Understanding the complex action mechanism of appetite regulation peptides can significantly impact therapeutic options in the treatment of obesity and other metabolic diseases. Hypothalamic alpha-melanocyte-stimulating hormone (α-MSH) is an anorexigenic peptide, closely related to the occurrence of obesity, playing a central role in food intake and energy expenditure. In the central nervous system, α-MSH is cleaved from proopiomelanocortin and then released into different hypothalamic regions to act on melanocortin 3/4 receptor-expressing neurons, lowering food intake, and raising energy expenditure via appetite suppression and sympathetic nervous system. Furthermore, it can increase the transmission of some anorexigenic hormones (e.g., dopamine) and interact with other orexigenic factors (e.g., agouti-related protein, neuropeptide Y) to influence food reward rather than merely feeding behavior. Therefore, α-MSH is a critical node of the hypothalamus in transmitting appetite suppression signals and is a key component of the central appetite-regulating circuits. Herein, we describe the role of α-MSH in appetite suppression in terms of specific receptors, effector neurons, sites of action, and the interaction with other appetite-relative peptides, respectively. We focus on the role of α-MSH in obesity. The status of research on α-MSH-related drugs is also discussed. With the intention of illuminating a new approach for targeting α-MSH in the hypothalamus as a strategy to manage obesity, we hope to further understand the direct or indirect mechanisms by which α-MSH exerts its appetite-regulating effects.

The commencement, periodicity, duration, and amplitude of eating episodes in people’s daily diets are aberrant with the rise in living standards and imbalances in the related regulatory peptides result, leading to a state of excess energy. Obesity, diabetes, and other energy metabolic diseases are all tightly related to increased appetite, regardless of whether it is temporary, as is clinically evident in transient bingeing, or persistent [1, 2]. The central nervous system (CNS) integrates neural and hormonal signals to elicit food intake [3], so a better understanding of the complex mechanisms behind the feeding behavior in the CNS may lead to novel approaches to obesity.

The central melanocortin system plays an integral role in the regulation of food intake [4]. The central melanocortin system is composed of proopiomelanocortin (POMC) neurons and agouti-related protein (AgRP) neurons in the arcuate nucleus (ARC) of the hypothalamus, including the neurotransmitters and neuropeptides released from these neurons and the receptors on which they act [5]. Alpha-melanocyte-stimulating hormone (α-MSH) is a critical node of the central melanocortin system. When POMC neurons are activated, α-MSH is released and subsequently binds to its receptors to exert an anorexigenic effect [6]. In recent years, the effect of α-MSH in suppressing appetite has been more researched and emphasized. Central administration of α-MSH influences food intake, satiety signals, food reward, and the release of peptides that regulate appetite, resulting in a significant reduction in food intake in rats, mice, and goldfish [7‒13]. The experimental modulation of multiple α-MSH receptor subtypes has been shown to affect food intake and/or body weight regulation in animal models. Moreover, α-MSH exerts an anti-obesity effect that partly depends on appetite suppression. Mice that lack the desacetyl-α-MSH and POMC exhibit hyperphagia and obesity [14, 15]. Overexpression of α-MSH in the nucleus of the solitary tract (NTS) attenuates diet-induced obesity [16]. The high concentration of α-MSH promotes better modulation of pathways in obese adolescents, following long-term weight loss therapy [17].

Considering the importance of α-MSH in food intake and the complexity of appetite regulation, it is thus necessary to consider that the appetite control role of α-MSH may provide new treatment strategies for obesity. This review aims to describe the related mechanisms involved in the central control of food intake at different stages of α-MSH from production to action. We paid attention to its acting on receptors as well as the indirect mechanism of α-MSH-regulating appetite including acting on different neurons, hypothalamic nucleus, and interacting with other hormones. At the same time, we focused on the role of α-MSH in obesity. Lastly, we summarized the research progress on α-MSH-related drugs based on a series of in vivo and in vitro studies.

The central melanocortin system integrates a variety of central and peripheral metabolic inputs, regulating energy homeostasis by controlling energy expenditure and food intake [5]. α-MSH as a critical node of the central melanocortin system, the precise balance of its production and degradation, and the accurate site of its projection and expression are the basis for the central melanocortin system to function properly.

α-MSH (first termed simply MSH before the discovery of β- and γ-MSH) is a POMC-derived peptide, first found in the pituitaries and considered a pituitary hormone [18]. However, it was later found that α-MSH can be produced by many extra pituitary cells including monocytes, astrocytes, gastrointestinal cells, and keratinocytes [19] and was also found in many other sites within the CNS, such as the hypothalamus, thalamus, midbrain [20], brainstem [4], pineal gland, forebrain, diencephalon [21], and the limbic system [22], additionally abundant in the ARC and NTS [21].

In the CNS, activation of POMC-expressing neurons triggers the production and release of α-MSH from axon terminals [23]. POMC neurons are abundant in ARC which can sense peripheral hormones and nutrients, such as leptin, insulin, interleukin-1β, glucose, etc. The receptors of these peptides widely express in POMC neurons [24, 25]. When binding to their specific receptors, these hormones will activate POMC neurons and promote POMC processing to α-MSH, then signals to decrease energy intake will be sent [26]. During the breakdown process, prohormone convertase 1/3 (PC1/3), prohormone convertase 2 (PC2), carboxypeptidase E (CPE), and α-amidating monooxygenase, respectively, cleave POMC and its subsequent products to generate pro-adrenocorticotrophic hormone (pro-ACTH), ACTH1–39, ACTH1–17, corticotropin-like intermediate peptide and desacetyl α-MSH1–13 [27]. The acetylation of α-MSH1–13 by N-acetyltransferase not yet identified will then produce acetyl-α-MSH1–13, and this process may serve as a protective measure that stabilizes the peptide against degradation to prolong its action on target cells [28]. Then the α-MSH1–13 may combine with its receptors or be degenerated and thus inactive by prolylcarboxypeptidase (PRCP) [28]. PRCP removes the C-terminal amino acid of α-MSH1–13, producing α-MSH1–12, which is not neuroactive [11, 29]. A deficiency in any of these processing enzymes can lead to inadequate α-MSH production, the disturbance of the central melanocortin system, and even the occurrence of obesity. For instance, Ruthellen Miller and colleagues found that α-MSH in PC2-deficient mice was essentially obliterated in the pituitary, hypothalamus, cortex, and other brain regions (collectively), and the absence of α-MSH was accompanied by accumulation of ACTH, ACTH-containing intermediates, and POMC precursor [30]. In PC1/3N222D/N222D mice, the hypothalamic α-MSH peptide is reduced, and this situation also happens in PC1/3 mutant mice and may partly contribute to the obesity in these mice [31]. Cpefat (a spontaneous mutation that inactivates CPE) mice having low levels of α-MSH in the hypothalamus also leads to severe obesity [32, 33]. Conversely, when the expression of CPE was enhanced, the processing of POMC to α-MSH increased, then the food intake was suppressed in mice [34]. Also, the expression of α-MSH can be influenced by nutritional status (fasting, postprandial status, overfeeding, etc.). The biosynthesis of α-MSH is decreased during fasting for 65 h [35]. The 16 days of high-fat diet (HFD) intake may drive an increase in the α-MSH expression, but the 14 weeks of HFD intake led to the downregulation of α-MSH in the ARC, indicating that the regulation of this peptide has a temporal course of response [36, 37].

Acting on Different Receptors

The central effect of α-MSH on food intake is primarily based on its binding with the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) in multiple brain regions (Fig. 1), which is regarded as the direct action of α-MSH on appetite [38]. However, the binding of α-MSH with these two receptors plays different roles in appetite regulation, which depends on the physiological processes associated with melanocortin receptors (MCRs). In this next segment, we focus on the respective pharmacological effects of MC3R and MC4R.

Fig. 1.

Regulation of food intake and energy homeostasis by α-MSH. α-MSH released from POMC neuron then acts on MC3/4R to suppress food intake, increase expenditure and decrease body weight (red arrows). AgRP neurons release AgRP to prevent the actions of α-MSH then play the opposite role to that of α-MSH (yellow arrows). α-MSH, alpha-melanocyte-stimulating hormone; AgRP, agouti-related protein; POMC, proopiomelanocortin; MC3R, melanocortin 3 receptor; MC4R, melanocortin 4 receptor.

Fig. 1.

Regulation of food intake and energy homeostasis by α-MSH. α-MSH released from POMC neuron then acts on MC3/4R to suppress food intake, increase expenditure and decrease body weight (red arrows). AgRP neurons release AgRP to prevent the actions of α-MSH then play the opposite role to that of α-MSH (yellow arrows). α-MSH, alpha-melanocyte-stimulating hormone; AgRP, agouti-related protein; POMC, proopiomelanocortin; MC3R, melanocortin 3 receptor; MC4R, melanocortin 4 receptor.

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Melanocortin 3 Receptor

The MC peptides act as agonists of MC3R with different affinities (γ-MSH > α-MSH = β-MSH > ACTH) [39], but among these peptides, α-MSH has the most potent anorectic effect [40]. Binding with MC3R, α-MSH can activate adenylate cyclase to elevate intracellular cyclic adenosine monophosphate (cAMP) levels to generate an anorexigenic signal [41]. MC3R is involved in adaptation to diet changes, regulating the will to eat the food. The discrepancy in appetitive responses from knockout animals shown in Table 1 suggested that MC3R plays a contextual role in appetite control and is amplified with hypocaloric and restricted feeding condition [42‒45]. C57BL/6J mice subjected to hypocaloric feeding schedules exhibit compulsive behavioral responses involving food anticipatory activity and caloric loading following, but these responses are not observed in MC3RTB/TB mice (the transcription of MC3R is suppressed). MC3RTB/TB mice show decreased meal size and duration and increased fat mass compared with wild-type mice [46]. Similarly, MC3R−/− mice adapted poorly to restricted feeding, displaying significant attenuation in food intake, locomotor activity, and energy expenditure, and the motivation to acquire food during nutrient scarcity also decrease in MC3R−/− mice, whereas fat mass increase, resulting in further weight loss [47, 48]. When fed a high-fat diet, there is no change in feeding or energy expenditure in MC3R−/− mice but developed a percentage of body fat similar to that observed in the hyperphagic MC4R−/− fed an HFD (40–45%) [42]. MC3R−/− mice exhibit mild obesity including increased adiposity and reduced lean mass (percentage of weight that is not fat) when a chow diet is administered [44]. However, MC3R−/− mice do not develop fatty liver disease, insulin resistance, and inflammation of white adipose tissue through their elevated adiposity and a comparable degree of adipocyte hypertrophy to the MC4R null and diet-induced obese (DIO) mice [42, 49, 50]. MC3R plays an important role in response to restricted feeding, and the increased fat mass of MC3R−/− mice is independent of food intake [51]. Therefore, it can be assumed that MC3R is required for communicating nutritional status to both central and peripheral tissues involved in nutrient partitioning, resulting in metabolism altering [47, 51].

Table 1.

Summary of studies regarding MC3R deficiency in different diet

SpeciesDietResultsRef
Mice HFD ↑Metabolic efficiency, fasting insulin, and glucose intolerance;↓Insulin signaling in muscle and adipose tissue [42] 
Mice HFD ↑Fat mass and feed efficiency;↓Lean mass; and developed hyperleptinaemic [43] 
Mice Low-fat high-carbohydrate diet ↑Locomotor activity anticipating mealtime;↓Food anticipatory activity [52] 
Mice Restricted feeding ↓Adaptation to the food restriction schedule, anticipatory activity and feeding activity;↑Body weight [47] 
Mice Restricted feeding ↑Expression of lipogenic genes, ketogenesis; and developed hyperinsulinemia, glucose intolerance [53] 
Mice Ad libitum feeding and caloric restriction ↓Motivation to self-administer food rewards during hypocaloric conditions but normal in ad libitum feeding conditions [48] 
Mice Hypocaloric feeding schedules ↓Meal size, duration, and self-administration of food rewards [46] 
Mice Chow diet ↓Lean mass and body length;↑Fat mass; and developed mild obesity [44] 
Rats Chow diet ↓Body weight and appetite [49] 
SpeciesDietResultsRef
Mice HFD ↑Metabolic efficiency, fasting insulin, and glucose intolerance;↓Insulin signaling in muscle and adipose tissue [42] 
Mice HFD ↑Fat mass and feed efficiency;↓Lean mass; and developed hyperleptinaemic [43] 
Mice Low-fat high-carbohydrate diet ↑Locomotor activity anticipating mealtime;↓Food anticipatory activity [52] 
Mice Restricted feeding ↓Adaptation to the food restriction schedule, anticipatory activity and feeding activity;↑Body weight [47] 
Mice Restricted feeding ↑Expression of lipogenic genes, ketogenesis; and developed hyperinsulinemia, glucose intolerance [53] 
Mice Ad libitum feeding and caloric restriction ↓Motivation to self-administer food rewards during hypocaloric conditions but normal in ad libitum feeding conditions [48] 
Mice Hypocaloric feeding schedules ↓Meal size, duration, and self-administration of food rewards [46] 
Mice Chow diet ↓Lean mass and body length;↑Fat mass; and developed mild obesity [44] 
Rats Chow diet ↓Body weight and appetite [49] 

Melanocortin 4 Receptor

MC4R is activated by the α- and β-MSH and blocked by AgRP. It is believed to be a strong candidate for appetite regulation for α-MSH has a strong affinity for MC4R, and MC4R is preferentially bound by α-MSH and less by γ-MSH in contrast with MC3R [45]. MC4R functions to regulate food intake and energy expenditure, and regulate insulin secretion, lipid metabolism, bone mineral density, and body length [11]. The deficiency of MC4R influences eating behaviors in humans and animals (Table 2) [54]. Experiments using MC4R-inactivated mice develop a maturity-onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia [55]. An increased feed efficiency (weight gain/kcal consumed) argues that mechanisms in addition to hyperphagia are instrumental in causing weight gain [56]. Consistent with the above results, in humans, the phenotypic features of MC4R deficiency include hyperphagia, increased fat and lean mass, and hyperinsulinemia [41]. Thus, obesity induced by MC4R deficiency is caused by the combined effects of increased food intake (hyperphagia) and decreased energy expenditure [57, 58].

Table 2.

Summary of studies regarding MC4R deficiency in eating behaviors

SpeciesResultsRef
Mice MC4R−/− mice show hyperphagia and subsequent fat deposition [59] 
Mice The concentration-response functions of MC4R−/− mice and wild-type mice were the same for the prototypical taste solutions (sucrose, NaCl, quinine, citric acid) [60] 
Mice Reduction of ethanol drinking by MT-II was not observed in MC4R−/− mice [61] 
Mice MC4R−/− mice exhibit signs of defective satiety and/or satiation with larger size of meals or a decreased intermeal interval when hyperphagia was induced by high-fat feeding [62] 
Rats Percentage of cumulative dietary intake of MC4R−/− rats in descending order of high-fat diet, chow diet, and high-sucrose diet [63] 
Human Obese patients showed a preference for fat meals compared to sucrose meals, and their preference for sucrose meals decreased as the sugar content increased [64] 
Human Obesity had impaired satiety, significantly delayed gastric emptying time, and increased percentage meal retention [65] 
SpeciesResultsRef
Mice MC4R−/− mice show hyperphagia and subsequent fat deposition [59] 
Mice The concentration-response functions of MC4R−/− mice and wild-type mice were the same for the prototypical taste solutions (sucrose, NaCl, quinine, citric acid) [60] 
Mice Reduction of ethanol drinking by MT-II was not observed in MC4R−/− mice [61] 
Mice MC4R−/− mice exhibit signs of defective satiety and/or satiation with larger size of meals or a decreased intermeal interval when hyperphagia was induced by high-fat feeding [62] 
Rats Percentage of cumulative dietary intake of MC4R−/− rats in descending order of high-fat diet, chow diet, and high-sucrose diet [63] 
Human Obese patients showed a preference for fat meals compared to sucrose meals, and their preference for sucrose meals decreased as the sugar content increased [64] 
Human Obesity had impaired satiety, significantly delayed gastric emptying time, and increased percentage meal retention [65] 

Acting on the Different Hypothalamic Nucleus

α-MSH can diffuse long distances to act far from the release site which leads to mismatches between it and its receptor localization in brain regions [66]. NDP-MSH (a stable α-MSH analog) injection in the paraventricular nucleus (PVN), medial preoptic nuclei, and dorsomedial hypothalamic nucleus (DMH) significantly reduced food intake, but LH and ARC are only weakly responsive to NDP-MSH [67], suggesting a possible role for the diffusion of α-MSH. The founding of this study not only showed us that hypothalamic nuclei vary in their sensitivity to α-MSH about their effect on feeding but also suggested that attention should be paid to the potential connections between the ARC and other nuclear areas in the activation and post-activation signaling of α-MSH. Due to the differences in the distribution, density, and types of melanocortin 3/4 receptor (MC3/4R) in the nuclear region, the effect of α-MSH in the hypothalamic nucleus is further different. For instance, the MC3R has a high expression in the ARC, ventromedial nucleus (VMH), ventral tegmental area (VTA), and the central linear nucleus of the raphe, with moderate expression in the anteroventral preoptic nucleus, lateral hypothalamic area, posterior hypothalamic area, medial habenular nucleus, and PVN [68, 69]. Therefore, the MC3R expression in VTA where the dopaminergic neurons are mainly situated has received attention. α-MSH significantly increased the firing rate of MC3R neurons through a mechanism independent of fast synaptic transmission and intracellular Ca2+ levels [70], which are involved in controlling appetitive behaviors [48]. The mesolimbic MC3Rs mediate enhanced motivational responses during caloric restriction which is also relative to dopamine neurons [48]. Compared with MC3R, MC4R has a high expression in the hypothalamus; it is also strongly expressed in the brainstem and moderately in the cortex, hippocampus, corpus striatum, amygdala, thalamus, spinal cord, and also detected in the peripheral nervous system [11, 41, 71]. The highest MC4R protein levels were found in the ARC and VMH, while they were significantly lower in the parabrachial nucleus and NTS. There was no difference in the protein levels between the area postrema and raphe pallidus, and the lowest MC4R protein levels were found in the PVN [72]. However, PVN has garnered the most attention because PVN neurons are anorexigenic, microinjections of α-MSH into PVN can engender satiety and hunger [67, 73], and those MC4R-expressing neurons in PVN are known to regulate satiety body weight [74]. It also found that the MC4R in PVN is indispensable to counteract hypoglycemia or glucopenia [75].

Acting on MC3/4R, α-MSH transduces an anorexigenic signal to various brain regions. The various nuclei of the hypothalamus involved in the central regulation of food intake include ARC, VMH, PVN, DMH, and lateral hypothalamic area (LHA), which have unique anatomical locations and functional characteristics and have a diversity of neuronal species [76]. The ARC is located adjacent to the median eminence, which lacks the blood-brain barrier (BBB) [12]. The ARC neurons including POMC neuron and AgRP neuron “directly” contact with peripheral satiety factors such as leptin and insulin so they were called “first-order neurons” [77]. POMC neurons and the POMC gene mainly originate and express in ARC, so the central effect of α-MSH on food intake is primarily based on the release from ARC or the projection of α-MSH-containing neurons in this area [78, 79]. Hypothalamic α-MSH is undetectable in the null mutations of the POMC gene mice [80]. The activation signaling of POMC neurons in ARC is well linked to obesity. After the ablation of POMC neurons, more than 80% of the ARC induces obesity, and chronic stimulation of POMC neurons can suppress daily food intake effectively and reduce body weight mildly, indicating that for obese individuals with severe POMC deficiency, the application of α-MSH may be more effective [81]. Compared to POMC neurons, AgRP neurons are restricted to the ARC [11]. The activation of AgRP neurons reduces the firing frequency of POMC neurons, and the secretion of α-MSH then promotes appetite, reduces metabolic rate, and increases weight [82]. VMH is an elliptical nucleus located above the ARC and is the primary center of satiety in the hypothalamus [83]. In the VMH, MC3/4R is located on the serotonergic factor 1 neurons where α-MSH acts [84]. It was reported that α-MSH via activation of MC4R in VMH suppresses food intake [85]. DMH is above the VMH. The role of the DMH in energy balance control mainly depends on neuropeptide Y (NPY) which produces an inhibitory action within meal satiety signals [86]. It was found that the projection of α-MSH-containing neurons ascends from the ARC and terminates in DMH [87]. The PVN, which is located adjacent to the third ventricle of the forebrain [88], is an important effector site for hunger/satiety regulation by ARCPOMC and ARCAgRP neurons [12]. The PVN regulates metabolism via neuroendocrine neurons that release oxytocin (OXT), antidiuretic hormone, thyrotropin-releasing hormone (TRH), and corticotropin-releasing hormone, and it regulates the sympathetic nervous system via a large population of pre-autonomic neurons [89]. These neurons such as OXT neurons and TRH neurons are the conspicuous targets for α-MSH [89]. The LHA occupies most of the lateral hypothalamus, receiving dense melanocortinergic inputs from the ARC of the hypothalamus and regulates multiple processes including food intake, reward behaviors, and autonomic function [90].

In addition to the hypothalamus, the brainstem NTS also plays a role in α-MSH-mediated control of food intake. The NTS is the first relay station for visceral afferent information which also expresses POMC neurons [78, 91]. NTS POMC neurons can be activated by leptin, cholecystokinin, and other satiety signals then trigger the release of α-MSH [78]. The action of α-MSH in the NTS has been shown to acutely reduce meal size and food intake [92]. The overexpression of POMC in the NTS leading to the nearly 21-fold increase of α-MSH produces a characteristic unabated hypophagia that is uniquely different from the anorexic tachyphylaxis in the hypothalamus [93]. The sustained anorectic response may result from the absence of compensatory elements in the NTS, such as increased AgRP (the natural antagonist of α-MSH) expression [93]. Another research has shown that the long-term α-MSH overexpression in the NTS attenuates diet-induced obesity which is associated with the change in vagal activity, and the vagal outflow to the stomach modulates gastric activity, which may have physiological relevance for food intake and gastric function [16, 94].

Acting on Different Neurons

After being released by POMC neurons, α-MSH acts on effector neurons containing MC3/MC4R through its diffusion action, or α-MSH-containing neurons establish synaptic connections with other neurons and then trigger the release of related hormones or other effects in these neurons, which in turn regulate feeding activity (Fig. 2). In what follows, we focus on appetite-related neurons and elaborate on the appetite-related effects that result from the action of α-MSH.

Fig. 2.

Interaction between α-MSH and appetite-related neurons. α-MSH exerts an appetite-regulating effect by binding with MC3/4R, or α-MSH-containing neurons make connections between appetite-related neurons via synapses. MCH, melanin-concentrating hormone; DA, dopamine; OXT, oxytocin; TRH, thyrotropin-releasing hormone; ARC, arcuate nucleus; LHA, lateral hypothalamic area; NAc, nucleus accumbens; PVN, paraventricular nucleus; SON, supraoptic nucleus; VTA, ventral tegmental area.

Fig. 2.

Interaction between α-MSH and appetite-related neurons. α-MSH exerts an appetite-regulating effect by binding with MC3/4R, or α-MSH-containing neurons make connections between appetite-related neurons via synapses. MCH, melanin-concentrating hormone; DA, dopamine; OXT, oxytocin; TRH, thyrotropin-releasing hormone; ARC, arcuate nucleus; LHA, lateral hypothalamic area; NAc, nucleus accumbens; PVN, paraventricular nucleus; SON, supraoptic nucleus; VTA, ventral tegmental area.

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OXT Neurons

OXT neurons in both the supraoptic nucleus (SON) and PVN of the hypothalamus are powerfully regulated by appetite-related signals that exert an appetite suppression effect consistent with α-MSH-containing neuron [95‒97]. In the past several decades, researchers found that the melanocortin signaling expressed in the PVN and SON is associated with OXT [98]. Patients with Prader-Willi syndrome present with hyperphagia, morbid obesity, significantly reduced serum α-MSH levels (properly reflecting its central production), and decreased number of OXT neurons in the PVN [99, 100]. In the SON and PVN, OXT neurons are contacted by α-MSH fibers from neurons in the ARC and express a large number of MC4R which is a conspicuous target for α-MSH [101, 102]. However, α-MSH has a selective modulatory action on OXT neurons in the SON via MC4R. Central administration of α-MSH induces Fos (the protein product of the immediate-early gene c-fos) expression and increases the intracellular calcium concentration in hypothalamic OXT neurons, resulting in the exocytosis of OXT, but it inhibits their firing rate and decreases OXT secretion from the pituitary gland [102]. OXT neurons project extensively to over 50 brain regions, including the pituitary, and then release OXT from their neurohypophysial terminals [103]. The release of OXT from the dendrites of magnocellular neurons is regulated semi-independently of secretion from the posterior pituitary, which may account for the selective modulatory effect of α-MSH mentioned above [102]. Compared with the non-pregnant rats, this effect in the hypothalamus was suppressed in pregnant rats. Intracerebroventricular (ICV) injection of α-MSH significantly inhibited the neuron firing of non-pregnant rats in SON but did not observe in pregnant animals, it did induce expression of c-fos during pregnancy, but this was significantly reduced compared to that observed in the non-pregnant group. These attenuated responses will increase appetite in pregnant females which allows the mother to provide the energy needed for the growth and development of the fetus [104].

The OXT in the NTS is also in relation to appetite regulation [105]. The NTS α-MSH also mediates the control of food intake which mention above. Focally injecting α-MSH into the PVN after fasting results in an increased number of c-Fos-containing neurons in the PVN and NTS, suggesting that α-MSH in the PVN may contribute to refeeding-induced satiety through effects on the NTS [106]. However, the relationship between α-MSH and OXT in the NTS has been rarely studied. It can be observed that intravenous injection of melanotan-II (MT-II), an analog of α-MSH, increased the firing rate of OXT neurons in the SON, and the expression of Fos in neurons of the SON, PVN, and NTS, and this response was attenuated by prior ICV administration of the SHU-9119 (an MC3/4R antagonist) [107]. This finding not only indicates that intravenous injection MT-II may act on peripheral targets and then signal to the NTS which receives visceral inputs through the vagal nerve but also compensates for the uselessness of systemic administration of α-MSH to stimulate the central OXT system due to its inability to penetrate the BBB in physiologically significant amounts [107].

Dopamine Neurons

Dopaminergic neurons regulate the motivational drive associated with behaviors such as eating, copulating, defending oneself, or taking addictive drugs [108]. Imaging studies show that morbid obese individuals have impairments in dopaminergic pathways [108], which are linked to the disruption in reward and conditioning to food [109]. In fact, obese individuals experience greater rewards from food consumption (consummatory food reward) and anticipated consumption (anticipatory food reward) than lean individuals [110]. The role of dopamine in modulating reward mainly depends on its projections from the VTA into the nucleus accumbens (NAc) [111]. MCRs are widely expressed in several brain regions involved in food reward and motivation, such as the NAc and the VTA, which indicates that the melanocortin system can modulate motivational aspects of food intake [112]. It was found that injection of α-MSH into the NAc caused a decrease in motivation for sucrose [112]. Also, there is a strong functional link between the melanocortin and dopamine systems [113]. So the melanocortin system complexly interacts with the dopamine system to regulate feeding, motivation, and multiple reward-related behaviors partly depend on α-MSH [13]. It can be explained that α-MSH may act on dopamine pathways and dopamine neurons by combining with MC3R and MC4R positive neurons expressing the dopamine neuron marker, or some α-MSH expressing neurons innervate dopamine neurons [114, 115]. It was found that α-MSH can activate dopamine neurons and increase dopamine release. In acute brain slices from mice, α-MSH specifically increased the firing rate of MC3R VTA neurons [70]. When injected into VTA, α-MSH increased dopamine turnover, and this condition was completely inhibited by preconditioning with the MC4R-selective antagonist HS131 [116‒118]. This role was also found in the lateral hypothalamus where α-MSH stimulates dopamine release during both the anticipatory and consummatory phases of feeding, decreases food intake, and inhibits sucrose intake [119]. The deficiency of MC3R in female mice specifically decreases NAc dopamine content [120]. Some contrasting data suggested that α-MSH decreases dopamine release; however, global deletion of the MC3R increases total dopamine by 42% in the VTA and decreases sucrose intake and preference in females [120]. Prolonged incubation of acute brain slices with MT-II led to the long-term depression of excitatory inputs to dopamine D1 receptor containing but not dopamine D2 receptor containing medium spiny neurons in the NAc [121]. The different effects of α-MSH on the dopamine pathway seem to depend on the direct postsynaptic effects and indirect presynaptic regulation of neurotransmitter release by α-MSH [119], even the differential appetite regulation by dopamine in the different areas [122‒125].

TRH Neurons

TRH was characterized based on its function as a releasing hormone involved in the regulation of the hypothalamic-pituitary-thyroid axis [126], but then it was found to act as a neuropeptide in central circuits regulating food intake and energy expenditure [127]. TRH can regulate energy homeostasis through the effects on thyroid function orchestrated through hypophysiotropic neurons in the PVN, or central effects on feeding behavior, thermogenesis, locomotor activation, and autonomic regulation [128, 129].

TRH and the melanocortin system are closely integrated and regulate distinct aspects of feeding and energy waste [130], where α-MSH seems to play an intermediate role. Immunohistochemical investigation demonstrates that the axons containing α-MSH establish morphological relationships with TRH-producing neurons in the PVN providing direct proof of the action of α-MSH on TRH [131]. Recently, Alvarez-Salas et al. [132] have shown that the endogenous activity of TRH in the NAc is another target of α-MSHergic neurotransmission, indicating that the accumbal TRHergic pathway is downstream of the effects of α-MSH in feeding. Pharmacological research also indicated the interaction between α-MSH and TRH [133, 134]. When binding MC4R on the TRH neuron in the PVN, α-MSH causes the phosphorylation of cAMP response element-binding protein (CREB) [135], then, P-CREB activates the prepro-TRH gene, eventually leading to TRH release [136]. This action prevents starvation-induced reduction in TRH expression and plays an important role in the regulation of TRH synthesis and secretion in fasted animals [132, 137].

Melanin-Concentrating Hormone Neurons

The neuropeptide melanin-concentrating hormone (MCH) is produced in the LHA and the adjacent incerto-hypothalamic area, manipulations of MCH or the MCH neurons impact both food intake and energy expenditure [138]. There is a functional interaction between MCH and α-MSH. MCH antagonizes the decreasing action of α-MSH on food intake when injected intracerebroventricularly and decreases the release of α-MSH from hypothalamic explants in vitro [139, 140]. However, MCH did not block α-MSH binding or cAMP production on cell lines expressing the MC3R or MC4R receptors [140]. Therefore, MCH is considered a functional antagonist of α-MSH. Mutually, the orexigenic effect of MCH in the center can be blocked by α-MSH [141, 142]. Whether the inhibitory effect of α-MSH on MCH is mediated by direct action on the receptors on the MCR is unknown because the presence of MC3R and MC4R was never demonstrated in MCH neurons [143]. Despite this, the researchers found an association between α-MSH and MCH neurons in that MCH neurons receive a dense innervation from α-MSH-IR fibers in both rat and human [144]. As the second-order neuron in the hypothalamus, MCH neurons receive the information from the first-order neuron [143], it can be inhibited by input from POMC neurons [145, 146].

Interacting with Appetite-Related Peptides

α-MSH and Ghrelin

Ghrelin is an appetite-stimulating hormone mainly produced in the stomach and small intestines that circulate in the blood and accesses the brain through the blood-cerebrospinal fluid barrier and the BBB. A smaller increment of circulating ghrelin can increase food intake in arcuate nucleus/median eminence while the higher increment of circulating ghrelin increases c-Fos expression in and access not only the ARC but also the area postrema [147]. Ghrelin exists in circulation in two major forms: acyl ghrelin and desacyl ghrelin [148] and acts via the growth hormone secretagogue receptor (GHS-R) highly expressed in the hypothalamic ARC [149]. GHS-R is specifically expressed in NPY neurons (94% co-localization vs. 8% in POMC neurons) [149]. Experiments using brain slices indicate that ghrelin stimulates presynaptic inputs that activate NPY-GFP neurons in situ [150]. Ghrelin treatment for ghrelin depletion mice (by gastrectomy surgery) can increase the expression of NPY mRNA while decreasing the mRNA expression of POMC [151]. These results indicate that ghrelin can work centrally by directly activating the NPY/AgRP neurons and indirectly inhibiting the POMC neurons (for the GHS-R on POMC neurons is few) to promote a positive energy balance, then exerts opposite effects on the expression of α-MSH [151, 152]. It is evidenced that peripheral and central administration of ghrelin increase PRCP mRNA expression then decreases hypothalamic α-MSH levels and thus affecting melanocortin signaling [153]. Based on the above evidence, it can be inferred that there is an interaction between ghrelin and α-MSH. In accordance with this, α-MSH can attenuate ghrelin-elicited food intake. ICV administration of α-MSH to rats significantly suppresses the ghrelin-induced increased food intake [154]. Erin Keen-Rhinehart found that ghrelin-induced increases in food hoarding can be attenuated by MT-II treatment indicating that activation of MC3/4 receptors can interfere with ghrelin-induced stimulation of feeding [155, 156]. In addition, α-MSH can partly abrogate the orexigenic effect of acyl ghrelin by influencing AgRP activity [157]. Meanwhile, α-MSH is involved in central acyl ghrelin-elicited small intestinal transit, fecal pellet output, and fecal weight [158]. However, α-MSH fails to attenuate gastric emptying elicited by ghrelin which can weaken the satiety signal, cause a sensation of hunger and shorten the interval between meals [159]. The suppression of α-MSH not only exhibits a dose-dependent effect but it also demonstrates that α-MSH can activate MC3R and MC4R to inhibit endogenous NPY and AgRP that can be stimulated by ghrelin.

α-MSH and NPY

Mounting neuroanatomical evidence suggests a possible interaction between NPY and α-MSH [160‒163]. However, coadministration of α-MSH and NPY has demonstrated conflicting results: (1) α-MSH does not prevent the increase in food intake elicited by NPY [142, 163] and (2) it significantly prevents this effect. MT-II, when co-administered with NPY, fully prevented the orexigenic action of NPY [164‒166], then this inhibitory effect has been demonstrated in neonatal broiler chicks and rats [167], suggesting that α-MSH can regulate the feeding behavior by interacting with NPY. Meanwhile, NPY also has an inhibitory effect on the release of α-MSH via reducing the conversion of POMC to α-MSH by decreasing PC2 protein which was mediated by early growth response protein 1 [168]. NPY treatment reduced hypothalamic α-MSH concentration which had been found in vivo (rat and frog) and in vitro (rat hypothalamic slices and frog melanotroph cells) [169‒172]. This regulation can attenuate the CREB signaling activated by α-MSH in TRH neurons and then promotes positive energy balance [168, 173].

α-MSH and AgRP

AgRP can block the effect of α-MSH by competitively inhibiting MCRs (specifically MC3R and MC4R) at the postsynaptic level [174] and acts as an inverse agonist at the MC4R that affects feeding behavior and energy homeostasis independently, then leading to increased food intake and body weight. The two functions mentioned above seem to be caused by the different structures of AgRP. The C-terminus of AgRP is important in the antagonistic function at the melanocortin receptors, whereas the N-terminal parts of AgRP which are unable to bind to MCRs have effects on energy expenditure. For example, hAgRP (aa87-132), a synthetic variant containing 46 C-terminal residues, can bind to MC3R, MC4R, and MC5R to inhibit the binding of α-MSH. But ICV injection of AgRP N-terminal parts of AgRP (aa25–51) increased body weight and epididymal/mesenteric fat weight, despite the absence of hyperphagia and cross-reactivity with MC4R [175‒179]. As AgRP and α-MSH receptors are common, the inverse agonistic effect mentioned above is also manifested in other nuclear regions and neurons. For example, the activation of α-MSH in the PVH, LHA, and parabrachial nucleus hypothalamus can induce satiety, while AgRP antagonizes the binding of α-MSH to MC3/4R, increasing food intake [180]. So the balance between the AgRP and α-MSH determines the extent of activation of MC3/4R in neurons onto which they project [181]. It was found that the expression of AgRP and NPY are correlated with body weight changes [182]. In obese adolescents, the ratio of AgRP/α-MSH and NPY/α-MSH is higher than normal weight, and the ratio is decreased when weight loss, suggesting that the high concentration of α-MSH may promote modulation of anorexigenic pathways in obesity and the inhibition of AgRP activity may be beneficial in treating obesity [17, 183].

Regulation of Appetite and Satiety

The development of obesity is closely linked to the regulation of appetite [2]. Low energy stores will increase the rewarding properties of food and reduce the response to satiety signals in the CNS, collectively resulting in increased food consumption until depleted fat stores are replenished. Conversely, the positive energy balance induced by overfeeding suppresses the rewarding properties of food, while increasing meal-induced satiety and thus reducing food intake [184]. α-MSH peptide is an energy balance regulator that influences food intake [11], satiety signals [12], food reward, and peptide release [13]. The frequent hunger feedback due to α-MSH deficiency or the imbalance between AgRP and α-MSH could lead to increased feeding signals and increase the risk of obesity development [174]. Although treated, appetite-related hormone levels in obese subjects do not immediately return to normal levels [185]. Moreover, different degrees of compensatory regulatory responses will occur in the energy homeostasis system, causing changes in the neurocircuitry, promoting food reward, and reducing satiety, causing overeating and weight regain [186]. It was found that both obese children and adolescents have significantly lower plasma α-MSH levels compared with their healthy peers [174, 183]. Though few studies examine the levels of central α-MSH in obese patients, peripheral α-MSH concentration is considered to correlate to CNS concentration [187, 188]. Adjusting individual energy intake and providing nutritional education in obese adolescents lower α-MSH level and decrease body weight [189]. Additionally, it was found that limiting feeding to the active period of MT-II administration can lower blood pressure [190] because eating during the active phase can attenuate the decline in heart function during aging and plays a role in the diurnal regulation of blood pressure [191‒193]. Therefore, the appetite-suppressing effect of α-MSH can be applied to influence the feeding schedule to constitute effective therapeutic strategies to obtain some clinical benefits in obesity and obesity-related metabolic disease [190].

Genetic Disorders in the Leptin-Melanocortin Pathway

α-MSH is important for the treatment of people who lack endogenous melanocortins in the brain and perhaps those with other monogenic obesity syndromes related to the central melanopsin pathway. In the hypothalamus, leptin binds the POMC neurons, causing the release of α-MSH, and then α-MSH activates MC3R and MC4R in multiple locations. Mice that lack desacetyl-α-MSH and POMC exhibit hyperphagia and obesity [14, 15]. Hence, due to genetic defects in the leptin-melanocortin pathway, such as leptin receptor (LEPR) deficiency, POMC deficiency, and proprotein convertase subtilisin/kexin type 1 (PSCK1) deficiency, patients develop hyperphagia and obesity, which have been related to the abnormal release and action of α-MSH [194, 195]. The substantial and durable reductions in hyperphagia and body weight produced by α-MSH analog setmelanotide are a breakthrough for leptin-melanocortin pathway disorders [196]. LEPR deficiency is an autosomal-recessive endocrine disease. Early-onset obesity (<age 5 years) and hyperphagia were the most common phenotypic features [197]. The severe obesity may lead to mortality before adulthood [198, 199]. The characteristics of POMC deficiency and LEPR deficiency have parallels. The mice lacking the POMC-derived peptides induce disease phenotypes similar to POMC-deficient patients [200]. POMC deficiency is an ultra-rare syndrome with a complete absence of MC4R stimuli [201]. POMC deficiency newborns tend to be of normal weight but then progress to hyperphagic with uncontrollable hunger and develop extreme obesity within a year, along with several endocrinological abnormalities [201, 202]. The proprotein convertase subtilisin/kexin type 1 (PCSK1) gene is also related to the leptin-melanocortin pathway encoding preproPC1/3, which is processed into proPC1/3 and then PC1/3. PC1/3 is vital for the processing of POMC to α-MSH [203]. PCSK1-deficient infants suffer from early malnutrition, become hyperphagia, and develop obesity, partly because PCSK1 is also expressed in enteroendocrine cells [204, 205]. Therefore, a genetic test is needed for patients with extreme early-onset (before age 5) and clinical features of a genetic obesity disorder and/or a positive family history of extreme obesity to proceed with early treatment [206].

Hypothalamic Inflammation

The development of obesity is associated with chronic HFD and hypothalamus inflammation, which cause dysfunction in POMC neuron activity, leading to a decrease in inhibitory synapses and apoptosis of POMC neurons and leptin resistance in the hypothalamus, disrupting appetite suppression mediated through α-MSH activation of the MCRs [207, 208]. It is reported that HFD induces activation of non-neuronal cells such as astrocytes and microglia to produce inflammatory reactions, inducing the expression of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α); moreover, hypothalamic inflammation is specific to the ARC [208, 209]. Prolonged exposure to an inflammatory environment decreases POMC synapses and affects inhibitory contacts, specifically those accompanying the obese phenotype [207]. The inflammation in the hypothalamus leads to an imbalance between food intake and energy expenditure [210]. Several lines of evidence suggest that α-MSH has the potential to ameliorate diet-induced hypothalamus inflammation. α-MSH has been shown to modulate peripheral inflammation by acting on MCRs in host cells. In the CNS, α-MSH directly acts on microglia and astrocytes that express the receptors [211]. It can be found that α-MSH inhibits the production of TNF-α, IL-6, and NO by murine microglia [212]. The inhibitory effect of α-MSH on brain TNF-α also occurred in brain tissue in vitro, indicating that α-MSH can act directly on brain cells to inhibit their production of TNF-α [213]. More specifically, intraperitoneal injection of MT-II can effectively improve HFD-induced leptin resistance, suppress food intake, induce weight loss, and increase energy expenditure [214]. Although there is no direct evidence that appetite regulation by α-MSH has a specific effect on hypothalamic inflammatory obesity, its anti-inflammatory and central modulatory effects suggest a potential ameliorative effect on obesity.

In conclusion, α-MSH, as a key link in the melanocortin pathway, plays an important role in the regulation of energy metabolism and appetite. There are still many potential uses for α-MSH in the treatment of obesity. However, α-MSH and its analogs have produced side effects such as nausea, headaches, spontaneous penile erection, fatigue, and skin hyperpigmentation in some cases due to the diversity and wide distribution of its receptors [215, 216]. Additional risks are related to the administration and dosage of these agents, such as intranasal administration, subcutaneous administration, and freeze-dried powders (in ampules of 10–100 mg), because they are needed to be operated by the users [217, 218]. Nevertheless, setmelanotide was approved in the USA as a subcutaneous injectable formulation for the treatment of chronic weight management in patients 6 years of age and older with obesity, resulting from POMC, PCSK1, or LEPR deficiency [215]. Reducing the collateral effects of agonistic effects of α-MSH on the receptors may produce dramatic clinical benefits.

α-MSH Analogs

The effect of α-MSH on feeding behavior can be used to help further modify obesity. However, the half-life of natural α-MSH is very short, so the development of its analogs is of great importance to explore the physiological effects of this peptide [219]. In recent decades, researchers have made significant breakthroughs in the development of α-MSH analogs (Table 3). Initially, the main focus was on α-MSH acting on MC1R receptors to exert regulatory pigmentation, and then gradually on its action on the central MC3/4R to regulate energy homeostasis.

Table 3.

Relevant background information for α-MSH analogs

NamePatent holderApplicationsCurrent states
Afamelanotide Clinuvel Pharmaceuticals Erythropoietic protoporphyria Received approval from the EMA, the US FDA, and the Australian TGA 
MT-II Competitive Technologies Attenuate skin conditions, aid weight loss (through appetite reduction), and improve sexual function Discontinued drug development 
MC4-NN1-0182 Novo Nordisk A/S Obesity Discontinued drug development 
MC4-NN2-0453 Novo Nordisk A/S Obesity Discontinued drug development 
Bremelanotide Palatin Technologies Hypoactive sexual desire disorder Received approval from the US FDA 
Setmelanotide Rhythm Pharmaceuticals POMC/LEPR/PCSK1 deficiency obesities Received approval from the US FDA 
NamePatent holderApplicationsCurrent states
Afamelanotide Clinuvel Pharmaceuticals Erythropoietic protoporphyria Received approval from the EMA, the US FDA, and the Australian TGA 
MT-II Competitive Technologies Attenuate skin conditions, aid weight loss (through appetite reduction), and improve sexual function Discontinued drug development 
MC4-NN1-0182 Novo Nordisk A/S Obesity Discontinued drug development 
MC4-NN2-0453 Novo Nordisk A/S Obesity Discontinued drug development 
Bremelanotide Palatin Technologies Hypoactive sexual desire disorder Received approval from the US FDA 
Setmelanotide Rhythm Pharmaceuticals POMC/LEPR/PCSK1 deficiency obesities Received approval from the US FDA 

[Nle4-D-Phe7]-α-MSH (melanotan I, [MT-I]) is the first α-MSH analog developed by Sawyer et al. [220] in 1980. Afamelanotide is the generic name of this substance [216], and Scenesse®, manufactured by Clinuvel Pharmaceuticals, is a prescription medication that contains afamelanotide [221]. Scenesse® was approved in the European Union in 2014 and then approved by the US Food and Drug Administration (FDA) in 2019 [222]. It can increase tolerance to the sun and light in adults with a confirmed diagnosis of erythropoietic protoporphyria by binding to MC1R to increase the release of eumelanin with more stability than natural α-MSH [220, 222, 223].

The second analog Ac-c[Nle4, Asp5, D-Phe7, Lys10]-α-MSH(4-10)-NH2 (MT-II) was discovered by Al-Obeidi and colleagues [224]. Compared to α-MSH, MT-II has an extraordinary potent and prolonged biological activity [224], and its cyclic structure confers better BBB permeability [225]. MT-II is used to attenuate skin conditions, aid weight loss (through appetite reduction), and improve sexual function because of its less selective nature [218, 226].

The third α-MSH analog, Ac-Nle-c[Asp, D-Phe, Arg, Trp, Lys]-OH, known as bremelanotide and PT-141, is a metabolite of MT-II [218]. Bremelanotide binds to central MCRs to activate sexual arousal and penile erections through a neural mechanism [227]. It received its first approval on June 21, 2019 in the USA for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder [228].

Another α-MSH analog MC4-NN1-0182 was developed at Novo Nordisk A/S [229]. MC4-NN1-0182 significantly reduced body weight in DIO rats and obese minipigs [229, 230]. Then MC4-NN2-0453, a long-acting, selective MC4R agonist, was used in human with overweight to obese but otherwise healthy subjects. MC4-NN2-0453 was comparatively more soluble at physiologic pH and more stable in solution than MC4-NN1-0182 and was well tolerated with high safety, but no significant pharmacodynamic effects, including the effect on body weight. It has been suggested that this substance may not be getting into the relevant effective fraction in the brain, or the central exposure may not have been high enough to mediate an effect on body weight [231].

As research on α-MSH and its analogs have revealed that α-MSH can act on different receptors to produce different effects, more and more studies are focusing on its effects on appetite and energy regulation [107, 232‒234]. In January 2016, the α-MSH analog setmelanotide also known as RM-493 or BIM-22493 was awarded orphan drug status for POMC deficiency and Prader-Willi syndrome by FDA [11, 235‒238]. This is the first α-MSH-based therapeutic for obesity. Setmelanotide is 10–20 times more potent than endogenous α-MSH at MC4R [239], activating the Gs signaling pathway more robustly without being efficiently antagonized by AgRP [196]. It can reduce hunger and body weight in patients by alleviating disorders, resulting from variants in the center, such as POMC deficiency obesity or LEPR deficiency obesity [235, 240].

PRCP Inhibitor

The inhibition of the catabolism of α-MSH is a promising strategy for the treatment of obesity, which can reduce the collateral effects of agonists on the organism. PRCP inactives α-MSH to regulate melanocortin signaling [29]. It has been reported that the inhibition of PRCP activity by small molecule protease inhibitors administered peripherally or centrally decreased food intake in wild-type and obese animals [28]. Efforts have been made to generate potent, brain-penetrant PRCP inhibitors. UM8190 is a selective PRCP inhibitor that showed an anorexigenic effect when systemically administered to fasted mice, reducing food intake in a dose- and time-dependent manner [241].

Other Medications

Based on the pharmacological mechanisms of hormones and receptor inhibitors or antagonists, the interaction of α-MSH with other hormones is worthy of being applied in the treatment of obesity. TTP2515, for example, is an orally active AgRP inhibitor that prevents AgRP from antagonizing α-MSH. Oral administration of TTP2515 blocks ICV injection AgRP-induced increases in food intake, weight gain, and adiposity in both DIO and leptin-deficient mice and does not cause weight loss in lean mice on a low-fat diet [242]. In recent years, several medications used to treat obesity act through dopaminergic receptors or melanocortin receptors. Bupropion is a dopamine and noradrenaline transporter inhibitor that can stimulate hypothalamic POMC neurons, resulting in decreased food intake and increased energy expenditure [108, 243]. Zonisamide enhances the activity of dopamine and prevents β-endorphin-mediated negative feedback on α-MSH release [108, 244]. The effect of the combination therapy of zonisamide and bupropion on body weight in obese individuals was examined and achieved a weight loss effect [245]. Naltrexone is an opioid receptor antagonist that can modulate the release of dopamine and block opioid receptor-mediated POMC autoinhibition [246‒248]. Contrave® is a combination of naltrexone and bupropion for the treatment of obesity [249]. It can decrease food intake and increase abstinence in cigarette smokers which is beneficial for obese smokers [108, 250].

α-MSH is a POMC-derived appetite-suppressing peptide with the ability to trigger changes in feeding behavior upon binding with MC3/4R. Homeostatic eating, hedonistic eating, and stress-induced eating are the three basic feeding habits that are governed by hunger and satiety signals and associated appetite regulatory peptides. These feeding behaviors are related to the development of obesity. In line with the feature of α-MSH, the expression of α-MSH was lower in some obese individuals, and the abnormal α-MSH secretion causes disturbance in energy equilibrium, indicating that α-MSH is involved in obesity [17, 174, 251‒253]. Although the central role of α-MSH in the regulation of food intake is well recognized, the process of initiating these feeding behaviors is complex and involves several hormone interactions, a network of circuits, as well as peripheral factors. The site of release and activity of α-MSH has an impact on its function. In the CNS, it is necessary to focus not only on its role in the ARC but also on MC3/4R-expressing neurons associated with, for example, the midbrain, as well as other hypothalamic nuclei regions, and the role of NTS in α-MSH-mediated control of food intake also deserves attention. The balance of α-MSH with other orexigenic peptides has also been investigated, and the serum α-MSH level might be a good biomarker for hypothalamic obesity, as well as for the detection of patients with PCSK1, POMC, and LEPR deficiencies, which may be another breakthrough for the treatment of obesity [99, 254]. Additionally, high-fat diet-induced obesity is associated with low-grade inflammation (including IL-1, IL-6, and TNF-α), which changes the levels of neuropeptides, potentially increasing appetite, and weight [255]. By downregulating inflammatory factors and changing cell response mechanisms, α-MSH is also an anti-inflammatory hormone that has the potential to treat obesity [256]. Few types of research, however, have focused on the relationship between its anti-inflammatory properties and obesity-related hypothalamus inflammation and appetite. In addition, both positive and negative feedback loops between internal and external environmental and homeostatic factors continuously alter hormone levels, changing appetitive and consummatory behaviors. Researchers have been studying the interaction between α-MSH and other hormones for the past few decades and have found contradicting occurrences resulting from various settings. It is still important to investigate the intricacy and specificity of how α-MSH affects hunger. The research revealed that α-MSH may be a promising therapeutic agent for the treatment of obesity. Currently, available anti-obesity medications have limited efficacy and a variety of negative effects [257]. The most effective approach to efficiently reducing body mass is bariatric surgery. However, bariatric surgery is still an option for extreme forms of obesity and seems unable to tackle the obesity pandemic expansion. The strategy of reducing body mass by targeting the central energy balance regulatory system is safe and has high efficiency [258]. Weight loss can be achieved through dietary restriction, after which the levels of the circulating mediators of appetite change, and this phenomenon even exists a year later [185]. Therefore, modulating hormones related to appetite may be needed to prevent obesity relapse. α-MSH is implicated in the control of food intake and inducing satiety through the CNS, it also brings down brain inflammation, lowers blood glucose, and reduces abdominal fat. Further investigations of appetite regulation mechanisms in α-MSH may facilitate the management of obesity.

The authors declare that they have no conflict of interest.

This project was funded by the National Natural Science Foundation of China (No. 82173944), Special Projects in Key Areas of Universities in Guangdong Province (No. 2021ZDZX4025), Guangdong Natural Science Foundation (No. 2021A1515011510), and Special Innovation Project of Guangdong University (No. 2019KTSCX073).

Qiwen Wu drafted the manuscript and prepared the figures. Jingmei Chen and Tingyu Hua provided suggestions. Jinyan Cai obtained the funding and reviewed the manuscript.

Data availability is not applicable to this article as no new data were created or analyzed in this study.

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