MC4R Dimerization in the Paraventricular Nucleus and GHSR/MC3R Heterodimerization in the Arcuate Nucleus: Is There Relevance for Body Weight Regulation?

Abstract

The worldwide obesity epidemic is increasing, yet at this time, no long-acting and specific pharmaceutical therapies are available. Peripheral hormonal signals communicate metabolic status to the hypothalamus by activating their corresponding receptors in the arcuate nucleus (ARC). In this brain region, a variety of G protein-coupled receptors (GPCRs) are expressed that are potentially involved in weight regulation, but so far, the detailed function of most hypothalamic GPCRs is only partially understood. An important and underappreciated feature of GPCRs is the capacity for regulation via di- and heterodimerization. Increasing evidence implicates that heterodimerization of GPCRs results in profound functional consequences. Recently, we could demonstrate that interaction of the melanocortin 3 receptor (MC3R) and the growth hormone secretagogue receptor (GHSR)-1a results in a modulation of function in both receptors. Although the physiological role of GPCR-GPCR interaction in the hypothalamus is yet to be elucidated, this concept promises new avenues for investigation and understanding of hypothalamic functions dependent on GPCR signaling. Since GPCRs are important targets for drugs to combat many diseases, identification of heterodimers may be a prerequisite for highly specific drugs. Therefore, a detailed understanding of the mechanisms and their involvement in weight regulation is necessary. Fundamental to this understanding is the interplay of GPCR-GPCR in the hypothalamic nuclei in energy metabolism. In this review, we summarize the current knowledge on melanocortin receptors and GHSR-1a in hypothalamic weight regulation, especially as they pertain to possible drug targets. Furthermore, we include available evidence for the participation and significance of GPCR dimerization.

Hunger and Satiety Gauge Reward Sensitivity

“…The two neuron-activating pathways, G s and G q , mediate distinct physiologic effects; knockout of PVH G q , but not G s , prevented the efficacy of MC4R agonism to prevent food intake (94). Conversely, the ghrelin receptor, when coupled with either MC3R or MC4R, selects for G s signaling in both proteins in the PVH, for example, emphasizing that in conditions of increased hunger, MSH activity may select for activation (95). One of the most commonly used non-selective synthetic MCR agonists, melanotan II (MTII), also selects for G s signaling (33, 95).…”

“…Conversely, the ghrelin receptor, when coupled with either MC3R or MC4R, selects for G s signaling in both proteins in the PVH, for example, emphasizing that in conditions of increased hunger, MSH activity may select for activation (95). One of the most commonly used non-selective synthetic MCR agonists, melanotan II (MTII), also selects for G s signaling (33, 95). AgRP, discussed above, is an inverse agonist of MC4R and reduces cAMP levels independent of the presence of any agonist (33–35).…”

A compendium of human genes regulating feeding behavior and body weight, its functional characterization and identification of GWAS genes involved in brain-specific PPI network

“…The key role in regulation of FB and energy balance belongs to the central nervous system, being implemented through a complex interplay among neurons. This interplay is supported by neurotransmitters (neuromediators, neuropeptides, and releasing factors), which modulate neuronal activity via interactions with cellular transmembrane receptors [33, 53, 54]. In turn, receptors activate signal transducers, which effect transcription factor activity [55].…”

Melanocortin-3 Receptors and Metabolic Homeostasis

“…For example, MC3Rs form heterodimers with ghrelin receptors (GHSR). 123,124 Heterodimers broaden the selection of ligands that can regulate receptor activity while also modulating post-receptor signaling pathways.…”