Biased signaling at neural melanocortin receptors in regulation of energy homeostasis

Abstract

The global prevalence of obesity highlights the importance of understanding on regulation of energy homeostasis. The central melanocortin system is an important intersection connecting the neural pathways controlling satiety and energy expenditure to regulate energy homeostasis by sensing and integrating the signals of external stimuli. In this system, neural melanocortin receptors (MCRs), melanocortin-3 and -4 receptors (MC3R and MC4R), play crucial roles in the regulation of energy homeostasis. Recently, multiple intracellular signaling pathways and biased signaling at neural MCRs have been discovered, providing new insights into neural MCR signaling. This review attempts to summarize biased signaling including biased receptor mutants (both naturally occurring and lab-generated) and biased ligands at neural MCRs, and to provide a better understanding of obesity pathogenesis and new therapeutic implications for obesity treatment.

Keywords: AgRP; Biased signaling; Energy homeostasis; Melanocortin-3 receptor; Melanocortin-4 receptor; Obesity.

Fig. 1. The central melanocortin system

POMC and AgRP neurons in the ARC are defined as “first order” neurons which integrate external stimuli and project to “second order” neurons with neural MCR expression. Neurons in PVN and IML mediate different physiological functions in energy homeostasis. MC3R and MC4R in POMC neurons can also serve auto-inhibitory and auto-excitatory roles to regulate energy homeostasis.

Fig. 2. Therapeutic relevance of biased signaling at neural MC4R

The MC4R could couple to Gs, Gq and Kir7.1. Normal balanced agonist activates MC4R and non-selectively induces Gs and Gq signaling and closure of Kir7.1, resulting in a negative energy balance with side effects. However, biased ligand activates MC4R and selectively induces Gq signaling and closure of Kir7.1, resulting a negative energy balance without side effects.