1680-P: A Novel Immunomodulatory Combination That Decreases Adipose Tissue and Systemic Inflammation and Improves Metabolism in Dio Mice

β3-adrenoceptors (B3AR) are major activators of lipolysis and thermogenesis in adipose tissue (AT). Obesity increases oxidative stress and AT inflammation leading to the attenuation of β3AR signaling. Alpha-lipoic acid (ALA) is a potent antioxidant. We hypothesized that the combination of ALA with CL316,243 (CL) -a selective B3AR agonist- restores the immune balance in diet-induced obesity (DIO) leading to increased B3AR function. We separated 40 DIO C57BL/6 male mice into 4 groups (n=10; individually caged) and treated them for five weeks with 1. vehicle control [IP (saline) + PO (drinking water)] 2. CL alone (0.01 mg/kg IP daily) 3. ALA alone (250 mg/kg orally in drinking water) 4. ALA+CL combination. All mice received ad-lib HFD (60% kcal fat). Systemic and epididymal white AT (epi-WAT) inflammation was decreased in ALA+CL compared to other groups, with lower serum IL-6 and IL-17 and lesser crown-like structures (CLS) on IHC for F4/80 and CD11c (M1-MΦ). Both IHC staining and mRNA expression of CD206 (M2-MΦ marker) confirm increased M2 MΦ’s in ALA+CL compared to other groups. Food intake was similar in all groups, yet mice receiving ALA+CL had a better metabolic profile: Lower body weight [+1.7 vs. -2.5g (-7%); p<0.01] and % body fat (+1.0 vs. -2.8g; (-9%), p<0.001) compared to controls preserved lean mass. Moreover, ALA+CL showed improved glucose tolerance compared to controls (intraperitoneal glucose tolerance test; AUC glycemia 31,033 ± 950 vs. 25,919 ± 620 min*ml/dl; p<0.01; AUC insulinemia 441.2 ± 55.7 vs. 279.3 ± 42.2 min*ng/ml; P<0.001). The downstream function of B3AR(lipolysis and thermogenesis) in WAT was improved in the combination group compared to all groups evidenced by markedly higher activated lipases and UCP-1 on Western blots (WB), and ucp-1 expression on mRNA analysis. Our study suggests that ALA, in combination with CL, modulates the immune response to obesity and augment catecholamine effect on lipolysis and thermogenesis in WAT.