Leptin and ghrelin dynamics: unraveling their influence on food intake, energy balance, and the pathophysiology of type 2 diabetes mellitus

Abstract

Purpose

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and impaired glucose homeostasis. In recent years, there has been growing interest in the role of hunger and satiety hormones such as ghrelin and leptin in the development and progression of T2DM. In this context, the present literature review aims to provide a comprehensive overview of the current understanding of how ghrelin and leptin influences food intake and maintain energy balance and its implications in the pathophysiology of T2DM.

Methods

A thorough literature search was performed using PubMed and Google Scholar to choose the studies that associated leptin and ghrelin with T2DM. Original articles and reviews were included, letters to editors and case reports were excluded.

Results

This narrative review article provides a comprehensive summary on mechanism of action of leptin and ghrelin, its association with obesity and T2DM, how they regulate energy and glucose homeostasis and potential therapeutic implications of leptin and ghrelin in managing T2DM.

Conclusion

Ghrelin, known for its appetite-stimulating effects, and leptin, a hormone involved in the regulation of energy balance, have been implicated in insulin resistance and glucose metabolism. Understanding the complexities of ghrelin and leptin interactions in the context of T2DM may offer insights into novel therapeutic strategies for this prevalent metabolic disorder. Further research is warranted to elucidate the molecular mechanisms underlying these hormone actions and to explore their clinical implications for T2DM prevention and management.

Introduction

Type 2 diabetes mellitus (T2DM) is a global health concern, and its prevalence has been steadily increasing over the years [1]. The International Diabetes Federation (IDF) estimated that approximately 537 million adults (ages 20–79) were living with diabetes worldwide in 2021 [2]. This includes both Type 1 and Type 2 diabetes. The IDF projects that the number of people with diabetes will rise to 643 million by 2030 and 784 million by 2045 if current trends continue [2]. Diabetes prevalence varies by region, with some regions experiencing higher rates than others. Countries with large populations, such as China and India, have a significant burden of diabetes cases. The Middle East and North Africa have reported high prevalence rates, as have some Pacific Island nations [3]. Other than being a major cause of morbidity and mortality globally, diabetes is also a leading cause of cardiovascular diseases, kidney failure, blindness, and lower-limb amputations [4]. Lifestyle factors, including poor diet, physical inactivity, and obesity, contribute significantly to the development of T2DM. Genetic factors also play a role, and there may be a higher risk in individuals with a family history of diabetes [5]. A significant number of people with diabetes are undiagnosed, emphasizing the importance of awareness and regular health check-ups. Early diagnosis and effective management are critical in preventing complications associated with diabetes. Many countries have implemented public health programs to address diabetes prevention and management, including lifestyle interventions and health education campaigns.

Food intake has been strongly linked with obesity. A diet high in fat, calories, and cholesterol increases the risk of obesity ultimately leading to diabetes [6]. Complex connections between hormones from the gastro-intestinal tract to the hypothalamus and subsequent feedback are involved in the sensations of hunger and satiety. To maintain energy balance, a number of hormones control satiety and appetite of which ghrelin and leptin are the important ones [7]. Ghrelin, primarily produced in the stomach, is recognized for its orexigenic effects and stimulation of growth hormone release. Emerging evidence suggests that ghrelin may also play a significant role in glucose metabolism. Studies have shown elevated ghrelin levels in individuals with T2DM, potentially contributing to insulin resistance and impaired glucose tolerance. Ghrelin may influence insulin sensitivity by modulating adipose tissue metabolism and promoting inflammation [8, 9]. Additionally, ghrelin’s effects on pancreatic beta cells and insulin secretion are areas of active investigation. Similarly, leptin produced by adipocytes, is a key regulator of energy homeostasis, acting to reduce appetite and increase energy expenditure. In obesity, there is often a paradoxical condition called leptin resistance, where elevated leptin levels fail to exert their appetite-suppressing effects. Leptin resistance has been linked to insulin resistance and T2DM. Leptin’s influence on insulin sensitivity involves complex interactions with central and peripheral pathways, including modulation of inflammatory processes and lipid metabolism [10–12].

This literature review aims to provide a comprehensive overview of the current understanding of how ghrelin and leptin influences food intake and maintain energy balance and its implications in the pathophysiology of T2DM.

Leptin: the satiety hormone

Leptin is a 167-amino-acid peptide hormone produced by adipocytes; that is remarkably stable between species. It is mostly found in adipose tissues and is produced by the obese (ob) gene, which is situated on chromosome 7 [13]. In order to sustain body fat stores, plasma leptin concentration regulates food intake and energy expenditure as it rises proportionately to body fat mass. Circulating leptin is secreted into the bloodstream and travels to the brain via the cerebrospinal fluid (CSF) and brain-blood barrier (BBB). Leptin regulates the body’s energy equilibrium by acting in a variety of ways on the ventromedial nucleus, lateral hypothalamus, and arcuate nucleus. It also has stimulatory and inhibitory effects on hunger [14, 15].

The LEPR gene in humans encodes the type I cytokine receptor leptin receptor, also known as Lep-R or OB-R [11, 16]. Lep-R, which has several subtypes expressed in various hypothalamic nuclei, is the main receptor for leptin. LepRb, a subtype of the leptin receptor, activates signalling cascades such as JAK2/ERK and STAT3 [17]. When leptin binds to Lep-R, it transphosphorylates three tyrosine residues (Y985, Y1077, and Y1138) to activate the receptor-associated kinase JAK2 which further phosphorylates STAT3 and STAT5 (Fig. 1). When phosphorylated STAT3 enters the nucleus, it increases pro-opiomelanocortin (POMC) expression while decreasing neuropeptide Y (NPY) expression which leads to decrease in the appetite [18, 19]. The LepRb-Y985 signals regulate the hepatic insulin sensitivity. Whole-body insulin sensitivity is improved when LepRb-Y985 signalling is absent, in part because more insulin is used to decrease hepatic glucose synthesis [20]. Leptin release controls energy storage levels in addition to being influenced by dietary intake, gender, age, physical activity, and blood sugar levels [12]. A recent structural analysis by Saxton et al., defined the cryo-EM structure of a stabilized leptin–LepR signalling complex [21]. The findings suggest that LepR activation is a two-step process wherein leptin first forms a 1:1 complex on the cell membrane with LepR by binding it via the high affinity site 2 interface. Leptin and the LepR Ig domain then trans-interact to create the site 3 interface, which dimerizes LepR to produce signalling competent 2:2 complexes. This opens up new possibilities for pharmacologically modulating leptin signalling and providing fresh insights into the mechanism of LepR activation as well as understand the downstream pathways.

Fig. 1.

Regulation of appetite by leptin via JAK2/STAT pathway. Leptin binds to the leptin receptor (LepRb) and activates the receptor-associated kinase JAK2 via transphosphorylation and phosphorylates tyrosine residues which further leads to phosphorylation of STAT3 and STAT5. Phosphorylated STAT3 and STAT5 when translocated to the nucleus, increases the expression of pro-opiomelanocortin (POMC) and inhibits the expression of neuropeptide Y (NPY) ultimately resulting in increased energy expenditure and decreased appetite. Created with BioRender.com

Leptin resistance in obesity and its link to T2DM

It is commonly believed that obesity and elevated leptin levels are signs of a leptin-resistant state because leptin inhibits overeating by interacting with certain leptin receptors. Hence obese people develop leptin resistance because their leptin response to calories is reduced. Leptin resistance shows symptoms of reduced feelings of satiety, excessive food ingestion, and a rise in total body mass increasing the risk of developing obesity [12]. Leptin synthesis and sensitivity to the hormone can be controlled and influenced by a number of significant genetic and environmental factors. Some of the potential underlying mechanisms of leptin resistance include abnormal signalling pathways within cells upon leptin binding to its receptors, interactions between the neural networks responsible for eating behaviour and higher cortical centers that control feeding, and genetic mutations in the leptin gene [22, 23]. Leptin itself plays a significant role in the development of leptin resistance and this phenomenon is known as “leptin-induced leptin resistance” [24]. In this vicious cycle, people who become leptin resistant are more likely to develop diet-induced obesity, which in turn raises leptin levels and exacerbates already-existing leptin resistance. In addition, abnormalities of autophagy, endoplasmic reticulum stress, and hypothalamus inflammation contribute to the emergence of obesity-related leptin resistance [25–27].

Leptin is transported from the blood to the brain’s interstitial tissue and cerebrospinal fluid through brain blood arteries that produce short versions of Lep-R, which bind to leptin [28]. The concentration of leptin in brain tissues and CSF fluid is maintained such that under normal conditions it does not rise above a range of 25–30 ng/mL in serum. Leptin resistance can develop at the blood-brain barrier (BBB), allowing for uncontrolled transit of the hormone from the blood to the brain. This mechanism, where high levels of leptin in the blood lead to decreased BBB permeability, contributes to the emergence of leptin resistance and obesity. Schwartz et al., demonstrated that under these circumstances, lower leptin concentrations were seen in the spinal fluid of obese people [29]. Other factors that have deregulatory effects on leptin’s transport across BBB include binding protein megalin [30], triglycerides [31], and acute phase C-reactive protein [32]. The transcription of the Lep-R gene determines leptin concentrations and leptin-related effects, therefore variables altering this can have a significant impact on adipose tissue state and the emergence of leptin resistance [12]. Several studies have suggested that deficiency of Lep-R gene can directly lead to leptin resistance [33, 34], while others have also demonstrated that genetic defects affecting domain structure of the leptin receptor leads to impairment of JAK2/STAT3 pathway ultimately resulting in leptin resistance and severe obesity [35, 36]. Notably, one of the main risk factors for the development of obesity is the decreased capacity of central Lep-R and peripheral leptin to work together to promote energy expenditure and suppress appetite. Elevated peripheral leptin levels therefore have the potential to prevent or reverse obesity. However, most obese humans and animals have high amounts of circulating leptin rather than being leptin deficient [37], and increasing leptin does not prevent the development of obesity [24, 38].

Numerous studies have shown that the majority of people with diet induced obesity exhibit leptin resistance, which is characterized by elevated blood levels of leptin and decreased leptin sensitivity. This resistance is correlated with the person’s BMI and adipose mass [22, 39, 40]. Up until the appropriate amount of leptin is reached, a reduction in adipocyte leptin levels may cause an increase in adipose tissue volume. In such situations, even though the person is obese, serum leptin levels remain physiological. This phenomenon has been seen among Pima Indians, who have a tendency towards obesity and have serum leptin levels that are generally low [41, 42]. However, additional studies are needed to prove that leptin resistance is inherited. Previous findings suggesting that hyperleptinemic individuals and animals respond less strongly to exogenous leptin further supports the idea that leptin resistance contributes to obesity [43, 44]. Although identifying the origins of leptin resistance is crucial, little is known about the cellular and molecular processes that underlie it. Surprisingly, a study by Knight et al., showed that even after prolonged exposure to a high-fat diet, obese animals with persistently low plasma leptin levels were highly responsive to exogenous leptin, suggesting that dietary fat is not sufficient to inhibit the leptin response [45]. The findings also imply that, hyperleptinemia itself may lead to leptin resistance by suppressing the body’s reaction to leptin. Moreover, additional studies have revealed that the type [46, 47] and length of a diet [48] may have an impact on the development of leptin resistance. According to recent studies looking at the metabolic and biochemical effects of high-fructose diets, fructose feeding appears to alter brain satiety factors and gene expression patterns, as well as cause inflammation and the development of leptin resistance [49, 50].

Leptin resistance and T2DM are interconnected through various mechanisms that involve disruptions in metabolic signaling and inflammatory processes. While the relationship between leptin resistance and T2DM is complex and the precise mechanisms are not fully elucidated, several factors including insulin resistance [51], inflammation [52], adipose tissue dysfunction [53], and disruption of energy homeostasis [54] contribute to how leptin resistance may potentially lead to the development of T2DM.

Ghrelin: the hunger hormone

Ghrelin is a 28 amino acid peptide that was first discovered in the stomach of rats [55]. It is a hormonal byproduct of human P/D1 cells (peptide synthesized from the human ghrelin gene, GHRL, on chromosome 3) and rat gastric A-like cells [56, 57]. Ghrelin’s mRNA is primarily found in stomach tissue, from where it interacts with the brain to regulate energy homeostasis. Through a sequence of post-transcriptional enzymes, ghrelin is activated, changing from preproghrelin to proghrelin [58–60]. Ghrelin can be found in the bloodstream in two different forms: acylated ghrelin mediated by the enzyme ghrelin-O-acyl transferase (GOAT) and non-acylated ghrelin, with non-acylated ghrelin present in much higher concentrations [61, 62]. Energy homeostasis involves maintaining a balance between energy intake and expenditure that is controlled by both food intake and energy storage. In order to keep blood sugar levels stable, insulin and glucagon must be in balance [63]. By stimulating the growth hormone secretagogue receptor 1a (GHS-R1a), the orexigenic hormone ghrelin acts as a critical component of the gut-brain axis to regulate energy homeostasis and reward signaling [64]. The hormone GHS-R1a is a typical G-protein-coupled receptor, exhibiting seven transmembrane domains, that is mainly expressed in different brain areas and also in the pituitary gland, pancreas, white adipose tissue, gastrointestinal system, cardiovascular tissues, adrenal gland and gonadal tissues [65, 66].

The orexigenic function of ghrelin is thought to be centrally mediated. Following intracerebroventricular (ICV) ghrelin injection, C-fos expression mapping revealed fos-immunoreactive neurons in areas predominantly associated with appetite control [67]. This includes the hypothalamic ventromedial nucleus (VMH) and the arcuate nucleus (ARC). This distribution matched the GHS-R1a distribution [68]. Additionally, c-fos expression was found to be elevated by ghrelin in Neuropeptide Y (NPY) neurons by double immunohistochemistry [69]. Agouti-related protein (AgRP) is well-known to be co-expressed by NPY neurons in the ARC. More conclusive evidence connects ghrelin’s effects on AgRP neurons in the central nervous system (CNS) with glucose homeostasis [70]. A study by Yanagi et al., demonstrated that blood glucose and glucagon levels were restored to normal in GHS-R1a knockout calorie-restricted mice by AgRP neuron-selective GHSR re-expression [71]. This illustrates how crucial ghrelin’s glucoregulatory activity is to the ARC’s ability to function during calorie restriction.

Previous evidences shows that the hypothalamus’ 5’ adenosine monophosphate-activated protein kinase (AMPK) maintains energy balance [72–74]. Potentially, AMPK controls energy balance by increasing hunger. It has been proposed that elevated ghrelin levels during fasting stimulate feeding by suppressing specific enzymatic steps in fatty acid production in the VMH through the action of AMPK (Fig. 2). An essential enzyme in the production of fatty acids is fatty acid-synthase (FAS). In the VMH, fasting specifically lowers FAS messenger ribonucleic acid mRNA expression. The fact that VMH FAS mRNA did not drop in GHS-R1a knockout mice while they were fasting demonstrated that this was ghrelin-dependent [75]. Alternative pathways for ghrelin’s orexigenic effects include vagal neurons [76, 77]. It is believed that the afferent vagus transmits appetite-controlling signals from the digestive system to the hypothalamus via the nucleus tractus solitaris in the brainstem, causing adaptive adjustments in energy homeostasis. Hence, the dorsal vagal complex may be a target for circulating ghrelin because it contains GHS-R1a [78, 79].

Fig. 2.

Ghrelin’s orexigenic action through AMPK pathway in ventromedial nucleus of the hypothalamus. Fasting stimulates ghrelin production by the endocrine cells of the stomach. Ghrelin phosphorylates AMPK through GHS-R1a receptor to bring about changes in the fatty acid biosynthesis which results in increased appetite. The figure is adapted and modified from Sovetkina et al., 2020 [80]. Created with BioRender.com

Role of ghrelin in appetite stimulation, energy and glucose homeostasis

Food intake plays a crucial role in maintaining glucose and energy balance [81]. The major function of ghrelin is thought to be hunger stimulation, which increases energy intake. It is possible that ghrelin plays a compensating function in energy imbalance because its secretion is enhanced during fasting when there is a negative energy balance and inhibited after feeding when there is a positive energy balance [64, 82]. Pharmacological evidence suggests ghrelin’s function in stimulation of appetite. Compared to anti-ghrelin immunoglobulin injection, chronic ICV ghrelin infusion significantly promotes eating and body weight growth in animals [83, 84]. It has been demonstrated that ghrelin levels closely track meal times. In humans, plasma ghrelin increases by around a factor of two before a meal and decreases shortly after [85, 86] suggesting that ghrelin is involved in the beginning of feeding. However, because the studies involved scheduled mealtimes, the participants knew when to expect meals. Therefore, an anticipated reaction to the food may have affected meal initiation instead of circulating ghrelin levels. Contrarily, physiological investigations cast doubt on the role of ghrelin in controlling hunger and weight. The administration of either a high-fat diet (HFD) or regular chow diet to ghrelin-knockout and control mice demonstrates indistinguishable differences in food intake and body weight [87, 88]. But given that ghrelin deficiency is a lifetime condition, such findings in germline ghrelin knockout models may be explained by developmental compensation. The role of ghrelin in the control of hunger and energy storage is nevertheless supported by quite a few research [89–91]. When compared to control mice, Zigman et al., found that both male and female GHS-R1a knockout mice consumed less food and gained less weight on HFD [87]. Lower body weight of GHS-R1a knockout mice on HFD suggests ghrelin causes body weight change in over-fed states, adapting to a positive energy balance by increasing fat storage.

According to available data, ghrelin affects both glucagon and insulin levels and therefore plays a crucial role in controlling blood glucose levels and subsequently glucose metabolism [92, 93]. A study by Nikolopoulos et al., demonstrated that both mouse pancreatic alpha-cells and islets of Langerhans contained GHS-R1a mRNA, according to quantitative polymerase chain reaction and histochemistry [94, 95]. This suggests that ghrelin acts directly at the pancreas. The two cell types’ levels of GHS-R1a mRNA were considerably decreased in high glucose circumstances, suggesting that ambient glucose levels control GHS-R1a expression. However, the usage of cells in vitro may not be comparable to the physiological effect in vivo, which limits both of these experimental findings. Furthermore, pancreatic GHS-R1a expression may differ between species [96, 97]. A negative correlation was found between the given glucose concentration and ghrelin release from cultured mouse gastric mucosal cells [98]. In addition, ghrelin secretion at low glucose concentrations was prevented by insulin injection. This shows that low glucose concentrations make ghrelin-releasing cells more sensitive to insulin and that glucose concentrations directly affect ghrelin-releasing cells. It is noteworthy that insulin can limit the amount of ghrelin secreted by cultured gastric mucosal cells, most likely by direct interaction with the highly expressed insulin receptors (IRs) in ghrelin cells. A study by Shankar et al., studied the nature of the IRs expressed by ghrelin cells to evaluate how it contributes to the reductions in plasma ghrelin caused by meals and obesity, as well to examine the physiological effects of interfering with that signalling using wild type and ghrelin-cell selection IR deletion (GhIRKO) mice. The study revealed that postprandial and obesity-associated reductions in plasma ghrelin require elevated insulin, which acts through ghrelin cell–expressed IRs to inhibit ghrelin release [99]. Overall, the evidence is overwhelming in favor of ghrelin’s role in glucose homeostasis. It is necessary for further studies to conduct human investigations to clarify ghrelin’s function as it is particularly important during extreme negative energy balance to stop life-threatening hypoglycemia and can raise blood sugar levels in such physiological conditions.

Both type 1 and advanced type 2 diabetes are characterized by insulin-induced hypoglycemia [100]. Because hypoglycemia carries a significant risk of injury, a highly developed counterregulatory response (CRR) system is in place to prevent, reduce, and reverse hypoglycemia. There are many regulatory factors that are associated with CRR response and one of the important factors is acyl-ghrelin. To characterize the permissive nature of acyl-ghrelin, Shankar et al., tested the idea that the normal CRR is susceptible to insulin-induced hypoglycemia, and that this is due to the hormone acyl-ghrelin, which protects against hypoglycemia in a preclinical fasting paradigm. Their findings implied that endogenously synthesized acyl-ghrelin modulates insulin sensitivity and permits the normal CRR in response to insulin-induced hypoglycemia [101]. Additionally, the same group also demonstrated that recurrent hypoglycemia does not modify the normal decrease in plasma ghrelin caused by insulin-induced hypoglycemia, nor does ghrelin affect blood glucose levels or the suppressed CRR hormone responses that occur during recurrent hypoglycemia [102]. Growing number of evidence suggest that ghrelin inhibition may help in the management of T2DM by reducing blood sugar levels and improving insulin sensitivity [80, 103, 104]. The effects of ghrelin on blood glucose are mediated through modifications to several pathways involving numerous downstream effectors. These downstream effectors are mediated through involvement of various organs including the pituitary gland, the ventromedial nucleus of hypothalamus, islets of pancreas, and gastrointestinal tract. The physiological conditions in which these downstream effectors are either increased or decreased varies as summarized in Fig. 3.

Fig. 3.

Various actions of ghrelin on glucose homeostasis. Different sets of downstream effectors are activated by ghrelin effects to control blood glucose, depending on the dietary and metabolic context. One of the important aspects of ghrelin’s effects on the central nervous system to boost blood glucose levels is by stimulating appetite. This appears to be the key to preventing life-threatening hypoglycemia in fat-depleted, starvation-like situations. During fasting conditions, ghrelin stimulates glucagon secretion by acting on the brain and pancreatic islets, which boosts hepatic glucose synthesis by acting on the brain. On the other hand, during postprandial conditions, ghrelin’s glucoregulatory activities reduces insulin sensitivity, inhibiting insulin secretion from pancreatic β-cells, and stimulates enteroendocrine L-cells to secrete GLP-1. Additionally, ghrelin decreases insulin sensitivity in obese people directly, which results in hyperglycemia and exacerbated glucose intolerance. Created with BioRender.com

Interplay between leptin and ghrelin in the pathophysiology of T2DM

Leptin- a peripheral anorexigen and ghrelin- a peripheral orexigen are the two hormones that play key roles in the regulation of appetite and energy balance, and they have an intricate interplay in the body. Under normal circadian rhythm, leptin levels typically rise during sleep, helping to maintain fasting metabolism, while ghrelin levels increase before meals. Similarly, when leptin levels are high (indicating sufficient energy stores), appetite is suppressed, and energy expenditure is increased. Conversely, when ghrelin levels are high (indicating the need for energy), appetite is stimulated suggesting that leptin and ghrelin work in a feedback loop.

Leptin and ghrelin intersect via a common factor, neuropeptide Y (NPY) which is located within the hypothalamic arcuate nucleus (ARC). Leptin exerts its effects through suppression of NPY whereas, ghrelin activates NPY neurons stimulating hunger centers. A seminal paper by Kohno et al., demonstrated that ghrelin induced calcium signalling in NPY neurons of ARC and leptin suppressed this ghrelin induced neural signalling and feeding [105]. In addition to ARC, NPY neurons are also effective in paraventricular hypothalamic nucleus (PVN) which is assisted by the release of gamma-aminobutyric acid (GABA) via distinct receptors [106, 107]. Further, NPY and GABA synergistically modulates POMC signals increasing appetite [108–110]. Evidence from the literature suggest that leptin inhibits feeding during the light phase by limiting the efflux of orexigenic NPY and GABA in the PVN [111]. It also increases the release of anorexigenic alpha-melanocyte stimulating hormone (α-MSH) and cocaine amphetamine regulating transcript (CART) in the PVN, either directly or indirectly through NPY [111–113]. In addition, by opposing NPY release and action in the PVN, leptin tonically restrains ghrelin secretion from the stomach and prevents its central orexigenic function [114, 115].

In the context of understanding how leptin and ghrelin levels are associated in the course of T2DM development it is not only important to investigate how these hormones are produced and in what quantity but also assess their receptor activity. According to the findings by Zhang et al., serum leptin had a positive correlation with insulin levels and insulin resistance, whereas ghrelin concentrations had a negative correlation [116]. These findings provided credence to the hypothesis that ghrelin and leptin may be important factors in the development of insulin resistance and hyperinsulinemia. The study also demonstrated a negative connection between serum leptin and fasting plasma ghrelin levels during the onset of T2DM, corroborating the antagonistic effects of ghrelin and leptin on metabolic syndrome as shown by others previously [117–119].

In summary, the intricate balance between ghrelin and leptin is crucial for maintaining metabolic homeostasis. Disruptions in this balance, such as elevated ghrelin levels or leptin resistance, may contribute to the pathogenesis of T2DM. Studies have explored the cross-talk between ghrelin and leptin signaling pathways and their impact on insulin action. Understanding these interactions may unveil potential therapeutic targets for T2DM management.

Influence of leptin and ghrelin on body weight, energy expenditure and metabolic rate

Several biological processes including reproduction [120], immune response [121], inflammation [122], and angiogenesis have all been linked to leptin action. Most intriguingly, leptin acts as a feedback system that instructs important brain regulatory centers to limit food intake, control body weight, and maintain energy homeostasis [123]. Leptin was only believed to be important for the long-term regulation of energy balance until a few years ago. However, according to more recent research, leptin may also be involved in the short-term control of food intake and body weight [54, 124, 125]. In addition to adipose tissue, the stomach also produces a minor quantity of leptin. Consequently, it has been proposed that leptin, in conjunction with other satiety peptides, may regulate meal size [126].

Numerous researchers for a long time have been interested in elucidating how leptin functions in the etiology of obesity [16, 127, 128]. But many experts began to realize a few years ago that leptin may play a more significant role in adaptation to calorie shortage. It has been demonstrated that fasting up to 36 h causes a considerable drop in plasma leptin levels. The drop in circulating leptin concentration is not exclusively caused by the change in adipose mass, as evidenced by the fact that the decline in plasma leptin was significantly larger than the change in adipose mass [123]. Additionally, leptin is implicated in the neuroendocrine response to hunger, which includes alterations in hormone concentrations and perhaps in sympathetic nervous system activity and reproductive function, as several investigations have shown [129, 130]. Low leptin concentrations are linked to disease states such as exercise-induced amenorrhea and anorexia nervosa, which exhibit similar alterations in neuroendocrine activity [131, 132].

The earliest evidence suggesting ghrelin is involved in the regulation of food intake and energy balance came from Tschop et al., from their in vivo experiments [133]. These initial findings led to the hypothesis that ghrelin signals the hypothalamus when higher metabolic efficiency is required. It has been shown that in healthy individuals, the pre-prandial rise in ghrelin levels corresponds with hunger scores, causing them to voluntarily start meals in the lack of cues linked to food or time [134, 135]. Furthermore, ghrelin can be infused or administered intravenously to stimulate appetite and food consumption in both healthy and obese individuals [136]. Taken together, this suggests that the short-term management of energy balance is mediated by ghrelin, which appears to act as a meal-initiation signal. Asakawa et al. hypothesized that the stimulatory impact of ghrelin on stomach emptying mediates the rise in food intake following its administration, based on the findings of research conducted on mice [137]. Given that circulating ghrelin levels in human subjects have been shown to be linked with stomach emptying, this may also be the case in humans. Additionally, it has been observed that when ghrelin is administered peripherally, rodents exhibit reduced energy expenditure [133, 138]. However, it hasn’t been proven in humans yet, and therefore it is unclear if ghrelin affects how energy expenditure is regulated. It is very well known that ghrelin controls hunger and energy expenditure, which encourages energy saving. There is limited evidence available regarding the metabolic activities of ghrelin in the obese state, despite some research suggesting that inhibiting ghrelin function reduces body weight gain and glucose intolerance on a high-calorie diet. An unpopular opinion is that during diet induced obesity (DIO), stomach cells secrete less ghrelin resulting in a state of central ghrelin resistance. Alternatively, diet-induced weight reduction can reverse ghrelin resistance, which is a defence mechanism to maintain a higher body weight set-point established during periods of food availability, maximizing energy reserves during periods of food scarcity [139].

Since the physiological response to food intake is reciprocally regulated by the interaction between leptin and ghrelin, the ratio of concentrations of these hormones could be termed as hunger signal. Several studies have utilized this index to evaluate patient benefits to surgery and treatment. A study by Crujeiras et al., used hypocaloric diet to induce weight loss in obese patients to monitor leptin/ghrelin ratio from baseline to the end of follow-up period of 32 weeks [140]. The study demonstrated that circulating leptin/ghrelin ratio could be used as a non-invasive tool to differentiate between obese patients who would regain weight post energy restriction treatment [140]. Another seminal study by Labayen et al., examined the influence of leptin and ghrelin on body weight and fat mass following an energy based dietary restriction in obese women. The study revealed that obese women who had baseline levels of higher leptin and lower ghrelin were more resistant to fat mass loss and suggested that leptin/ghrelin ratio could be a potential biomarker for predicting metabolic responses to calorie restriction treatment [141]. A recent study investigated how leptin/ghrelin ratio changes to meals with different macronutrient contents and concluded that obesity affects the feeling of satiety post meal rich in carbohydrates. This difference between non-obese and obese men was observed in both fasting as well as post-prandial state [142].

Therapeutic implications of leptin and ghrelin

Obesity associated complications is becoming a bigger health burden due to its rising prevalence worldwide. There is an urgent need for the development of measures to tackle the obesity epidemic because obesity is a significant risk factor for the onset of cardiovascular illnesses and T2DM. The roles of ghrelin and leptin in T2DM highlight their potential as therapeutic targets. Interventions aimed at modulating ghrelin and leptin levels or enhancing their sensitivity may hold promise in improving insulin sensitivity and glycemic control. However, challenges exist in developing targeted therapies without undesirable side effects, emphasizing the need for further research in this area.

Although leptin has been considered as one of the therapeutic candidates for obesity, the effect has been limited due to the apparent development of leptin resistance and decreased blood brain barrier transport. There is evidence suggesting that administration of recombinant adeno- associated virus (AAV) vector encoding leptin gene to rodents for prolonged period of time significantly reduced fat and improves the symptoms of metabolic syndrome [143]. AAV vectors’ low toxicity and capacity to promote transgenic expression for prolonged periods of time make them especially well-suited for central leptin gene therapy [144]. Additionally, it has been demonstrated that leptin treatment in diabetic mice can reverse hyperglycemia and reduce mortality [145, 146].

Drugs that target ghrelin’s orexigenic or obesity-related properties have been actively developed by pharmaceutical companies [147]. By encouraging glucose-dependent insulin secretion, weight loss, and appetite suppression, ghrelin receptor antagonists have been found to limit GH secretion and so ameliorate the diabetic condition [148, 149]. It has been demonstrated that the peptide inverse agonist DLys3-GHRP6, which inhibits GHRP-induced GH production, decreases food intake and body weight [150]. Additionally, acylated ghrelin when injected into mature rats or mice reduces feed efficiency, obesity, and body weight gain via an immunological response generated against acylated ghrelin [84, 104]. In a nutshell, understanding the physiology of leptin and ghrelin is essential to identifying and creating the most effective plans for modulating the pathways in a pharmacologically helpful approach. The cellular and molecular causes of selective leptin resistance are still unknown, similarly, very little is currently known about ghrelin resistance. Although a number of theories have been put out, further research is required to completely comprehend the physiological importance and molecular underpinnings of ghrelin resistance. Understanding the processes behind selective resistance to the hunger and satiety hormones will be crucial to treating the disorders that are frequently linked to obesity and thereby T2DM. As much as ghrelin system holds a therapeutic possibility to treat obesity and T2DM, one needs to be aware of the potential hazards of modulating the pathway as it is associated with hippocampal neurogenesis which are particularly linked to neurodegenerative disorders [151–153]. Since there is a significant positive correlation between T2DM individuals developing Alzheimer’s or even Parkinson’s disease, such individuals are not ideal for these treatments.

It is worthwhile to note the role of these hormones in diseases or conditions serving as comorbid features along with T2DM. Since T2DM is associated with chronic stress, it is important to underscore the multifactorial nature of ghrelin signaling as it is known to respond to varieties of stress. Some studies have observed elevated levels of ghrelin to stress and even have classified ghrelin as one of the biomarkers of stress [154–156]. Since ghrelin was shown to be a hormone that promotes hunger, it has been shown to play a variety of other roles in learning, memory, reward, and stress management. Although beneficial in its normal doses, extended exposure to the hormone has been connected to maladaptive behaviours and responses in the context of mental illness [157]. There are possibilities of ghrelin signaling abnormalities brought on by prolonged stress which could increase a person’s vulnerability to post-traumatic stress disorder (PTSD) and co-occurring disorders including depression and alcoholism. Hence, manipulation of ghrelin has therapeutic potential in treating such stress-related illness. Interestingly, a recent study investigated the levels of leptin and ghrelin in SARS-CoV2 infected population to evaluate the protective role of these hormones in the inflammatory process [158]. Although the study did not observe any significant changes in leptin levels, serum ghrelin levels were significantly elevated in patients challenged with six months of SARS-CoV2 infection. It can be speculated that ghrelin plays a role in regulation of immune response by reducing oxidative stress and attempting to block host cell-virus interaction. Further studies are needed before ascertaining any possibilities of utilizing these hormones in the direction of therapeutics.

Conclusion

The literature suggests that ghrelin and leptin play intricate roles in the pathophysiology of T2DM, influencing insulin sensitivity, glucose metabolism, and overall energy homeostasis. Understanding the complexities of ghrelin and leptin interactions in the context of T2DM may offer insights into novel therapeutic strategies for this prevalent metabolic disorder. Further research in addition to the ongoing ones is warranted to elucidate the molecular mechanisms underlying these hormone actions and to explore their clinical implications for T2DM prevention and management.

Funding

No funding was received to assist with the preparation of this manuscript.

Declarations

Competing interests

The authors have no competing interests to declare that are relevant to the content of this article.