Agouti-related
peptide (AgRP), the endogenous antagonist to the
melanocortin 3 and 4 receptors, elicits robust
hyperphagia and
weight gain in rodents when administered directly into the central nervous system. The relative influence of AgRP to cause
weight gain in rodents partially depends on the activity level of the
melanocortin agonist-producing
proopiomelanocortin neurons. Both
proopiomelanocortin and AgRP neurons within the arcuate nucleus receive energy storage information from circulating peripheral signals such as
leptin and
insulin. Another modulator of AgRP activity includes the cell surface molecule
syndecan-3. Because
leptin and
insulin affect food intake in a sexually dimorphic way in rodents and syndecan-3-deficient mice regulate adiposity levels through distinct physiological mechanisms, we hypothesized that AgRP-induced
weight gain would also be sexually dimorphic in rats. In the present study, the behavioral and physiological effects of centrally-administered AgRP in male and female were investigated. In male rats, AgRP (1 nmol) induced 5 days (P < 0.0001) of significantly elevated feeding compared with vehicle-treated controls, while females displayed 3 days of
hyperphagia (P < 0.05). However, 1 wk after the injection, both male and female rats gained the same percent
body weight (6%). Interestingly, female rats exhibited a greater reduction in energy expenditure (Vo2) following AgRP compared with male rats (P < 0.05). Removal of the gonads did not alter cumulative food intake in male or female rats but did attenuate the dramatic reduction in Vo2 exhibited by females. Both intact and gonadectomized rats demonstrated significantly increased respiratory quotient supporting the anabolic action of AgRP (P < 0.01). These findings are novel in that they reveal sex-specific underlying physiology used to achieve
weight gain following central AgRP in rats.