Neural melanocortin receptors in obesity and related metabolic disorders

Abstract

Obesity is a global health issue, as it is associated with increased risk of developing chronic conditions associated with disorders of metabolism such as type 2 diabetes and cardiovascular disease. A better understanding of how excessive fat accumulation develops and causes diseases of the metabolic syndrome is urgently needed. The hypothalamic melanocortin system is an important point of convergence connecting signals of metabolic status with the neural circuitry that governs appetite and the autonomic and neuroendocrine system controling metabolism. This system has a critical role in the defense of body weight and maintenance of homeostasis. Two neural melanocortin receptors, melanocortin 3 and 4 receptors (MC3R and MC4R), play crucial roles in the regulation of energy balance. Mutations in the MC4R gene are the most common cause of monogenic obesity in humans, and a large literature indicates a role in regulating both energy intake through the control of satiety and energy expenditure. In contrast, MC3Rs have a more subtle role in energy homeostasis. Results from our lab indicate an important role for MC3Rs in synchronizing rhythms in foraging behavior with caloric cues and maintaining metabolic homeostasis during periods of nutrient scarcity. However, while deletion of the Mc3r gene in mice alters nutrient partitioning to favor accumulation of fat mass no obvious role for MC3R haploinsufficiency in human obesity has been reported. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.

Keywords: Genetic model; Human; Melanocortin receptor; Metabolic homeostasis; Nervous system; Obesity.

Figure 1. The melanocortin peptides and their receptors

Structure and processing of POMC hormone precursor (A). Affinity of MCRs for the melanocortins (B).

Figure 2. The hypothalamic melanocortin system

POMC (red) and AgRP (green) neurons in the ARC are referred as “first order” neurons integrating information about the energy state and relaying those information to “second order” neurons expressing MCRs.

Figure 3. Divergent pathways in MC4Rs-mediated regulation of energy homeostasis

POMC (red) and AgRP (green) neurons in the ARC send projections to the forebrain, while only POMC neurons may send projections to the brainstem (DMV) and spinal cord (IML). MC4Rs (purple) expressed in the PVN are sufficient to regulate satiety. MC4Rs expressed on preganglionic neurons in the DMV have an inhibitory effect on parasympathetic tone, while in the IML they exert an excitatory effect on the sympathetic outflow.

Figure 4. MC3Rs are required for entrainment to caloric cues

Examples of double-plotted actogram of wheel turns under a 12:12 light-dark cycle in wild-type (A) and loxTB Mc3r (B) mice fed ad libitum for 17 days and provided once a day with a hypocaloric meal for 19 days. The red line shows the time of food presentation.