MON-680 Beta 3 Adrenergic Receptor Regulation of Leptin Within Adipose Tissue

Abstract Disclosure: S.R. Heaselgrave: None. S.C. Wyler: None. S. Thomas: None. M. Galvan: None. A. Tinajero: None. T. Fujikawa: None. J.K. Elmquist: None. Background: Leptin, synthesized in adipose tissue, is a critical controller of energy balance, influencing fed and fasted metabolism. However excessive leptin production can result in leptin resistance and disrupted energy balance. It is believed beta 3 adrenergic receptors (β3-AR) play a crucial role in preventing this and maintaining leptin within a homeostatic range as global deletion of β3-AR greatly increases circulating leptin levels. However, it is unclear if this apparent regulatory role of β3-AR is controlled by globally expressed β3-AR or specifically those located within adipose tissue, the site of leptin synthesis. We investigated this, using a novel mouse model allowing for expression of β3-AR in adipocytes only. Methods: Male mice with a transcriptional block (TB) of the gene encoding β3-AR, Adrb3, were bred resulting in a global prenatal knockout (Adrb3TB). Mice were subsequently crossed with an adiponectin-Cre mouse, resulting in re-expression of Adrb3 exclusively within adipocytes (Adrb3TB; Adipo-Cre). To investigate adipocyte β3-AR regulation of leptin production, a β3-AR agonist (CL316,243; 1mg/kg) or vehicle control (saline) was administered to 8-week-old Adrb3TB and Adrb3TB; Adipo-Cre mice as well as WT littermates (n=4) 2 hours prior to sacrifice. Plasma leptin and gonadal white adipose tissue (gWAT) leptin gene expression were assessed. Results: Saline treated Adrb3TB mice had a trended increase in plasma leptin compared to WT littermates (p=0.09), whilst not differing from Adrb3TB; Adipo-Cre. CL316,243 treatment non-significantly decreased WT and Adrb3TB; Adipo-Cre plasma leptin whilst having no effect in Adrb3TB mice. gWAT leptin gene expression was significantly lower in saline treated Adrb3TB mice compared to WT littermates (p=0.03) and trended lower compared to Adrb3TB; Adipo-Cre mice (p=0.07). CL316,243 did not significantly alter leptin expression in Adrb3TB or WT mice but trended towards a decrease in Adrb3TB; Adipo-Cre mice (p=0.07). Conclusions: These findings indicate that adipocyte β3-AR are at least partially responsible for regulating leptin production. However, further investigation, involving additional flox and cre models, is required to determine the extent of their control. It is interesting that Adrb3TB mice experienced increased plasma leptin, despite displaying reduced gWAT leptin expression. This indicates an ultimately futile compensatory mechanism whilst also demonstrating a disconnect between leptin gene expression and production in mice lacking β3-AR. Presentation: Monday, July 14, 2025