Melanin-concentrating hormone (MCH) is a neuropeptide, a chemical messenger used by nerve cells, produced in the hypothalamus. The hormone’s name comes from its discovery in fish, where it causes skin paling by concentrating melanin. In mammals, MCH does not affect pigmentation. Instead, it regulates energy balance, sleep, and mood. The broad influence of MCH helps explain how these physiological processes are interconnected.
Understanding MCH Production and Signaling
Melanin-concentrating hormone is synthesized from a larger precursor molecule called prepro-MCH (Pmch). The neurons responsible for producing MCH are found in two specific brain regions: the lateral hypothalamus and the zona incerta. From these areas, MCH-producing neurons send long projections to numerous other parts of the brain, allowing MCH to exert its influence broadly.
To transmit its signal, MCH binds to specific receptors on other neurons, primarily the MCH receptor 1 (MCHR1). MCHR1 is a G protein-coupled receptor (GPCR), which senses molecules outside the cell and activates internal signal transduction pathways. When MCH binds to MCHR1, it alters the receiving cell’s internal biochemistry and electrical responsiveness. The distribution of these receptors throughout the brain is extensive. MCHR1 is found in high concentrations in areas associated with feeding, reward, and emotion, such as the nucleus accumbens and the amygdala. This widespread receptor placement forms the “hardware” that allows MCH signals originating in the hypothalamus to coordinate complex behaviors and physiological states across different brain systems.
MCH in Appetite and Metabolism Control
MCH functions as an orexigenic peptide, meaning it stimulates appetite. Administering MCH in rodent models leads to increased food intake, particularly influencing the motivation to consume highly palatable, energy-dense foods. The hormone’s expression levels naturally rise during fasting to signal a need for energy. MCH also manages the body’s energy budget by promoting energy conservation through reduced energy expenditure and physical activity. Animal studies show that mice overexpressing the MCH gene tend to gain weight, while those lacking MCH or its MCHR1 receptor are leaner and more resistant to diet-induced obesity.
MCH is part of a complex network that governs energy homeostasis. Its actions are intertwined with other regulators; for instance, MCH levels are suppressed by leptin, a hormone from fat cells that signals satiety. Its appetite-stimulating effects also involve interactions with other orexigenic signals like neuropeptide Y (NPY) and agouti-related peptide (AgRP). This positions MCH as an integrator that helps balance energy intake with expenditure.
The Influence of MCH on Sleep Patterns
The MCH system is a promoter of sleep, with a strong influence on Rapid Eye Movement (REM) sleep. Neurons that produce MCH show their highest activity during REM sleep and the transition into sleep. This neurobiological activity corresponds with behavioral outcomes, as studies show administering MCH increases the total amount of both REM and non-REM sleep and reduces the time it takes to fall asleep.
MCH promotes sleep by inhibiting the brain’s arousal systems. MCH neurons project to and dampen the activity of wake-promoting centers, placing it in opposition to the orexin/hypocretin system, which promotes wakefulness. Genetic studies support this role, as mice lacking MCH receptors exhibit alterations in their sleep architecture. Conversely, direct stimulation of MCH neurons can induce both non-REM and REM sleep, even during an animal’s normal active period, indicating the system can override waking signals.
MCH’s Connection to Mood and Stress
MCH is involved in regulating mood and the body’s response to stress. Dysregulation of the MCH system is linked to behaviors associated with anxiety and depression in animal models. The hormone’s role in mood appears to be context-dependent.
Some studies indicate that blocking MCH signaling with MCHR1 antagonists can produce antidepressant and anxiety-reducing effects. For instance, chronic stress increases MCH expression in emotional circuits, and activating the MCH pathway to the amygdala can promote anxiety-like behaviors in mice. Conversely, other findings suggest MCH may have calming effects under certain conditions, indicating it is a modulator that helps shape emotional responses through its interactions with other neurotransmitter systems.
MCH System as a Therapeutic Target
The MCH signaling system is an attractive target for therapeutic intervention, particularly for obesity. Pharmaceutical research has focused on developing MCH receptor 1 (MCHR1) antagonists. The goal of these drugs is to block the orexigenic and energy-conserving effects of MCH, thereby reducing food intake, increasing energy expenditure, and promoting weight loss.
In animal models of diet-induced obesity, MCHR1 antagonists have successfully reduced body weight and hedonic feeding (eating for pleasure). However, developing these drugs for human use has been challenging, with few candidates advancing to late-stage clinical trials. A primary hurdle is MCH’s widespread functions, as blocking its action for weight loss could lead to unintended side effects on sleep and mood.
The system’s involvement in other functions opens possibilities for different applications. Modulating MCH signaling could be explored for treating conditions like cachexia (severe weight loss), sleep disorders, or mood disturbances. Developing drugs that can target one function without disrupting others remains a substantial clinical challenge.