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.
Z.A. Sater: None. C. Cero: None. H.J. Lea: None. K.Y. Zhu: None. O. Gavrilova: None. A.M. Cypess: None.