PMID- 36291579 OWN - NLM STAT- MEDLINE DCOM- 20221031 LR - 20230118 IS - 2218-273X (Electronic) IS - 2218-273X (Linking) VI - 12 IP - 10 DP - 2022 Sep 25 TI - Deletion of Growth Hormone Secretagogue Receptor in Kisspeptin Neurons in Female Mice Blocks Diet-Induced Obesity. LID - 10.3390/biom12101370 [doi] LID - 1370 AB - The gut peptide, ghrelin, mediates energy homeostasis and reproduction by acting through its receptor, growth hormone secretagogue receptor (GHSR), expressed in hypothalamic neurons in the arcuate (ARC). We have shown 17beta-estradiol (E2) increases Ghsr expression in Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons, enhancing sensitivity to ghrelin. We hypothesized that E2-induced Ghsr expression augments KNDy sensitivity in a fasting state by elevating ghrelin to disrupt energy expenditure in females. We produced a Kiss1-GHSR knockout to determine the role of GHSR in ARC KNDy neurons. We found that changes in ARC gene expression with estradiol benzoate (EB) treatment were abrogated by the deletion of GHSR and ghrelin abolished these differences. We also observed changes in metabolism and fasting glucose levels. Additionally, knockouts were resistant to body weight gain on a high fat diet (HFD). Behaviorally, we found that knockouts on HFD exhibited reduced anxiety-like behavior. Furthermore, knockouts did not refeed to the same extent as controls after a 24 h fast. Finally, in response to cold stress, knockout females had elevated metabolic parameters compared to controls. These data indicate GHSR in Kiss1 neurons modulate ARC gene expression, metabolism, glucose homeostasis, behavior, and thermoregulation, illustrating a novel mechanism for E2 and ghrelin to control Kiss1 neurons. FAU - Conde, Kristie AU - Conde K AUID- ORCID: 0000-0002-9525-4606 AD - Graduate Program in Neuroscience, Rutgers University Robert Wood Johnson Medical School, The State University of New Jersey, New Brunswick, NJ 08901, USA. AD - Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA. FAU - Kulyk, Danielle AU - Kulyk D AD - Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA. FAU - Vanschaik, Allison AU - Vanschaik A AD - Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA. FAU - Daisey, Sierra AU - Daisey S AD - Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA. FAU - Rojas, Catherine AU - Rojas C AD - Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. FAU - Wiersielis, Kimberly AU - Wiersielis K AD - Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA. AD - Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. FAU - Yasrebi, Ali AU - Yasrebi A AD - Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA. FAU - Degroat, Thomas J AU - Degroat TJ AD - Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA. FAU - Sun, Yuxiang AU - Sun Y AD - Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX 77843, USA. FAU - Roepke, Troy A AU - Roepke TA AUID- ORCID: 0000-0001-5426-2266 AD - Graduate Program in Neuroscience, Rutgers University Robert Wood Johnson Medical School, The State University of New Jersey, New Brunswick, NJ 08901, USA. AD - Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA. AD - Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. AD - Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. AD - Rutgers Center for Lipid Research, the Center for Nutrition, Microbiome, and Health, and the New Jersey Institute of Food, Nutrition, and Health, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA. LA - eng GR - P30ES005022/ES/NIEHS NIH HHS/United States GR - T32 ES007148/ES/NIEHS NIH HHS/United States GR - R01MH123544/MH/NIMH NIH HHS/United States GR - R24 HD102061/HD/NICHD NIH HHS/United States GR - R21 ES027119/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20220925 PL - Switzerland TA - Biomolecules JT - Biomolecules JID - 101596414 RN - 74913-18-1 (Dynorphins) RN - 4TI98Z838E (Estradiol) RN - 0 (Ghrelin) RN - IY9XDZ35W2 (Glucose) RN - 0 (Kisspeptins) RN - 86933-75-7 (Neurokinin B) RN - 0 (Receptors, Ghrelin) SB - IM MH - Animals MH - Female MH - Mice MH - Arcuate Nucleus of Hypothalamus/metabolism MH - Diet, High-Fat/adverse effects MH - Dynorphins/metabolism MH - Estradiol/pharmacology/metabolism MH - Ghrelin/metabolism MH - Glucose/metabolism MH - Kisspeptins/genetics/metabolism MH - Neurokinin B/metabolism MH - Neurons/metabolism MH - Obesity/genetics/metabolism MH - *Receptors, Ghrelin/genetics PMC - PMC9599822 OTO - NOTNLM OT - 17beta-estradiol OT - GHSR OT - Kisspeptin OT - energy homeostasis OT - ghrelin OT - reproduction COIS- The authors declare no conflict of interest. EDAT- 2022/10/28 06:00 MHDA- 2022/10/29 06:00 PMCR- 2022/09/25 CRDT- 2022/10/27 01:12 PHST- 2022/08/29 00:00 [received] PHST- 2022/09/16 00:00 [revised] PHST- 2022/09/22 00:00 [accepted] PHST- 2022/10/27 01:12 [entrez] PHST- 2022/10/28 06:00 [pubmed] PHST- 2022/10/29 06:00 [medline] PHST- 2022/09/25 00:00 [pmc-release] AID - biom12101370 [pii] AID - biomolecules-12-01370 [pii] AID - 10.3390/biom12101370 [doi] PST - epublish SO - Biomolecules. 2022 Sep 25;12(10):1370. doi: 10.3390/biom12101370.