Melanocortin-4 receptor–regulated energy homeostasis

Abstract

The melanocortin system provides a conceptual blueprint for the central control of energetic state. Defined by four principal molecular components—two antagonistically acting ligands and two cognate receptors—this phylogenetically conserved system serves as a prototype for hierarchical energy balance regulation. Over the last decade the application of conditional genetic techniques has facilitated the neuroanatomical dissection of the melanocortinergic network and identified the specific neural substrates and circuits that underscore the regulation of feeding behavior, energy expenditure, glucose homeostasis and autonomic outflow. In this regard, the melanocortin-4 receptor is a critical coordinator of mammalian energy homeostasis and body weight. Drawing on recent advances in neuroscience and genetic technologies, we consider the structure and function of the melanocortin-4 receptor circuitry and its role in energy homeostasis.

Central role for melanocortin-4 receptors in offspring hypertension arising from maternal obesity

“…T he main focus of research into the central melanocortin system has been on melanocortin-4 receptor(s) (Mc4r) and their relation to energy homeostasis, with relatively few studies addressing the role of Mc4r in cardiovascular control (1,2). However, it is clear that this system plays an important role in the control of blood pressure (BP) (3,4).…”

Molecular Mechanisms of Reward and Aversion

“…In contrast, the proopiomelanocortin (POMC) expressing neurons of ARC are responsible for promoting satiety and cessation of feeding, in combination with increasing energy expenditure and weight loss. The functional transmitters of POMC-neurons are the bioactive products α-, β-and γ-melanocyte stimulation hormones; these are part of the melanocortin-peptides, which arise from POMCprocessing (Krashes, Lowell and Garfield, 2016). Subpopulations of ARC POMC neurons have also been reported to either co-release the neurotransmitter GABA or Glutamate (Atasoy et al, 2014).…”

“…The ARC POMC and AgRP neurons target most of the same brain areas, with the strongest innervation occurring in hypothalamic structures (such as the paraventricular hypothalamic nucleus (PVH), lateral hypothalamus, medial preoptic nucleus, dorsomedial hypothalamus) and the paraventricular thalamic nucleus (Wang et al, 2015;Betley et al, 2013;Atasoy 2008). Multiple studies have revealed that the appetite reducing effect of melanocortin signaling primarily is mediated by ARC POMC-neurons projecting to the PVH (as reviewed by Krashes, Lowell and Garfield, 2016). Interestingly, the use of modern techniques such as chemogenetics and optogenetics for activation of ARC AgRP and POMC neurons have demonstrated different temporal dynamics of this circuitry.…”

“…The MC4R is known to be a cornerstone in appetite and energy balance control. MC4Rs are activated by α-melanocyte stimulating hormone (α-MSH) released from POMC neurons, while AgRP acts as an antagonist (Krashes, Lowell and Garfield, 2016). MC4R mutations leading to deficient signaling is the most prevalent monogenic cause of obesity in human beings (Farooqi et al, 2003).…”

“…Interestingly, a recent study uncovered a G-protein independent mechanism in PVH-neurons, where MC4Rs recruit the inward rectifying potassium channel Kir7, which leads to Kir7-closure and thereby depolarization (Ghamari-Langroudi et al, 2015). Based on these findings it has been suggested that the MC4Rs may be promiscuous between different G-protein and nonG-protein pathways (Krashes, Lowell and Garfield, 2016). The MC4Rs are present throughout the brain in areas targeted by AgRP and POMC neurons (Liu et al, 2003;Kishi et al, 2003), and in this manner are expressed on both circuitry involved in satiety regulation and energy homeostasis, but also on neurons regulating motivation and affective state.…”