The central melanocortin system as a treatment target for obesity and diabetes: A brief overview

Abstract

The melanocortins are derived from proopiomelanocortin (POMC) and include three forms of melanocyte-stimulating hormone (α-, β-, γ-, MSH) and adrenocorticotropic hormone. α-MSH, a potent POMC-derived neuropeptide, binds to melanocortin 4 receptor (MC4R) in the brain to reduce food intake (via appetite suppression) and increase energy expenditure (via sympathetic nervous system) after integration of central neuronal signal (e.g. serotonin, glutamate) and peripheral signals such as anorexigenic hormones (e.g. leptin, insulin) and nutrient (e.g. glucose). Mutations in POMC or MC4R can cause increase in food intake and body weight. Weight gain and obesity in turn result in a phenotypic switch of white adipose tissue, which then secretes proinflammatory cytokines that play a role in the development of insulin resistance and type 2 diabetes. Besides α-MSH's effects in decreasing food intake and body weight, α-MSH also carries protective anti-inflammatory properties in both immune cells and non-immune cells (e.g. adipocyte) that express melanocortin receptors. Since type 2 diabetic patients who have overweight or obese are recommended to lose body weight while current available anti-obesity drugs have various side effects, α-MSH-based therapeutics might be hopeful for the management of both obesity and type 2 diabetes.

Introduction

The melanocortins consist of three forms of melanocyte-stimulating hormone (α-, β-, γ-, MSH) and adrenocorticotropic hormone (ACTH). These peptide hormones are derived from proopiomelanocortin (POMC). Due to a diverse distribution of their five melanocortin receptor subtypes (MC1R-MC5R), the melanocortins have numerous functions, including central effects such as energy homeostasis, sexual behavior, memory, and antipyretic effects as well as peripheral effects such as secretion of corticosteroids, pigmentation, anti-inflammatory and lipolytic actions (Wikberg, 1999). α- and β-MSH are important in controlling appetite and obesity but most of the attention has focused on α-MSH due to the absence of β-MSH in rodents (Lee et al., 2006; Raffan et al., 2016). γ-MSH is also available in the brain (Kawai et al., 1984) which binds exclusively to MC3R (Roselli-Rehfuss et al., 1993). Generally, actions of melanocortins are controlled by an integration of diverse hormonal and neuronal inputs (Schwartz et al., 2000; Morton et al., 2006).

It has been suggested that blood glucose level can be regulated by POMC neurons in the hypothalamus and disturbance in the melanocortin system leads to the development of obesity in both human and animals (Ruud et al., 2017; Dodd et al., 2018). Since MC4R is important for regulation of food intake and body weight, severe early-onset obesity may be a result of biallelic variants in genes that affects the MC4R pathway (Clement et al., 2020). Obesity is characterized by the excessive accumulation of body fat in white adipose tissue and adipose tissue secrets high levels of non-esterified fatty acids, glycerol, hormones, proinflammatory cytokines, and other factors that are involved in the development of insulin resistance and type 2 diabetes (Kahn et al., 2006). In many developed countries, the number of type 2 diabetic patients has increased due to a rise in obesity, and further increase is anticipated (Wild et al., 2004). Although type 2 diabetic patients are commonly treated with approved drugs such as metformin and insulin, these therapeutics are shown to be less effective in children and adolescents (Bacha, 2019). In addition, sulphonylureas and insulin that control blood sugar level in diabetic patients are often associated with weight gain (Adler, 2002). Therefore, any agent that decreases body weight and simultaneously lowers fat mass will certainly be the better treatment for obesity and type 2 diabetes. α-MSH is a potent POMC-derived neuropeptide in the melanocortin system; it can reduce food intake, body weight, fat mass in addition to increasing energy expenditure. Importantly, α-MSH inhibits the release of inflammatory cytokines and chemokines. Based on these beneficial effects, α-MSH-based therapeutics might be hopeful for the management of obesity in addition to diabetes. While most of the earlier reviews are focused on the regulation of POMC neurons by insulin and leptin as well as neuropeptide Y (NPY), this review is mainly concentrated on several neurotransmitters that are produced in the central nervous system as well as peripheral hormones that can enter the brain to influence POMC neurons. Also, it reviewed α-MSH analogs that have role in the management of food intake and body weight. Understanding the regulation of POMC neurons and α-MSH analogs would help us to find pharmaceutical options for the management of weight loss and inflammation, a feature associated with obesity.