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

Endocrinology Unit (V.S.D., N.M.M., J.R.S.) and Molecular Physiology (J.J.M.), Queen’s Medical Research Institute, Edinburgh EH16 4TJ, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Prof. Jonathan R. Seckl, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom. E-mail: J.Seckl{at}ed.ac.uk.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyzes regeneration of active intracellular glucocorticoids in fat, liver, and discrete brain regions. Although overexpression of 11ß-HSD1 in adipose tissue causes hyperphagia and the metabolic syndrome, male 11ß-HSD1 null (11ß-HSD1^–/–) mice resist metabolic disease on high-fat (HF) diet, but also show hyperphagia. This suggests 11ß-HSD1 may influence the central actions of glucocorticoids on appetite and perhaps energy balance. We show that 11ß-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 11ß-HSD1^–/– mice and decreased melanocortin-4 receptor mRNA expression in control but not 11ß-HSD1^–/– mice. 11ß-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 11ß-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 11ß-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 11ß-HSD1^–/– mice, whereas the opioid antagonist naloxone given with HF induced a rise in arcuate AGRP and blocked HF-diet induction of 11ß-HSD1. These data suggest that 11ß-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.

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