Goodin SZ, Keichler AR, Smith M, Wendt D, Strader AD. Effect of gonadectomy on AgRP-induced weight gain in rats. Am J Physiol Regul Integr Comp Physiol 295: R1747-R1753, 2008. First published October 15, 2008 doi:10.1152/ajpregu.90345.2008.-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 Ͻ 0.0001) of significantly elevated feeding compared with vehicletreated controls, while females displayed 3 days of hyperphagia (P Ͻ 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 (VO 2) following AgRP compared with male rats (P Ͻ 0.05). Removal of the gonads did not alter cumulative food intake in male or female rats but did attenuate the dramatic reduction in VO 2 exhibited by females. Both intact and gonadectomized rats demonstrated significantly increased respiratory quotient supporting the anabolic action of AgRP (P Ͻ 0.01). These findings are novel in that they reveal sex-specific underlying physiology used to achieve weight gain following central AgRP in rats.AgRP; melanocortin; energy expenditure; sex; food intake THE HYPOTHALAMUS OF THE CENTRAL nervous system contains multiple circuits that are critical for the regulation of energy balance. Behavioral, genetic, and anatomical data all point to the melanocortin system as being one of the most important of the hypothalamic pathways that regulate body weight (8,16,20). Despite the wealth of research on the melanocortin regulatory system, little effort has been dedicated to male and female differences in melanocortin signaling. Nearly all previous work on energy balance and the melanocortin system has focused on male rodents.It is widely accepted that the hypothalamus receives input from the periphery that relates to the current adiposity level of an animal. Primarily, these peripheral signals are the adiposederived hormone leptin and the pancreatic hormone insulin (7,22). These adiposity signals are relayed to the hyp...

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