title: Evidence that diet-induced hyperleptinemia, but not hypothalamic gliosis, causes ghrelin resistance in NPY/AgRP neurons of male mice.
abstract: High-fat diet (HFD) feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/Agouti-related peptide neurons. In the current study, we investigated the time course over which this occurs and the mechanisms responsible for ghrelin resistance. After 3 weeks of HFD feeding, neither peripheral nor central ghrelin increased food intake and or activated NPY neurons as demonstrated by a lack of Fos immunoreactivity or whole-cell patch-clamp electrophysiology. Pair-feeding studies that matched HFD calorie intake with chow calorie intake show that HFD exposure does not cause ghrelin resistance independent of body weight gain. We observed increased plasma leptin in mice fed a HFD for 3 weeks and show that leptin-deficient obese ob/ob mice are still ghrelin sensitive but become ghrelin resistant when central leptin is coadministered. Moreover, ob/ob mice fed a HFD for 3 weeks remain ghrelin sensitive, and the ability of ghrelin to induce action potential firing in NPY neurons was blocked by leptin. We also examined hypothalamic gliosis in mice fed a chow diet or HFD, as well as in ob/ob mice fed a chow diet or HFD and lean controls. HFD-fed mice exhibited increased glial fibrillary acidic protein-positive cells compared with chow-fed mice, suggesting that hypothalamic gliosis may underlie ghrelin resistance. However, we also observed an increase in hypothalamic gliosis in ob/ob mice fed a HFD compared with chow-fed ob/ob and lean control mice. Because ob/ob mice fed a HFD remain ghrelin sensitive, our results suggest that hypothalamic gliosis does not underlie ghrelin resistance. Further, pair-feeding a HFD to match the calorie intake of chow-fed controls did not increase body weight gain or cause central ghrelin resistance; thus, our evidence suggests that diet-induced hyperleptinemia, rather than diet-induced hypothalamic gliosis or HFD exposure, causes ghrelin resistance.
authors.affiliation: Department of Physiology (D.I.B., S.H.L., Q.W., R.S., A.R., M.B.L., H.A.C., H.C.P., Z.B.A.), Monash University, Clayton, Victoria 3800, Australia; Traditional Chinese Medicine Department (Q.W.), Peking Union Medical College Hospital, Beijing, China 100730; Department of Physiology (J.B., A.J.H.), Bosch Institute, The University of Sydney, New South Wales 2006, Australia; and Department of Animal Physiology (A.T.), Faculty of Biology, Philipps University, Marburg, D-35043 Marburg, Germany.
authors.forename: Dana I
authors.initials: DI
authors.lastname: Briggs
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Lockie
authors.forename: Jonas
authors.initials: J
authors.lastname: Benzler
authors.forename: Qunli
authors.initials: Q
authors.lastname: Wu
authors.forename: Romana
authors.initials: R
authors.lastname: Stark
authors.forename: Alex
authors.initials: A
authors.lastname: Reichenbach
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hoy
authors.forename: Moyra B
authors.initials: MB
authors.lastname: Lemus
authors.forename: Harold A
authors.initials: HA
authors.lastname: Coleman
authors.forename: Helena C
authors.initials: HC
authors.lastname: Parkington
authors.forename: Alex
authors.initials: A
authors.lastname: Tups
authors.forename: Zane B
authors.initials: ZB
authors.lastname: Andrews
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism / Q000502:physiology; D059305:Diet, High-Fat / Q000009:adverse effects; D004351:Drug Resistance / Q000502:physiology*; D054439:Ghrelin / Q000494:pharmacology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000209:etiology / Q000503:physiopathology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D020738:Leptin / Q000097:blood* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000503:physiopathology
chemical_list: D054369:Agouti-Related Protein; D054439:Ghrelin; D005904:Glial Fibrillary Acidic Protein; D020738:Leptin; D009478:Neuropeptide Y; D049452:Green Fluorescent Proteins