|Year : 2022 | Volume
| Issue : 1 | Page : 12-16
Role and significance of ghrelin and leptin in hunger, satiety, and energy homeostasis
Charu Kharbanda1, Savita Bansal2, Prachi Saffar Aneja3
1 Department of Physiology, BJMC, Ahmedabad, Gujarat, India
2 Department of Pathology, FDS, MRIIRS, Faridabad, India
3 Department of Anatomy, SGT Medical College, Gurugram, Haryana, India
|Date of Submission||10-Sep-2021|
|Date of Acceptance||28-Sep-2021|
|Date of Web Publication||22-Apr-2022|
Department of Pathology, FDS, MRIIRS, Faridabad - 121 004, Haryana
Source of Support: None, Conflict of Interest: None
Hunger is a set of internal experiences that lead a human or animal to seek food. Satiety is a desire to limit further food intake or the state of being gratified after completing a meal. The objective of this review article is to discuss the influence of ghrelin and leptin in hunger, appetite, satiety, and long-term energy homeostasis. The data for this review were collected through an extensive journal search. Electronic databases (Medline and PubMed) were thoroughly consulted, and few articles were obtained from the website: Google Scholars (http://scholar.google.com). Ghrelin and leptin are concerned with food intake and energy homeostasis. Ghrelin increases food intake and affects food patterns, whereas leptin induces satiety. Circulating leptin levels are directly proportion to the amount of body fat, thereby reflecting the status of long-term energy stores. Recent work suggests that leptin plays a more important role in the maintenance of weight loss than weight loss per se and ghrelin increases appetite, adjusts energy balance, and enhances the release of growth hormone from the pituitary gland
Keywords: Appetite, energy homeostasis, ghrelin, leptin, metabolism, satiety
|How to cite this article:|
Kharbanda C, Bansal S, Aneja PS. Role and significance of ghrelin and leptin in hunger, satiety, and energy homeostasis. J Sci Soc 2022;49:12-6
| Introduction|| |
Hunger is a set of internal experiences that lead a human or animal to seek food. It is an uncomfortable sensation or craving for food, whereas appetite describes the preferences surrounding the selection of food that is found. Satiety is a desire to limit further food intake or the state of being gratified as after completing a satisfying meal. There are various factors in our body which influence the phenomenon of hunger and satiety [Figure 1].
The purpose of this review article is to discuss the role and significance of ghrelin and leptin which are relatively newer peptides influencing hunger, appetite, satiety, and long-term energy homeostasis.
The information regarding this review paper was collected through an extensive journal search. Electronic databases (Medline and PubMed) were thoroughly consulted for different publications on these two hormones. The references thus collected were evaluated for their relevance regarding ghrelin and leptin based on their abstracts and titles. Few articles were obtained from the website: Google Scholars (http://scholar.google.com).
The articles used in this paper are all written in English language and have been published before February 2020.
| Results and Discussion|| |
In this study, we found out that ghrelin is the only “peripheral hunger peptide” that regulates short-term food intake and long-term body weight regulation. In contrast to ghrelin which is a single peripheral peptide known to stimulate hunger, there are many peripheral peptides that are associated with satiety. The list of satiety hormones is far too extensive to discuss in this review. We have therefore focused on leptin which plays a key role as satiety peptide.
Discovery of ghrelin started with hypothalamus; also referred to as “Casablanca of the central nervous system;” in an effort to find out a growth hormone secretagogue which increases growth hormone secretion in pituitary. Scientists discovered an endogenous peptide which had GH-releasing activities and named it ghrelin where “Ghre” means “to grow.” The name can also be seen as an abbreviation for growth hormone; GH followed by “relin” a suffix.
Ghrelin is a 28-amino acid peptide that is mainly released from the oxyntic cells of stomach mucosa. Substantial amount of these cells is also present in intestines. Ghrelin receptor is a classic G-protein coupled receptor.
Physiological actions of ghrelin
Appetite and food intake
Ghrelin administration to human intravenously stimulates appetite and food intake and reduction in energy expenditure accounting for increased weight gain. Ghrelin is secreted in pulsatile manner as its levels increases before the onset of meal, during fasting, and decreases after feeding., This pulsatile secretion of ghrelin suggests that ghrelin may act as a signal for meal initiation whereas its peak levels are associated with meal patterns. Ghrelin acts by both central and peripheral pathways. Ghrelin locally synthesized in hypothalamus acts centrally, whereas ghrelin secreted by stomach crosses the blood–brain barrier and reaches target places. In hypothalamus, ghrelin acts by stimulating orexigenic peptides and inhibiting anorexigenic substances [Table 1].
Neurons expressing ghrelin send efferents to arcuate nucleus producing NPY (neuropeptide Y) and AgRP (agouti-related peptide) [Figure 2] and inhibiting Proopiomelanocortin (POMC) and AgRP corticotropin-releasing factor.,
Molecular mechanism of food intake
Hypothalamic 5'AMP-activated protein kinase (5'AMPK) has a pivotal role in ghrelin's effect of increasing appetite and food intake., AMPK is a serine/threonine-protein kinase sensing the energy status of cells. AMPK regulates fuel availability by stimulating ATP-producing pathways and inhibiting ATP-consuming pathways. Following ATP depletion, AMP rises and its phosphorylation occurs. pAMPK induces the phosphorylation of acetyl-CoA carboxylase (ACC), leading to the inhibition of ACC activity and the decrease in malonyl CoA levels and finally resulting in increased fatty acid oxidation through the carnitine palmitoyltransferase1. Following increased fatty acid beta-oxidation, reactive oxygen species (ROS) are generated and stimulates uncoupling protein–-2 (UCP-2) which promotes ROS scavenging and stimulate NPY/AgRP transcription. The activation of hypothalamic AMPK signaling cascade results in an increase of appetite and food intake.
Ghrelin has also been shown to activate Sirtuin-1 (SIRT-1), p53, and mammalian target of rapamycin (mTOR). SIRT-1 is deacetylase; activated in response to calorie restriction that acts through the tumor suppressor p53. SIRT-1 and p53 are required for ghrelin-induced AMPK activation and consequent orexigenic action. mTOR is a ser/threonine kinase acting as a cellular sensor of energy balance changes, growth factors, nutrients, and oxygen [Figure 3].
mTOR is regulated by cellular AMP/ATP ratio; mTOR activity decreases when AMP/ATP ratio decreases (high energy). Hypothalamic mTOR signaling is involved in food intake. In the arcuate nucleus of hypothalamus, it appears that mTOR is activated by AMPK. Activated mTOR phosphorylates S6 kinase-1, S6 ribosomal proteins (S6), and initiation factor 4E binding protein. In the hypothalamus, mTOR and S6K-1 are only located on NPY/AgRP and POMC neurons within the arcuate nucleus. It has been shown that hypothalamic mTOR signaling mediates the orexigenic actions of ghrelin. Ghrelin-mediated mTOR activation, in turn, activates NPY and AgRP synthesis, leading to food intake.
Ghrelin is involved in long-term body weight regulation. Ghrelin levels decrease with weight gain resulting from different conditions as overfeeding, pregnancy, olanzapine treatment, or high-fat diet. Conversely, ghrelin levels decrease with weight loss resulting from conditions such as food restrictions (anorexia nervosa), severe CHF, lung carcinoma, colon cancer, and breast cancer. In vivo, chronic ghrelin administration induces adiposity. In addition to increasing food intake, ghrelin decreases energy expenditure, consequently decreasing utilization and oxidation of fat whereas increasing carbohydrate utilization. Furthermore, ghrelin shifts food preferences toward high-fat diet [Figure 4].
The discovery of leptin is relatively new and it also changed our notion of adipose tissue just being a simple energy depot to an active endocrine organ. Leptin is derived from a Greek word “leptos” which means thin. Leptin is a 167-amino acid peptide that is mainly derived from white adipose tissue but is also found in other tissues such as placenta, mammary gland, ovary, skeletal muscle, stomach, pituitary gland, and lymphoid tissue. Leptin is encoded by ob gene. Leptin levels fluctuate according to the changes in calorie intake with a marked decrease during starvation. Leptin is secreted in a pulsatile manner, displaying a circadian rhythm with lowest levels at midafternoon and highest levels at midnight. The levels of leptin secretion are similar in obese and lean subjects, but the pulse amplitude is higher in obese subjects.
Physiological actions of leptin
Appetite and food intake
Leptin exerts its metabolic effects through various leptin receptors which are named as LEP-R or OB-R. In humans, long isoform LEP-Rb and short isoform LEP-Ra, c, d of leptin receptors are present. Most of the actions of leptin are mediated by OB-Rb isoform. While LEP-Rb is responsible for the suppression of food intake and stimulation of energy expenditures, the short isoform of LEP-Rb mediates the transport of leptin across the blood–brain barrier. The long isoform of leptin receptor (LEP-Rb) is highly expressed in hypothalamus and other brain regions, where it induces satiety and considered as main leptin receptor.
In the arcuate nucleus of hypothalamus, leptin interacts with a complex neural circuit to control food intake, activating anorexigenic neurons that synthesize POMC, α-MSH, and cocaine and amphetamine-regulated transcript and inhibiting orexigenic neurons that synthesize AgRP and NPY.
LEP-R, when activated, incites several signaling pathways, but activation of Janus kinase-2 and signal transducer and activator transcription-3 signaling plays a crucial role in leptin's ability to regulate satiety. During fasting and starvation, circulating leptin levels fall considerably. The obese individual usually has high levels of leptin secretion from adipose tissues, but these high levels of leptin fail to reduce excess adiposity, indicating leptin resistance. Moreover, exogenous leptin administration has little effect on the body fats in such subjects. Leptin resistance may be due to the disruption of leptin signaling in hypothalamus and other central nervous system (CNS) neurons, impaired leptin transport across the blood–brain barrier, hypothalamic inflammation, endoplasmic reticulum stress, and autophagy.,
Energy homeostasis and obesity
Body weight is maintained by balance in energy intake and energy expenditure. When there is positive energy balance in the form of excess energy intake and fat accumulation then occurs obesity. Adipose tissues remain in close communication with brain for maintaining energy homeostasis and body weight. Adipokines such as leptin convey the message of positive energy balance and excess fat accumulation to the hypothalamus which senses and integrates these signals and tries to change feeding behavior energy expenditure to maintain the body weight. Leptin increases energy expenditure stimulating brown adipose tissue thermogenesis by increasing the expression of UCP-1.
In mice, genetic leptin deficiency (ob/ob mice) or lack of functional leptin receptors leads to morbid obesity and Type-2 diabetes. In human, congenital leptin deficiency causes severe hyperphagia and early-onset obesity. Leptin replacement therapy helps to reverse this type of obesity and also improves obesity-related metabolic disorders in leptin-deficient patient.
Leptin and metabolism
Leptin affects peripheral insulin sensitivity through CNS mechanisms independent of its effects on food intake and weight. Leptin potently suppresses hepatic glucose production partly by ameliorating hyperglucagonemia and increase peripheral glucose uptake through multiple mechanisms including POMC and AgRP-expressing neurons in arcuate nucleus.
In addition to regulating insulin sensitivity, leptin alters glucose homeostasis through insulin. Leptin inhibits insulin gene expression and glucose-stimulated insulin secretion and these actions adapt glucose levels to body fat stores. In turn, insulin stimulates both leptin synthesis and secretion, thus stabilizing an adipose-islet axis. Leptin also protects pancreatic beta cells from lipotoxicity in various animal models.
Clinical application of leptin
Leptin treatment has robust effects in states of leptin deficiency. Leptin replacement dramatically reduces body weight and fat and reverses metabolic abnormalities in individuals with congenital leptin deficiency. In subjects with congenital or acquired lipoatrophy, leptin treatment improves several metabolic parameters including insulin sensitivity, dyslipidemia, and hepatic steatosis. In contrast, the common forms of obesity and Type-2 diabetes are accompanied by leptin resistance. A combination therapy of leptin and leptin sensitizers has been suggested to overcome leptin resistance.
| Conclusion|| |
Recent work suggests that ghrelin, the only known peripheral hunger peptide, increases appetite, adjusts energy balance, and enhances the release of growth hormone from the pituitary gland. It is a known fact that levels of ghrelin are elevated in cachectic status. Many clinical trials which show beneficial effects of ghrelin against loss of appetite and cachexia have been undergoing. The pathophysiological role of ghrelin in patients who are undergoing chemotherapy and loss of appetite have yet to be known. Leptin plays a more important role in the maintenance of weight loss than weight loss per se. Studies have shown that leptin can be considered asweight loss treatment, but studies are underway to determine whether leptin replacement can be an effective therapy for the maintenance of weight loss.
The authors acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. The authors are also grateful to authors/editors/publishers of all those articles, journals, and books from where the literature for this article has been reviewed and discussed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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File: Hunger and satiety signals.png, From Wikimedia Commons, the free media repository.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]