Poster Presentation 4th Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity Meeting 2024

Effect of β-catenin deletion in the paraventricular nucleus of the hypothalamus: differential impacts on body weight and glucose metabolism in mice (#182)

Mohammed Z Rizwan 1 2 3 , Pramuk Keerthisinghe 2 4 , Charlie Fang 1 2 3 , Peter Shepherd 3 5 , Alexander Tups 2 3 4 , Dave R Grattan 1 2 3 , Mohammed Rizwan 1 2 3
  1. Department of Anatomy, School of Biomedical Sciences University of Otago, Dunedin, New Zealand
  2. Centre for Neuroendocrinology, University of Otago, Dunedin, New Zealand
  3. Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
  4. Department of Physiology, School of Biomedical Sciences University of Otago, Dunedin, New Zealand
  5. Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

To maintain a stable body weight, energy intake (by ingestion) and energy expenditure (by exercise, basal metabolism and thermogenesis) need to be balanced. Human genome-wide association studies suggest that genetic variations in the Wnt-signalling pathway play a major role in the pathogenesis of type-2 diabetes and obesity. β-catenin is a key signalling effector of the Wnt-signalling pathway, and we have recently discovered that specific deletion of β-catenin from the arcuate nucleus of the hypothalamus (ARC) in mice resulted in significant weight gain, especially when challenged with high-fat diet, associated with impaired glucose clearance. The paraventricular nucleus of the hypothalamus (PVN) receives multiple projections from various areas of the brain, and is shown to be capable of detecting and integrating orexigenic and anorexigenic signals from the ARC. Due to its role in regulating food intake and body weight, together with expression of β-catenin, we sought to determine the role of β-catenin in the PVN, with respect to neuroendocrine regulation of body weight and glucose homeostasis. Using male and female adult β-cateninflox mice, we performed bilateral injections of AAV2-mCherry-Cre into the PVN to specifically delete β-catenin expression in that region. In the male knockout mice, despite having a small but significant difference in weekly food intake (P=0.03), there was no difference in body weight or body composition compared to controls. Surprisingly, the female knockout mice exhibited a reduction in gain in weight (P=0.02) compared to controls, despite showing no difference in weekly food intake and body composition. In addition, while the male knockout mice displayed an impaired glucose clearance (P=0.01), the female knockout mice displayed an improved glucose clearance (P=0.01), compared to their respective controls. This study highlights a critical role for β-catenin in the PVN regulating feeding, body weight and glucose metabolism, and reveals potential opposing effects between males and females.