β3-adrenergic receptor activation exacerbates brain injury in acute ischemic stroke
K Cheung, A Xu, G Camici, C Diaz-CanestroAbstract
Introduction
Brown adipose tissue (BAT) is recognized as an endocrine organ secreting signalling molecules known as “batokines” with both paracrine and autocrine roles. Recent studies indicate that certain batokines decrease neuroinflammation, a key process in the pathophysiology of acute ischemic stroke (AIS). However, the role of increasing activity and mass of BAT in ischemia-reperfusion (I/R)-induced brain injury remains unclear.
Purpose
This study aimed to investigate the role of BAT in the pathophysiology of AIS using an experimental mouse model of stroke.
Methods
11-14-week- old male and female C57BL/6 mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 45 min followed by 48 h of reperfusion. To activate BAT, mice were randomly allocated to receive a daily injection of either a selective β3-adrenergic receptor agonist (β3-AR) (CL316,243, 1 mg/kg/day, s.c.) or vehicle upon reperfusion. Stroke size, neurological deficits and behavioural performance were assessed using 2,3,5-triphenyltetrazolium chloride (TTC) staining, Bederson Neurological Deficit Scale, and Rotarod test, respectively.The thermogenic profile was assessed by quantifying mRNA expression of six thermogenesis-related genes in brown and white adipose tissue (WAT) using quantitative real-time PCR (qPCR).
Results
Male mice treated with CL316,243 exhibited larger infarct volumes compared to vehicle-treated mice (77.26 ± 3.57 vs 50.99 ± 1.51 mm3, p=0.002, n=4-5) (Figure 1A). Similarly, CL316,243-treated mice display higher neurological deficits compared to vehicle-treated mice in male (3.25 ± 0.48 vs 1.80 ± 0.66, p=0.004, n=4-5) (Figure 1B) at 48h after stroke. Moreover, CL316,243-treated mice displayed increased mortality when compared with vehicle-treated mice in males (50% vs 28.6%, p= 0.619, n=7-8) and females (100% vs 0%, p=0.014, n=4-8) (Figure 1B). CL316,243 significantly upregulated Ucp1 in BAT (4.61-fold, p=0.035) and increased Ucp1 (13.70-fold, p=0.032), Elovl3 (15.77-fold, p=0.016), and Dio2 (2.96-fold, p=0.050) in WAT compared with the vehicle group (n=4-5).
Conclusion
Our findings demonstrate that post-ischemic administration of the β3-AR agonist CL316,243 exacerbates ischemic brain injury in male mice and is associated with increased mortality in both sexes compared with vehicle-treated animals. Notably, this detrimental effect is more pronounced in females, suggesting a potential sex-dependent difference in response to β3-ARactivation. Collectively, these results warrant further investigation into the therapeutic potential of β3-AR antagonism in AIS.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.