt to energy demands. Ghrelin acts on the lateral hypothalamus, while leptin acts on the arcuate nucleus within the middle (tuberal) region. The lateral hypothalamus has also been shown to form and store memories associated with predicting food availability within an environment due to its interaction with ghrelin.[16] 

Within the gut are short-acting signals such as cholecystokinin (CCK) and gut distension, promoting "fullness" and satiety.[17] CCK activates the nucleus of the solitary tract and relays information to the hypothalamus. Similarly, other long-acting signals such as hormone peptide YY and incretin glucagon-like peptide inhibit appetite, regulating a long-term sense of energy homeostasis. These processes show that the hypothalamus is the key central integrator of various hunger signals from the body. Each of these signals acts on different nuclei within the hypothalamus to regulate energy homeostasis.[18] Any disruption to these signaling pathways would affect the overall energy balance of an organism. The gut and adipose tissue are crucial in signaling the hypothalamus when more or less energy intake is required.

Function

The function of various hormones in regulating appetite and satiety is to maintain energy homeostasis. Multiple hormones such as ghrelin, leptin, cholecystokinin, and other peptides all relay peripheral signals to the hypothalamus. Any imbalance of these hormones leads to various pathologies that this article will explore in another section. As such, this section will examine the functions of several hormones in appetite and satiety control. The two hormones most closely associated with energy homeostasis leading to sensations of hunger and satiety are ghrelin and leptin. Any shift in the delicate balance between ghrelin and leptin drastically affects our body's ability to regulate energy demands and storage, leading to pathophysiology.

Ghrelin. Originally, ghrelin was discovered as a growth hormone-releasing peptide that acted on the hypothalamus. Subsequent studies then showed that levels of ghrelin increased before meals and had a role in increasing body weight, thus earning the name "hunger hormone."[3] The lateral area of the hypothalamus is responsible for hunger and becomes stimulated by ghrelin. Since then, many studies have attempted to adjust the balance between ghrelin and leptin for therapeutic uses. Although ghrelin is most prominently known for its role in stimulating appetite, it is also involved in regulating sleep-wake rhythms, taste sensation, and glucose metabolism.[19] Studies continue to explore the growing relationship between ghrelin and glucose metabolism, showing ghrelin's ability to decrease insulin release.[20]

Leptin. Leptin is perhaps best understood as the opposite of ghrelin, acting as the body's satiety signal. Together with ghrelin, leptin exists in balance to regulate energy homeostasis. The ventromedial region of the hypothalamus is responsible for satiety and is stimulated by leptin. Furthermore, leptin inhibits stimulation of the lateral hypothalamus to inhibit the effects of ghrelin. As an adipocyte-derived hormone, leptin sends signals to the medial hypothalamus regarding energy storage within the body. However, leptin also has many other roles within the body, such as reproduction, blood pressure, and vast effects on the immune system.[21] These additional functions of leptin have an overall impact on energy metabolism and act to change the balance within the body. Similarly, the relationship between inactive leptin and obesity has been the topic of much research.[22]

Mechanism

Activation of key receptors within the pathways is crucial for producing the desired regulatory effect between appetite and satiety. As such, the communication between the GI tract and the hypothalamus requires hormones that act on the appropriate receptors within the central nervous system (CNS). Ghrelin is derived from the GI and targets regions of the hypothalamus to provide the sensation of hunger. Sympathetic and parasympathetic pathways each play significant roles in signaling our brain when to eat. As such, ghrelin acts on the growth hormone secretagogue receptor (GHSR-1a) to promote feelings of hunger and food anticipation.[10] Studies have shown that our body can adapt to ghrelin signals over time and initiate the appropriate response based on metabolic status and environment.[23] 

The mechanism by which leptin regulates energy homeostasis and blood glucose levels has yet to be fully understood. Expression of the leptin receptor, LepRb, is higher in the CNS, with studies showing that leptin acting on the CNS is sufficient to lower blood glucose.[24] Leptin receptors primarily exert a GABAergic effect in several nuclei within the hypothalamus, including the ventromedial nucleus, dorsomedial nucleus, lateral hypothalamus, and arcuate nucleus. However, the main effect of leptin comes about when it acts on the arcuate nucleus. The two main neurons within the arcuate nucleus are pro-opiomelanocortin (POMC) and agouti-related protein (AgRP).[24] 

Leptin stimulates POMC and inhibits AgRP causing these neurons to project to the ventromedial hypothalamus. POMC activates alpha-melanocyte-stimulating hormone (alpha-MSH), which then acts to inhibit food intake. Research has also shown that leptin receptors exist in the hippocampus, impacting cognitive function and plasticity.[25] As such, researchers have explored leptin's role in obese and non-obese individuals, with different mechanisms in different individuals, and have also found leptin to potentially play a role in tumor formation and metastasis.[26]

Pathophysiology

A balance between ghrelin and leptin is essential in maintaining adequate energy homeostasis. Furthermore, the interactions of these signals between the GI tract and adipocyte storage allow the appropriate signals to be sent to various nuclei within the hypothalamus to exert the desired effect. An imbalance causes diverse pathophysiology related to weight imbalance and improper energy homeostasis.

Obesity: With the prevalence of obesity continuing to rise, secondary diseases associated with obesity continue to rise, including diabetes mellitus, hypertension, liver disease, stroke, and myocardial infarctions. Furthermore, the social stigma related to obesity is associated with unemployment and social disadvantages.[4] The role and effects of leptin have been explored in an attempt to find treatments for obesity. Leptin resistance has been shown in obese individuals, perhaps due to impaired leptin signaling pathways.[27] In a healthy response, high circulating leptin levels inhibit food intake and promote a decrease in weight. Individuals who show leptin resistance or leptin deficiency tend to correlate with obesity. Mutations involved in the leptin gene pathway could be responsible for causing obesity. Leptin resistance can either be associated with a decreased ability of leptin to reach the hypothalamus and the CNS or with leptin's defects in downstream signaling.[5]

Eating Disorders: Anorexia nervosa and bulimia nervosa are both eating disorders associated with irregular eating patterns and concerns with body shape and weight. Many of these disorders have a psychological component and were long thought to be psychiatric disorders. However, new data has shown that individuals with anorexia nervosa have higher plasma ghrelin levels than normal individuals. Similarly, research has shown that individuals with bulimia nervosa have elevated fasting plasma ghrelin levels compared to individuals of similar BMIs.[28] This new information shows problems that once appeared to be psychiatric may also have a hormonal component.

Prader-Willi Syndrome: Prader-Willi Syndrome (PWS) is a genetic form of obesity, with deficits in ghrelin-signaling due to deficits in the expression of chromosome 15q11.2-q13. Hyperphagia is a typical symptom shown at a very young age. Children typically present with hypotonia, narrow forehead, developmental disability, almond-shaped eyes, small hands and feet, and short stature.[29] In some individuals with PWS, ghrelin levels can elevate in both fasting and fed states.[30] The relationship between ghrelin and PWS is not exactly well understood since not all individuals with PWS have elevated ghrelin levels, and hyperphagia at a young age does not necessarily correlate with a change in ghrelin levels.[31]

Rheumatoid Arthritis: Besides regulating weight, leptin also has pro-inflammatory effects, especially within the joints. Research has demonstrated that patients with rheumatoid arthritis have elevated levels of leptin in the bloodstream.[32]

Mood Disorders: Ghrelin and leptin play an essential role in energy homeostasis, and pathophysiology related to energy imbalance drastically affects mood disorders. While ghrelin is mainly known as the hunger hormone, it is also involved in the reward and motivation signaling pathways, which link to stress, anxiety, and depression.[33] Although some studies have shown that leptin administration reduces symptoms of depression, others do not find significant differences in ghrelin levels between those with depression versus healthy individuals.[34] Ghrelin and leptin are involved in mood disorders, but the extent has yet to be fully explored.

Clinical Significance

Ghrelin and leptin exist as key hormones with regulatory effects of clinical significance in treating various disorders. In cancer cachexia, ghrelin has already shown promise as a therapeutic option with its anti-inflammatory action on cancer cells. Through its effects on muscle catabolism, anti-apoptotic mechanism, and reducing the adverse effects of chemotherapy, ghrelin may help treat cancer cachexia.[35] The effects of ghrelin on the rest of the body's metabolism are vast, and avenues for anti-inflammation, improvement of cardiac performance, and stress modulation are continually under investigation.[36] 

Synthetic ghrelin-receptor agonist analogs like Anamorelin have shown beneficial effects.[37] The effects and circulation of leptin have also been experimented with regarding weight loss.[38] Many of these studies are still undergoing clinical trials, hoping they will have significant clinical benefits in the future.