title: 11 beta-hydroxysteroid dehydrogenase type 1 induction in the arcuate nucleus by high-fat feeding: A novel constraint to hyperphagia?
abstract: 11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes regeneration of active intracellular glucocorticoids in fat, liver, and discrete brain regions. Although overexpression of 11 beta-HSD1 in adipose tissue causes hyperphagia and the metabolic syndrome, male 11 beta-HSD1 null (11 beta-HSD1-/-) mice resist metabolic disease on high-fat (HF) diet, but also show hyperphagia. This suggests 11 beta-HSD1 may influence the central actions of glucocorticoids on appetite and perhaps energy balance. We show that 11 beta-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 ( approximately 8 wk) hyperphagia and decreased food efficiency in 11 beta-HSD1-/- mice and decreased melanocortin-4 receptor mRNA expression in control but not 11 beta-HSD1-/- mice. 11 beta-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 beta-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 11 beta-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 beta-HSD1-/- mice, whereas the opioid antagonist naloxone given with HF induced a rise in arcuate AGRP and blocked HF-diet induction of 11 beta-HSD1. These data suggest that 11 beta-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.
authors.affiliation: Endocrinology Unit, Queen's Medical Research Institute, Edinburgh EH16 4TJ, Scotland, United Kingdom.
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Densmore
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Morton
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D054369:Agouti-Related Protein; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000201:enzymology*; D003345:Corticosterone / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D004790:Enzyme Induction; D005260:Female; D015870:Gene Expression; D006963:Hyperphagia / Q000201:enzymology*; D007328:Insulin / Q000097:blood; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000737:chemistry; D009478:Neuropeptide Y / Q000235:genetics; D011333:Pro-Opiomelanocortin / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000819:agonists; D013963:Thyroid Hormones / Q000097:blood; D015430:Weight Gain; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
chemical_list: D054369:Agouti-Related Protein; D004041:Dietary Fats; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D011506:Proteins; D012333:RNA, Messenger; D044105:Receptor, Melanocortin, Type 4; D017450:Receptors, Opioid, mu; D013963:Thyroid Hormones; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D011333:Pro-Opiomelanocortin; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone