Oral Presentation ESA-SRB-NZSE-CaSR 2026 in conjunction with ENSA

Hypothalamic CaSR in the control of energy and skeletal metabolism (147422)

Kevin Murphy 1 , Jennifer Park-Sigal 2 , Mariana Norton 1 , Chia-Ling Tu 2 , Zhiqing Cheng 2 , Nicole Fadahunsi 1 , Hokyou Lee 2 , Sunhee Kim 2 , Alfred Li 2 , Lea T Grinberg 3 4 , Gavin A Bewick 5 , Wenhan Chang 2
  1. Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom
  2. Endocrine Research Unit, Department of Veterans Affairs Medical Center, and the UCSF Diabetes Center, University of California, San Francisco, CA, USA
  3. Departments of Pathology and Laboratory Medicine and Neurosciences, Mayo Clinics, Florida, USA
  4. Department of Pathology, LIM-22, University of Sao Paulo, Sao Paulo, Brazil
  5. Department of Diabetes and Obesity, King's College London, London, United Kingdom

The CaSR is expressed in hypothalamic neuronal populations that regulate growth and energy homeostasis, including growth hormone stimulating hormone (GHRH) and anorectic proopiomelanocortin (POMC) neurons found in the hypothalamic arcuate nucleus. The hypothalamus, and particularly the arcuate nucleus, play important roles in appetite and wider metabolic control. Embryonic deletion of the Casr gene in neurons to create NeuronCaSR-/- mice allowed us to investigate the role of this receptor in the central nervous system in regulating growth, skeletal development, and energy metabolism. NeuronCaSR-/- mice had reduced size, weight and bone mass compared to littermate controls, and a dysregulated growth hormone axis. They also demonstrated increased fat mass and circulating leptin levels, leptin resistance, and decreased glucose tolerance. They had reduced hypothalamic expression of POMC and increased expression of the orexigenic agouti-related peptide (AgRP).  Knockdown of CaSR in adult mice specifically in the hypothalamic arcuate nucleus, where GHRH, POMC and AgRP neurons reside, also resulted in increased body weight, adiposity, leptin resistance, and glucose intolerance, and reduced bone mass.

Together these data suggest that neuronal CaSR regulates energy and skeletal metabolism and body growth by modulating hypothalamic function, representing a new model for central integration of calcium regulation with wider metabolic function.