Introduction

The melanin-concentrating hormone (MCH) receptors form a small family of two receptor subtypes MCH₁ and MCH₂. They exist throughout species, from fishes to mammals. In fishes MCH is a 17 amino-acid, cyclic peptide, responsible for the bleaching of fish skin [11]. Similarly, in mammals, MCH is a 19 amino-acids cyclic peptide [19] that is not linked to pigmentation [26] but was, originally believed to be essentially centred on appetite regulation and obesity [17] [23]. Later on, it has been shown to possess actions in several homeostasis processes, like sleep and emotionality [1] [9]. Indeed, several antagonists at MCH₁ showed antidepressant and anxiolytic activies [6]. Other compounds enhanced social recognition, maybe through an increased concentration of acetylcholine in the frontal cortex [13].

Two receptors

MCH is encoded as a preprohormone, which also gives rise to two other neuropeptides: neuropeptide E-I and neuropeptide N-G [16]. MCH is mainly synthesized in cell bodies of the lateral hypothalamus and zona incerta in the central nervous system [24]. MCH is also synthesized in peripheral organs such as gut [10], arteries [4] and pancreas β-cells [18]. The receptors have been cloned recently. As a matter of fact, MCH₁ was known for quite some time as SLC1, an orphan receptor that was adopted in 1999 by at least 3 different groups [8] [25] [7]. The subsequent search for analogues of the protein, led to the cloning of a second receptor, MCH₂ [30] [14] [22] [21]. This second receptor is expressed in human, dog and ferret, but not in rodents [29] and displays a ca. 10-fold less potent affinity for MCH than MCH₁

Expression

The highest expressions of both receptors in higher species are found in the brain: frontal cortex, amygdala and nucleus accumbens, but also in the arcuate nucleus and in the ventral medial hypothalamus. The receptors are also moderately expressed in peripheral organs

Genetic manipulations

MCH overexpressing transgenic mice are hyperphagic and develop obesity. As a support to the implication of MCH₁ , knock out (KO) mice for MCH₁ are leaner [27], even on high fat diet. This is attributed to increased energy expenditure, coming mainly from increased locomotor activity and increased resting energy expenditure. Paradoxically, these mice show significant hyperphagia, but alo cognitive deficits in inhibitory passive avoidance tests [2]. As rodents do not express MCH₂, no KO models are yet available.

Pharmacology

The molecular pharmacology of MCH₁ has been studied in detail. Several dozens of MCH analogues have been synthesized and tested by binding and functional assays and leading to the discovery of peptide super-agonists and partial antagonists [3] [5]. Some of them have been tested on MCH₂, and present major selectivity to MCH₁. SAR is now well-established concerning the peptide ligands (MacNeil and Bednarek, 2009, in press). Small molecules have been synthesized as potent and moderately selective MCH₁ antagonists (see reviews [12]). The first one, T-226296, from Takeda, is among the most potent [28]. The development of MCH₁ antagonists have been hindered because of lack of specificity or associated toxicities, such as affinity for hERG [15] channel. Many compounds have nevertheless been described see review by Rivera et al. [20].

Future trends

The exact role of MCH₁ in obesity is still not completely understood. Major discrepancies exist between pharmacological treatments with MCH₁ antagonists and KO mice phenotype. Furthermore, the absolute specificities of reported antagonists to MCH₁ is not validated. More compounds need to be discovered to validate the role of MCH and MCH₁ in obesity, energy expenditure, locomotion and probably mood. Due to the lack of animal models, MCH₂ role is not yet known.

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