Giles S H Yeo, Daniela Herrera Moro Chao, Anna-Maria Siegert, Zoe M Koerperich, Mark D Ericson, Stephanie E Simonds, Courtney M Larson, Serge Luquet, Iain Clarke, Shubh Sharma, et al.
Background: Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in controlling mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variations in fl uencing the population distribution of body weight. At the end of 2020, the U.S. Food and Drug Administration (FDA) approved setmelanotide, a melanocortin 4 receptor agonist, for use in individuals with severe obesity due to either pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) de fi ciency.
Scope of review: Herein, we chart the melanocortin pathway ’s history, explore its pharmacology, genetics, and physiology, and describe how a neuropeptidergic circuit became an important druggable obesity target.
Major conclusions: Unravelling the genetics of the subset of severe obesity has revealed the importance of the melanocortin pathway in appetitive control; coupling this with studying the molecular pharmacology of compounds that bind melanocortin receptors has brought a new obesity drug to the market. This process provides a drug discovery template for complex disorders, which for setmelanotide took 25 years to transform from a single gene into an approved drug.
Keywords Melanocortin; Hypothalamus; Obesity; Genetics; Pharmacology; Therapy
Obesity is associated with comorbidities such as type 2 diabetes, cardiovascular disease, and certain cancers and is arguably the greatest public health threat of the twenty-fi rst century. While its increasing prevalence worldwide has clearly been driven by our changing lifestyle, a powerful genetic component underlies the large variations in body weight within this modern environment. Twin and adoption studies have revealed the heritability of the body mass index (BMI; weight in kg/height in m 2) to be between 40% and 70% [1,2]. Over the past two decades, studies of human and mouse genetics have uncovered a number of circuits within the brain that play a central role in modulating mammalian appetitive behaviour and metabolism. The best characterised is the hypothalamic leptin-melanocortin signalling pathway, genetic disruption of which causes the majority of monogenic severe obesity disorders in both mice and humans. The melanocortin system refers to a set of hormonal and neuro-peptidergic pathways that are comprised of three main components: pro-peptide proopiomelanocortin (POMC), which is post-translationally processed by prohormone convertases into a number of biologically active moieties, including a-melanocyte stimulating hormone (MSH), b-MSH, g-MSH, and adrenocorticotrophin (ACTH) [3], the eponymous melanocortin peptides; the fi ve G protein-coupled melanocortin re-ceptors, MC1R-MC5R, that mediate their actions [4]; and endogenous antagonists of those receptors, agouti and agouti-related protein (AgRP). The system is responsible for a dizzying array of functions, from melanogenesis and adrenal development, to energy homeostasis and sexual behaviour. We focus on the melanocortin pathway ’s role in regulating food intake and body weight in particular. At the end of 2020, the U.S. the Food and Drug Administration (FDA) approved the MC4R agonist setmelanotide for chronic weight management in adult and paediatric obesity patients due to POMC, proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) de fi ciency [5]. We chart the pathway ’s history, explore its pharmacology, genetics, and physiology, and describe how a neuropeptidergic circuit became an important druggable obesity target.
The effects of ACTH and MSH on the adrenal gland and pigmentation, respectively, were well known before direct effects of melanocortin peptides on the brain were described in the 1950s [6]. In the late 1970s, the discovery of melanocortin peptide immunoreactivity in the rat brain, coupled with cloning the POMC gene and the subsequent demonstration that it was expressed in the hypothalamus in the early 1980s indicated the existence of a brain melanocortin system [7]. The arcuate nucleus of the hypothalamus (ARC) and the nucleus of the tractus solitarius (NTS) are the main sites of POMC expression in the brain. However, it took until the late 1980s before binding sites for melanocortins could be demonstrated in the brain [8]. By that time, various effects were described of MSH and ACTH fragments on rodent behaviours [9], but the prominent effects of melanocortins on feeding and body weight regulation remained unknown. There were only a handful of studies describing the effect on feeding [10]. In 1992, receptors for the two “original ” melanocortin peptides, a-MSH and ACTH, were cloned [11]. MSH was so named because of the peptide ’s ability to stimulate the synthesis of melanin by melanocytes, and its receptor, initially called MSH-R, was cloned from a melanoma sample known to be able to bind high levels of MSH. Given that a-MSH represents the fi rst 13 amino acids of ACTH, literally being a part of the longer 39 amino acid peptide, it is unsurprising that their receptors share a great deal of sequence homology, which was how the ACTH-R was cloned. Similar methods leveraging sequence homology were then used to clone three additional melanocortin receptors, two of which were expressed primarily in the brain and the other in peripheral tissues. Their eventual names re fl ected the order in which they were cloned, with MSH-R and ACTH-R being renamed MC1R and MC2R, respectively; the two brain receptors followed as MC3R [12,13] and MC4R [12] and fi nally the peripheral MC5R was cloned [14].
POMC is expressed in hair follicles, the skin, pituitary cells, and neurons in the hypothalamus and brain stem [3]. The precursor peptide of POMC is cleaved by peptidases including PCSK1, proprotein con-vertase subtilisin/kexin type 2 (PCSK2), carboxypeptidase E (CPE), peptidyl-a-amidating monooxygenase (PAM), N-acetyltransferase (N-AT), and prolyl carboxypeptidase into different products in different cell populations, yielding, for example, ACTH in the pituitary corticotrophs vs a- and b-MSH in neurons localised to the arcuate nucleus (ARC) of the hypothalamus. Within the pituitary, POMC is expressed in excitable cells that produce ACTH and cells in the intermediate lobe that express a-MSH [3]. While agonists stimulate the production of cyclic adenosine monophosphate (cAMP) and recruitment of b-arrestin, they regulate a variety of physiological effects [4]. These include skin and hair pigmentation (MC1R), steroidogenesis (MC2R), appetite, satiety, en-ergy homeostasis (MC3R/MC4R), and exocrine gland function (MC5R) in mice. The linking of the melanocortin system to the regulation of body weight came with the study of a bright yellow mouse with severe obesity. Because the coat colour of animals is easily observed, pigmentation genetics became popular, including the hunt for genetic loci affecting coat colour. One of the classical genetic loci that in fl uenced coat colour and pigmentation in several mammalian species was the extension locus, which encoded MC1R [15]. Yet another was the agouti locus, shown to be upstream of extension or MC1R. Agouti is normally expressed in the skin and acts as an antagonist on MC1R [16], blocking the production of darker melanin and producing lighter phaeomelanin, which in mice is a yellow-orange colour. Agouti mice have a mutation within the promotor that results in constitutive and ectopic production of the agouti peptide [17,18]. However, in addition to altered pigmentation, because agouti, which is normally expressed only in the skin, when ectopically expressed in the brain also antag-onises MC4R [16,19], the mice are also hyperphagic and severely obese. The demonstration that Agouti also acts as an antagonist for the MC4R was a hallmark fi nding that launched the awareness that the melanocortin system plays a role in body weight regulation [16]. Based on its homology to agouti, agouti-related protein (AgRP) was cloned and shown to be expressed in the hypothalamus as natural antagonists of MC3R and MC4R [20], but not MC1R. Thus, transgenically over-expressing AgRP in mice resulted in hyperphagia and obesity, but not the characteristic coat colouration seen in agouti mice. We now know that a key physiological role of MC4R neurons within the para-ventricular nucleus of the hypothalamus (PVN) is sensing the balance of orexigenic AgRP and anorexigenic melanocortin signals and to regulate feeding behaviour and energy expenditure [21] (Figure 1).
Within the ARC, POMC neurons are found adjacent to the medium eminence/tubero-infundibular zone at the base of the third ventricle, just above the pituitary stalk. Most of these neurons co-express cocaine- and amphetamine-related transcript (CART) peptide and project widely throughout the brain [22]. In the brainstem, NTS POMC neurons are thought to respond to, among other signals, gut-secreted cholecystokinin (CCK) [23] and adipocyte-derived leptin [24]. Over the past 20 years, the role of ARC POMC neurons in energy homeostasis, particularly in response to the adipocyte-derived hor-mone leptin, has been extensively studied [22]. Various peptide products of the POMC precursor have different receptors, so one needs to be cautious about fully ascribing POMC neuron actions with a discrete peptide receptor. Nevertheless, melanocortin peptides acting through central MC4R have a clear role in regulating appetite, energy expenditure, and body weight [22]. Because much of the initial char-acterisation of POMC peptides was performed in rodents that crucially lack cleavage sites to produce b-MSH, a-MSH was thought to be the key effector with respect to energy homeostasis. However, genetic evidence from humans [25] and dogs [26] point to b-MSH having at least as important a role as a-MSH, particularly in signalling through MC4R. Additionally, melanocortin peptides have been shown to regulate glucose homeostasis [27], erectile function [28], and car-diovascular tone [29], and peripherally to regulate skin and coat col-ouration, in fl ammation, skeletal muscle glucose uptake, and gut function [4]. POMC neurons are central mediators of endocrine signals. A signi fi cant proportion of ARC POMC neurons are activated by leptin expressi
