Deletion of Growth Hormone Secretagogue Receptor in Kisspeptin Neurons in Female Mice Blocks Diet-Induced Obesity
Kristie Conde,
Danielle Kulyk,
Allison Vanschaik,
Sierra Daisey,
Catherine Rojas,
Kimberly Wiersielis,
Ali Yasrebi,
Thomas J. Degroat,
Yuxiang Sun,
Troy A. Roepke
Affiliations
Kristie Conde
Graduate Program in Neuroscience, Rutgers University Robert Wood Johnson Medical School, The State University of New Jersey, New Brunswick, NJ 08901, USA
Danielle Kulyk
Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
Allison Vanschaik
Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
Sierra Daisey
Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
Catherine Rojas
Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
Kimberly Wiersielis
Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
Ali Yasrebi
Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
Thomas J. Degroat
Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
Yuxiang Sun
Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX 77843, USA
Troy A. Roepke
Graduate Program in Neuroscience, Rutgers University Robert Wood Johnson Medical School, The State University of New Jersey, New Brunswick, NJ 08901, USA
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 17β-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.
