11-hydroxysteroid dehydrogenase type 1 (11-HSD1) catalyzes regeneration of active intracellular glucocorticoids in fat, liver and discrete brain regions. While overexpression of 11-HSD1 in adipose tissue causes hyperphagia and the metabolic syndrome, male 11-HSD1 null (11-HSD1^-/-) mice resist metabolic disease on high fat (HF) diet, but also show hyperphagia. This suggests 11-HSD1 may influence the central actions of glucocorticoids on appetite and perhaps energy balance. We show that 11-HSD1^-/- mice express lower hypothalamic mRNA levels of the anorexigenic cocaine and amphetamine-regulated transcript (CART) and melanocortin-4 receptor (MC4R), but higher levels of the orexigenic melanin-concentrating hormone (MCH) mRNAs than controls (C57BL/6J) on a low fat diet (11% fat). HF (58% fat) diet promoted transient (8 weeks) hyperphagia and decreased food efficiency in 11-HSD1^-/- mice and decreased melanocortin 4 receptor (MC4R) mRNA expression in control but not 11-HSD1^-/- mice. 11-HSD1^-/- mice showed a HF-mediated up-regulation of the orexigenic agouti-related peptide (AGRP) mRNA in the arcuate nucleus which paralleled the transient HF hyperphagia. Conversely, control mice showed a rapid (48 h) HF-mediated increase in arcuate 11-HSD1 associated with subsequent down-regulation of AGRP. This regulatory pattern was unexpected since glucocorticoids increase AGRP, suggesting an alternate hyperphagic mechanism despite partial co-localization of 11-HSD1 and AGRP in arcuate nucleus cells. One major alternate mechanism governing selective fat ingestion and the AGRP system is endogenous opioids. Treatment of HF fed mice with the mu opioid agonist DAMGO recapitulated the HF-induced dissociation of arcuate AGRP expression between control and 11-HSD1^-/- mice, whereas the opioid antagonist naloxone given with HF induced a rise in arcuate AGRP and blocked HF-diet induction of 11-HSD1. These data suggest that 11-HSD1 in brain plays a role in the adaptive restraint of excess fat intake, in part by increasing inhibitory opioid tone on AGRP expression in the arcuate nucleus.