Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals

Abstract

The melanocortin receptor (MC3-R and MC4-R) antagonist, agouti-related protein (AGRP), is a potent stimulant of food intake. We examined the effect of chronic intracerebroventricular (ICV) AGRP treatment on energy metabolism and pituitary function in ad libitum fed rats and rats administered AGRP and then pair-fed to a saline control group. Chronic ICV AGRP (83-132) administration (1 nmol/day for 7 days) significantly increased food intake and body weight in ad libitum fed animals compared with saline-treated controls (body weight on day 7: 272 ± 6 [saline] vs. 319 ± 8 g [AGRP ad libitum fed]; P < 0.001). A significant increase in the epididymal fat pad weight, interscapular brown adipose tissue (BAT) weight, and plasma leptin was also observed in the ad libitum fed group. In the AGRP pair-fed group, a significant increase in the epididymal fat pad weight, BAT weight, and plasma leptin was again observed, suggesting that AGRP caused metabolic changes independent of increased food intake. BAT uncoupling protein 1 (UCP-1) content was significantly decreased compared with saline controls in both the AGRP ad libitum fed (21 ± 8% of saline control; P < 0.01) and AGRP pair-fed groups (24 ± 7% of saline control; P < 0.01). Plasma thyroid-stimulating hormone (TSH) was significantly suppressed compared with saline controls in both the AGRP ad libitum fed and AGRP pair-fed groups (3. T he hypothalamic melanocortin system is a regulator of energy homeostasis. The agouti-related protein (AGRP), produced in the arcuate nucleus, is an antagonist at the melanocortin 3 and 4 receptors (MC3-R and MC4-R), which are distributed throughout the brain. The proopiomelanocortin (POMC) products, such as ␣-melanocyte-stimulating hormone (␣-MSH), act as agonists at the melanocortin receptors (1-3). Hypothalamic POMC mRNA, AGRP mRNA, and the density of MC4-R have been shown to be altered with nutritional status (4,5). Defects of POMC processing and mutations of MC4-R in humans and mice are associated with gross obesity (6-11).5Administration of the synthetic MC3/4-R agonist MT II into the forebrain ventricles or directly into the paraventricular nucleus (PVN) of the hypothalamus of rats or mice produced a dosage-dependent reduction in food intake and body weight (12)(13)(14). A single injection of either the endogenous (AGRP ) or the synthetic (SHU9119 and HS014) MC3/4-R antagonists stimulated food intake in rodents (12,13,15,16). Chronic administration of the more selective MC4-R antagonist, HS028, for 7 days via an osmotic minipump significantly increased food intake and body weight. Tachyphylaxis to HS028 did not occur. However, neither energy expenditure nor pituitary function were examined in this study (17). Previous results from this department have demonstrated that AGRP (83-132), the endogenous hypothalamic melanocortin receptor antagonist, significantly increased 24-h food intake and antagonized the anorectic effects of ␣-MSH (16).The melanocortin system also influences energy expenditure. Intracerebroventricular (ICV) administra...

a-MSH enhances activity-based anorexia

“…Whereas a-MSH treatment increased FAA, AGRP (83-132) treatment did not influence FAA or total RWA. Furthermore, AGRP (83-132) treatment did not change HPA axis activity in ABA, similar to results from another study reporting that chronic AGRP (83-132) treatment in ad libitum fed and foodrestricted rats does not influence plasma corticosterone levels or adrenal gland weight [42]. Hence, it appears that stimulation of MCRs by a-MSH and suppression of MCRs by AGRP influence ABA, although not all parameters of ABA were influenced by both treatments.…”

AgRP(83–132) and SHU9119 differently affect activity-based anorexia

“…Whereas SHU9119 acts as a competitive antagonist, with modest partial agonism at the MC3-R (Hruby et al, 1995), AgRP acts as an inverse agonist, decreasing constitutive activity of MC3-R and MC4-R Haskell-Luevano and Monck, 2001;Nijenhuis et al, 2001). Both compounds induce hyperphagia in ad libitum fed rats (Adage et al, 2001;Small et al, 2001). However, AgRP but not SHU9119 increased feeding and body temperature in ABA rats.…”

Interactions between the melanocortin system and the hypothalamo–pituitary–thyroid axis

“…In rodents, chronic AgRP injection increases BAT weight due to increased adiposity, but reduces BAT UCP-I protein and plasma TSH [60]. Interestingly, these effects are independent of food intake.…”

“…Conversely, CNS infusion of AgRP to ad libitum fed rats produces central hypothyroidism, with reduced plasma thyroid hormones, inappropriately normal or decreased TSH and suppressed PVN pro-TRH mRNA expression [20,60]. However, CNS administration of AgRP did not affect type 2 deiodinase activity in brown adipose tissue (BAT), a major effector organ for thyroid hormones in regulating thermogenesis [20].…”