MTII attenuates ghrelin- and food deprivation-induced increases in food hoarding and food intake

Abstract

Food deprivation triggers a constellation of physiological and behavioral changes including increases in peripherally-produced ghrelin and centrally-produced agouti-related protein (AgRP). Upon refeeding, food intake is increased in most species, however hamsters primarily increase food hoarding. Food deprivation-induced increases in food hoarding by Siberian hamsters are mimicked by peripheral ghrelin and central AgRP injections. Because food deprivation stimulates ghrelin as well as AgRP synthesis/release, food deprivation-induced increases in hoarding may be mediated by melanocortin 3 or 4 receptor (MC3/4-R) antagonism via AgRP, the MC3/4-R inverse agonist. Therefore, we asked: Can a MC3/4-R agonist block food deprivation-or ghrelin-induced increases in foraging, food hoarding and food intake? This was accomplished by injecting melanotan II (MTII), a synthetic MC3/4-R agonist, into the 3 rd ventricle in food deprived, fed or peripheral ghrelin injected hamsters and housed in a running wheel-based food delivery foraging system. Three foraging conditions were used: a) no running wheel access, non-contingent food, b) running wheel access, non-contingent or c) a foraging requirement for food (10 revolutions/pellet). Food deprivation was a more potent stimulator of foraging and hoarding than ghrelin. Concurrent injections of MTII completely blocked food deprivation-and ghrelin-induced increases in food intake and attenuated, but did not always completely block, food deprivation-and ghrelin-induced increases in food hoarding. Collectively, these data suggest that the MC3/4-R are involved in ghrelin-and food deprivation-induced increases in food intake, but other neurochemical systems, such as previously demonstrated with neuropeptide Y, also are involved in increases in food hoarding as well as foraging.

Obesity Impairs the Action of the Neuroendocrine Ghrelin System

“…This reflects the physiological role of ghrelin, that is, to defend body weight and glucose homeostasis during times of food shortage. In support of this, ghrelin stimulates many appetitive ingestive behaviors in the mouse, including exploratory sniffing [72], foraging, and food hoarding [73]. Ghrelin also affects complementary parameters of food intake including promoting learning and memory [74], decreasing anxiety [75,76], and enhancing the rewarding properties of food [41,62,77].…”

Ghrelin Gene Products and the Regulation of Food Intake and Gut Motility

“…Acyl ghrelin definitely activates NPY/AgRP neurons in the arcuate nuclei, as shown by the increase of intracellular Ca 2ϩ concentration, which was via an AMPK-mediated, protein kinase A-and N-type channel-dependent signaling mechanism (Kohno et al, 2003(Kohno et al, , 2008 and c-fos immunoreactivity (Hewson and Dickson, 2000;Kamegai et al, 2000Kamegai et al, , 2001Shintani et al, 2001;Cowley et al, 2003;van den Top et al, 2004;Chen et al, 2005b;Date et al, 2005;Kobelt et al, 2005;Inhoff et al, 2008) in the arcuate nuclei. Chemical (Tamura et al, 2002), vectormediated (Bewick et al, 2005), pharmacological (Nakazato et al, 2001;Asakawa et al, 2001b;Keen-Rhinehart and Bartness, 2007), or genetic blockade (Chen et al, 2004;Shaw et al, 2005) of NPY and/or AgRP signaling cascade completely abolished or attenuated the orexigenic effects of acyl ghrelin. Among them, central Y 1 receptor (Asakawa et al, 2001b;Shintani et al, 2001) as well as melanocortin receptor subtype 3 and 4 (MC 3 -R and MC 4 -R) (Shaw et al, 2005;Keen-Rhinehart and Bartness, 2007) are responsible for acyl ghrelin-induced hyperphagic effects.…”

“…Chemical (Tamura et al, 2002), vectormediated (Bewick et al, 2005), pharmacological (Nakazato et al, 2001;Asakawa et al, 2001b;Keen-Rhinehart and Bartness, 2007), or genetic blockade (Chen et al, 2004;Shaw et al, 2005) of NPY and/or AgRP signaling cascade completely abolished or attenuated the orexigenic effects of acyl ghrelin. Among them, central Y 1 receptor (Asakawa et al, 2001b;Shintani et al, 2001) as well as melanocortin receptor subtype 3 and 4 (MC 3 -R and MC 4 -R) (Shaw et al, 2005;Keen-Rhinehart and Bartness, 2007) are responsible for acyl ghrelin-induced hyperphagic effects.…”

“…Initial studies using antagonism of GHS-R1a or ghrelin's downstream mediator (i.e., AgRP, via injecting melanotan II into the third ventricle) showed reduced acyl ghrelin-and food deprivation-induced food intake, body weight gain, and food hoarding in mice and hamsters (Keen-Rhinehart and Bartness, 2007). Another study revealed that small-molecule GHS-R1a antagonists improved glucose tolerance, suppressed appetite, and promoted weight loss in rats , suggesting promising clinical therapeutic value of GHS-R1a antagonism for controlling the obesity pandemic in developed countries.…”

Leptin inhibits food-deprivation-induced increases in food intake and food hoarding

“…For example, we now know that food deprivation triggers increases in circulating concentrations of the largely stomach-derived peptide ghrelin in Siberian hamsters (34), as it does in laboratory rats (57) and humans (2), and that peripheral ghrelin treatment stimulates foraging and food hoarding and, to a lesser extent, food intake in Siberian hamsters (34). We also now know that the ability of food deprivation or ghrelin to stimulate appetitive and consummatory ingestive behaviors is impaired by central treatment with anorexigenic agents such as the neuropeptide Y (NPY), a Y1-receptor antagonist 1229U91, and the melanocortin 3/4 receptor agonist melanotan II (35,36).…”