11β-Hydroxysteroid Dehydrogenase Type 1 Induction in the Arcuate Nucleus by High-Fat Feeding: A Novel Constraint to Hyperphagia?

Abstract

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes regeneration of active intracellular glucocorticoids in fat, liver, and discrete brain regions. Although overexpression of 11β-HSD1 in adipose tissue causes hyperphagia and the metabolic syndrome, male 11β-HSD1 null (11β-HSD1−/−) mice resist metabolic disease on high-fat (HF) diet, but also show hyperphagia. This suggests 11β-HSD1 may influence the central actions of glucocorticoids on appetite and perhaps energy balance. We show that 11β-HSD1−/− mice express lower hypothalamic mRNA levels of the anorexigenic cocaine and amphetamine-regulated transcript and melanocortin-4 receptor, but higher levels of the orexigenic melanin-concentrating hormone mRNAs than controls (C57BL/6J) on a low-fat diet (11% fat). HF (58% fat) diet promoted transient (∼8 wk) hyperphagia and decreased food efficiency in 11β-HSD1−/− mice and decreased melanocortin-4 receptor mRNA expression in control but not 11β-HSD1−/− mice. 11β-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 11β-HSD1 associated with subsequent down-regulation of AGRP. This regulatory pattern was unexpected because glucocorticoids increase AGRP, suggesting an alternate hyperphagic mechanism despite partial colocalization of 11β-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 μ opioid agonist DAMGO recapitulated the HF-induced dissociation of arcuate AGRP expression between control and 11β-HSD1−/− mice, whereas the opioid antagonist naloxone given with HF induced a rise in arcuate AGRP and blocked HF-diet induction of 11β-HSD1. These data suggest that 11β-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.