A C-Terminal Fragment of Agouti-Related Protein Increases Feeding and Antagonizes the Effect of Alpha-Melanocyte Stimulating Hormone in Vivo

Abstract

Agouti-related protein (Agrp) is present in rat and human hypothalamus and is structurally related to agouti protein. Overexpression of either of these proteins results in obesity. However the effect of exogenous Agrp and its in vivo interaction with alpha-melanocyte stimulating hormone (alphaMSH), the likely endogenous melanocortin 3 and 4 receptor (MC3-R and MC4-R) agonist, have not been demonstrated. We report that 1 nmol of Agrp(83-132), a C-terminal fragment of Agrp, when administered intracerebroventricularly (ICV) into rats, increased food intake over a 24-h period (23.0+/-1.4 g saline vs 32.9+/-2.3 g Agrp, p<0.05). The hyperphagia was similar to that seen when 1 nmol of the synthetic MC3-R and MC4-R antagonist SHU9119 was given i.c.v. (19.6+/-1.8 g saline vs 32.5+/-1.7 g SHU9119, p<0.001). Both Agrp(83-132) and SHU9119 blocked the reduction in 1-h food intake of i.c.v. alphaMSH at the beginning of the dark phase. This effect occurred independently of whether the antagonists were administered simultaneously, or nine hours prior, to the alphaMSH. We have also shown Agrp(83-132) is an antagonist at the MC3-R and MC4-R, with similar inhibition of cAMP activation to that previously reported for the full length peptide. In conclusion, Agrp(83-132) administered i.c.v. increases feeding with long lasting effects and is able to inhibit the action of alphaMSH. This interaction may be mediated by the MC3-R and/or MC4-R.

Resolving Behavioral Output via Chemogenetic Designer Receptors Exclusively Activated by Designer Drugs

“…Using combinatorial knock-out mouse lines, the early feeding phase following DREADD-mediated ARC AgRP activation was attributed to the role of the fast-acting neurotransmitter GABA and/or NPY, while AgRP was capable of promoting food intake over an extended period of time , supporting previous pharmacology studies (Clark et al, 1984;Rossi et al, 1998;Semjonous et al, 2009). However, it should be noted that these experiments were performed in genetic knock-out models that cannot account for compensatory mechanisms that likely play a role in shaping homeostatic feeding circuits (Luquet et al, 2005).…”

A derivative of the melanocortin receptor antagonist SHU9119 (PG932) increases food intake when administered peripherally

“…Central administration of the α-MSH derivative melanotan-II (MT-II) reduces food intake and increases oxygen consumption through activation of Mc4r [8,28]. Conversely, central administration of non-selective antagonists of the MC3R and Mc4r, such as the endogenous antagonist agouti-related peptide (AgRP) or the synthetic melanocortin analog SHU9119, increase food intake and body weight when administered intracerebroventricularly [10,32]. The regulation of feeding behavior and energy expenditure by MSH is through to primarily involve Mc4r [8,28].…”

Central blockade of melanocortin receptors attenuates the metabolic and locomotor responses to peripheral interleukin-1β administration

“…These two neuropeptides are expressed in separate neuronal populations within the arcuate nucleus and both cell types express MC3R, suggesting either auto-regulation and/or cross talk between these two neuronal populations (Bagnol et al, 1999). One of the more intensely studied aspects of melanocortin biology is their involvement in the regulation of both food intake and energy metabolism (Forbes et al, 2001); α-MSH inhibits food intake (Ludwig et al, 1998), while AgRP is a potent stimulator of food intake (Rossi et al, 1998). With regard to receptors, MC3R knockout mice demonstrate increased adiposity and enhanced feed efficiency (Chen et al, 2000), while MC4R knockout mice are hyperphagic and obese (Huszar et al, 1997).…”