Abstract
Extensive studies in rodents with melanin-concentrating hormone (MCH) have demonstrated that the neuropeptide hormone is a potent orexigen. Acutely, MCH causes an increase in food intake, while chronically it leads to increased weight gain, primarily as an increase in fat mass. Multiple knockout mice models have confirmed the importance of MCH in modulating energy homeostasis. Animals lacking MCH, MCH-containing neurons, or the MCH receptor all are resistant to diet-induced obesity. These genetic and pharmacologic studies have prompted a large effort to identify potent and selective MCH receptor antagonists, initially as tool compounds to probe pharmacology in models of obesity, with an ultimate goal to identify novel anti-obesity drugs. In animal models, MCH antagonists have consistently shown efficacy in reducing food intake acutely and inhibiting body-weight gain when given chronically. Five compounds have proceeded into clinical testing. Although they were reported as well-tolerated, none has advanced to long-term efficacy and safety studies.
Highlights
The mammalian form of melanin-concentrating hormone (MCH), is a 19-amino acid cyclic peptide encoded within a 165amino acid preprohormone (Figure 1) (Vaughan et al, 1989)
MCH has been associated with a wide variety of behaviors, but the focus of this review is the role of MCH in energy homeostasis
The amino acid sequence of MCH is identical in all mammals evaluated and alternative processing of the preproMCH peptide can generate two additional putative peptides, designated neuropeptide E-I (NEI) and neuropeptide G-E (NGE) (Nahon et al, 1989)
Summary
The mammalian form of melanin-concentrating hormone (MCH), is a 19-amino acid cyclic peptide encoded within a 165amino acid preprohormone (Figure 1) (Vaughan et al, 1989). MCH has been associated with a wide variety of behaviors (see recent reviews by Saito and Nagasaki, 2008; Antal-Zimanyi and Khawaja, 2009; Chung et al, 2011), but the focus of this review is the role of MCH in energy homeostasis. A few MCHR1 antagonists have entered development, no compound has successfully demonstrated anti-obesity efficacy in a clinical trial. It remains unclear if this lack of clinical efficacy is due to a lack of efficacy via the MCH1R pathway or to the inability of teams to identify safe and well-tolerated compounds with sufficient potency and pharmacodynamics properties to test the hypothesis. In 3T3-L1 adipocytes, MCH rapidly induced a threefold to fivefold www.frontiersin.org
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