The mammalian form of melanin-concentrating hormone (MCH), is a 19-amino acid cyclic peptide encoded within a 165-amino acid preprohormone. 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). Several in vivo studies have shown that MCH plays a role in a variety of physiologic processes mediated within the central nervous system (CNS), including energy homeostasis sleep and arousal, and emotionality. Although less studied, MCH may also have a role in peripheral tissues such as in gut and pancreatic islet function.
Figure 1. The amino acid structure of mammalian MCH.
Two MCH G-protein coupled receptors (GPCRs) have been characterized. MCHR1 is found in all vertebrates, while MCHR2 is found in non-rodent higher species, including primates.
Neurobiology, rodent genetics, and rodent pharmacologic studies all demonstrate that MCH and the MCH receptors are involved in regulating body weight. On the basis of this information, many pharmaceutical companies have pursued the development of MCHR1 antagonists for the treatment of obesity. Unfortunately, although 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. This review summarizes the evidence for a role of MCH and its receptors in energy homeostasis and the progress made to date toward identifying small-molecule antagonists to treat obesity.
Originally described as the orphan receptor SLC-1/GPR24, MCHR1 was later shown by five groups to be activated by MCH. The 402-amino acid rodent and human MCHR1 receptors are highly homologous, sharing ∼95% identity, and the highest expression of the receptors is within the brain. Like many family A GPCRs, the MCHR1 receptors have consensus N-glycosylation sites at the amino terminus and several potential phosphorylation sites in the intracellular loops.
In recombinant cell lines, the natural ligand, MCH, binds to MCHR1 with ∼1 nM affinity, and it couples to Gi, Go, and Gq proteins. Thus, activation of MCHR1 leads to an increase in intracellular Ca++ accumulation acting through the Gq-coupled pathway and/or to lowered cyclic adenosine monophosphate (cAMP) levels via the Gi/o-coupled pathway. Further analyses of the signaling of MCHR1 in recombinant cell lines and in brain slices demonstrates that activation of MCHR1 also leads to ERK phosphorylation. In 3T3-L1 adipocytes, MCH rapidly induced a threefold to fivefold increase in MAPK pathway activities. It is unclear if all, or some, of these signaling pathways contribute to MCH-mediated events in vivo.
A second MCHR was later identified and termed MCHR2 by six groups. The functional role of MCHR2 is not well defined, in part because it is not expressed in rodents and related species (hamsters, guinea pigs, or rabbits), but it is expressed in humans, dogs, ferrets, and monkeys. The amino acid sequence identity between MCHR1 and MCHR2 is low, ∼38%, with the highest homology in the seven-transmembrane domains that form the ligand binding pocket. Although MCH binds to MCHR1 and MCHR2 with a similar nanomolar affinity, the signal transduction mechanism of MCHR2 is limited to the Gq-mediated increase in intracellular Ca++ levels. MCHR2 is largely co-expressed with MCHR1 in the CNS, although peripheral expression was also found in adipocytes, pancreas, prostate, and intestine. The phylogenetic tree of MCH-related receptors contains opioid, somatostatin, galanin, urotensin 2, and orphan receptors. MCH receptors have the highest homology (about 40%) with the somatostatin receptors.
Melanin-concentrating hormone has been implicated in many behaviors. The hypothalamus is one of the primary sites in which MCH-containing nerve fibers and MCH receptors are extensively expressed. Although most of the MCH neurons are located within the incerto-hypothalamic and lateral hypothalamic area (LHA), a recent review by Bittencourt details the locations throughout the brain of MCH nerve terminals. Neural signaling by MCH via its receptors has been implicated in the control of energy balance, but due to the wide distribution of MCH-containing fibers throughout the brain, the critical sites of action for particular behaviors have not been identified. In male rats, neurons expressing MCH are found in the LHA and medial zona incerta, as well as, sparsely, in the olfactory tubercle and pontine reticular formation. The wide distribution of MCH fibers suggests the involvement of this neuropeptide in a variety of functions, including arousal, neuroendocrine control, and energy homeostasis.
Melanin-concentrating hormone-expressing neurons in the LHA play an integrative role between signals from the periphery, acting via first-order neurons in the arcuate nucleus, and then from extra-hypothalamic systems, which modulate regulation of feeding, drinking, and seeking behaviors. Factors from the periphery affect brain activity, resulting in changes in food intake and energy expenditure. Neurons from the arcuate nucleus detect changes in homeostatic parameters and transmit information to other brain areas, including the LHA. These secondary area neurons have widespread projections throughout the brain, and their activation leads to coordinated and altered behaviors. About 25% of the LHA neurons projecting to the pedunculopontine tegmental (PPT) nucleus are immunoreactive for MCH, and 75% of the LHA neurons projecting to the cerebral motor cortex also contain MCH. Also, 15% of the incerto-hypothalamic neurons projecting to the PPT express MCH immunoreactivity. The MCH neurons express glutamic acid decarboxylase mRNA, a gamma-aminobutyric acid (GABA) synthesizing enzyme, indicating that the MCH/GABA neurons are involved in inhibitory modulation and their activation may lead to decreased motor activity in states of negative energy balance. Like MCH, vasopressin and oxytocin can influence energy homeostasis and other behaviors. Whole-cell recording in hypothalamic brain slices from the MCH-green fluorescent protein transgenic mouse revealed that both vasopressin and oxytocin evoked a substantial excitatory effect on MCH-expressing cells. Both neuropeptides reversibly increased spike frequency and depolarized the membrane potential in a concentration-dependent manner, suggesting that vasopressin or oxytocin exerts a robust excitatory effect on presumptive GABA cells that contain MCH.
Interestingly, projections to ventral medullary sites apparently play a role in the inhibitory effect of MCH on energy expenditure, but not food intake. In the rat, a significant proportion (5–15%) of primarily perifornical and far-lateral hypothalamic MCH neurons project to the dorsal vagal complex. Retrograde tracing in the caudal brainstem demonstrated that MCH-immunoreactive axons are distributed densely in the nucleus of the solitary tract, in the dorsal motor nucleus of the vagus, and in sympathetic premotor areas in the ventral medulla. In medulla slice preparations, MCH inhibited the amplitude of excitatory postsynaptic currents. Administration of MCH in the fourth ventricle in freely moving rats decreased core body temperature, but it did not change locomotor activity or food and water intake.
The MCH pathways from the lateral hypothalamus to the mammillary nucleus may also enable the animal to look for food during the initial moments of appetite stimulation.
