Melanin-concentrating hormone neurons affect adipose tissues and modulate weight gain.

Abstract

Melanin-concentrating hormone (MCH) is a hypothalamic peptide released in the systemic circulation by the pituitary. MCH was initially described as a mediator in the control of skin colour change in fish and later in the regulation of human skin pigmentation (Saito & Nagasaki, 2008). In the hypothalamus of mammals, MCH-producing neurons have been identified in the lateral hypothalamic area and in the zona incerta of the hypothalamus (Saito & Nagasaki, 2008). Widespread areas in the brain, including sparse hypothalamic neurons, project to hypothalamic MCH neurons, which projections are widely distributed in the neuroaxis. Diverse inputs provide cues from homeostatic systems to hypothalamic MCH neurons. MCH-producing neurons also produce and release other neurotransmitters which, together with their widespread outputs, support their effects in modulating several homeostatic functions, including energy balance, food intake, sleep and motivated behaviour (Saito & Nagasaki, 2008). Chronic treatment with MCH or overexpression of MCH increases food intake, decreases energy expenditure and induces obesity in mice. Additionally, hypothalamic levels of MCH mRNA are upregulated in genetically obese mice (for review on the effects of MCH in food intake and energy expenditure, see Saito & Nagasaki (2008)). Therefore, there is compelling evidence for an endogenous role for brain MCH in energy metabolism. Determining the location, the network and the actions of MCH neurons in energy expenditure may lead to novel specific and efficient strategies to treat obesity and other metabolic conditions. MCH receptors types 1 (MCHR1) and 2 (MCHR2) are coupled to Gi/o proteins and to Gq proteins, respectively (Lembo et al. 1999; Saito & Nagasaki, 2008). Thus, activation of MCHR1 or MCHR2 usually triggers opposing effects on neuronal activity, with the first inhibiting and the latter favouring neuronal activity. In general, mammals express both receptor types, with the exception that rodents do not express MCHR2 (Saito & Nagasaki, 2008). In a recent research article in The Journal of Physiology, Izawa et al. (2022) studied the effects of postnatal ablation of MCH neurons in adult mice and found that MCH neurons modulate energy expenditure and weight gain. In addition, Izawa et al. (2022) show that MCH neurons are polysynaptically connected to BAT and suggest that MCH neurons suppress BAT activity via projections to the rostral raphe pallidus area (rRPa), also referred to as the medullary raphe nucleus. The rRPa includes raphe pallidus nucleus neurons, and some neurons in the raphe magnus nucleus, and contains sympathetic premotor neurons for BAT and other thermoeffectors that regulate body temperature (Morrison & Nakamura, 2019). rRPa neurons integrate excitatory and inhibitory inputs and modulate the sympathetic nerve activity (SNA) to the BAT. The physiological and pathological conditions recruiting the pathway MCH neurons/rRPa for the control of BAT thermogenesis and energy expenditure remain to be identified. In their study, Izawa et al. (2022) showed that ablation of MCH neurons increased the number of c-Fos-labelled cells in the rRPa of mice at room temperature. The average number of c-Fos-labelled cells was similar to that observed when wild-type mice were exposed to a cold ambient temperature, which is a condition that activates rRPa neurons and increases the sympathetic drive to BAT, thus generating heat to maintain a constant body temperature (Morrison & Nakamura, 2019). The presence of axons labelled for MCH in the rRPa (Izawa et al. 2021) supports a direct action of MCH neurons on rRPa neurons that express MCHR1 (Lembo et al. 1999). Accordingly, MCHR1-mediated inhibition of rRPa neurons for BAT would inhibit BAT thermogenesis. Further studies are needed to clarify whether MCH neurons modulate the activity of rRPa neurons for BAT via the MCH/MCHR1 pathway. Izawa et al. (2022) show evidence for increased energy expenditure in their animal model. MCH neuron-ablated mice displayed increased oxygen consumption, carbon dioxide production, tyrosine hydroxylase immunostaining in BAT and protein expression of two key mitochondrial thermogenic markers in BAT: uncoupling protein 1 (UCP1) and cytochrome c oxidase 4 (COX4), and reduced ageing-induced body weight gain. It remains to be clarified whether MCH neurons tonically inhibit rRPa neurons that contribute to BAT SNA. Additionally, the marked reduction in white adipose tissue (WAT) weight (Izawa et al. 2022) could result from an increased WAT SNA or from an increased demand for energetic substrates generated by BAT thermogenesis that would indirectly induce WAT lipolysis. Both processes are likely to occur simultaneously, resulting in reduced WAT weight over the 12 weeks of ablation. While MCH neuron activity could be modulating energy expenditure via BAT inhibition, the contribution of MCH neurons to increased energy expenditure could also be a consequence of the effects of MCH neurons on other brain functions that secondarily contribute to increasing energy expenditure. For instance, Izawa et al. (2022) observed an increase in the locomotor activity of MCH neuron-ablated mice during the active period, which was attributed to the effects of MCH in motivated behaviour, and could contribute to the increased BAT metabolism over the 12 weeks of ablation. Additionally, MCH neuron ablation increases wakefulness with decreased non-REM (NREM) sleep, while activation of MCH neurons increases REM sleep (Tsunematsu et al. 2014). The reduction in the sympathetic tone contributes to the fall in body temperature that is associated with sleep. In this scenario, MCH neurons could play an important role in the physiological suppression of BAT thermogenesis and energy expenditure during sleep; therefore, when these neurons are ablated, the suppression is attenuated. Another hypothesis to be considered in studies using MCH neuron-ablated mice is that the enhanced sympathetic activity induced by the neuronal ablation increases body temperature and, consequently, reduces the facilitation for the initiation of sleep. This is a reasonable hypothesis if the increase in BAT thermogenesis is not accompanied by compensatory heat loss by vasodilatation of the skin vasculature, for instance, which would maintain a constant body temperature during the period of enhanced energy expenditure. Alternatively, MCH neuron ablation might oppose the occurrence of NREM sleep, thus leading to a sleep deprivation-like state that increases energy expenditure. The recent findings on the effects of MCH in energy expenditure provide a foundation for further studies addressing a hypothetical model in which rRPa-projecting MCH neurons release MCH, which activates MCHR1 in a subset of BAT-sympathetic premotor neurons in the rRPa, thus inhibiting these cells and, consequently, restraining BAT SNA and inhibiting BAT thermogenesis. The functional pathway described may integrate the MCH system to the brain network controlling BAT thermogenesis and encourage further studies addressing the role of MCH neurons in physiological and pathophysiological conditions such as exposure to extreme ambient temperatures, fevers, hypothermia, weight gain, obesity and other metabolic disorders. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The author confirms there are no conflicts of interest relevant to the contents of this article. Sole author. The author thanks Dr Christopher J. Madden for comments on the manuscript.