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Objectives: Beta‐3 adrenergic receptors (β3‐AR) stimulate lipolysis and thermogenesis in white and brown adipose tissue (WAT and BAT). Obesity increases oxidative stress and inflammation that attenuate AT β3‐AR signaling. The objective of this study was to test the hypothesis that the combination of the β3‐AR agonist CL‐316,243 (CL) and the antioxidant alpha‐lipoic acid (ALA) would lower inflammation in diet‐induced obesity (DIO) and improve β3‐AR function. Methods: A total of 40 DIO mice were separated into four groups: Control (per os and intraperitoneal [IP] vehicle); CL alone (0.01 mg/kg IP daily); ALA alone (250 mg/kg in drinking water); or ALA+CL combination, all for 5 weeks. Results: Food intake was similar in all groups; however, mice receiving ALA+CL showed improved body composition and inflammation as well as lower body weight (+1.7 g Control vs. −2.5 g ALA+CL [−7%]; p < 0.01) and percentage of body fat (−9%, p < 0.001). Systemic and epididymal WAT inflammation was lower with ALA+CL than all other groups, with enhanced recruitment of epididymal WAT anti‐inflammatory CD206+ M2 macrophages. β3‐AR signaling in WAT was enhanced in the combination‐treatment group, with higher mRNA and protein levels of thermogenic uncoupling protein 1 and AT lipases. Conclusions: Chronic treatment with ALA and a β3‐AR agonist reduces DIO‐induced inflammation. AT immune modulation could be a therapeutic target in patients with obesity. [ABSTRACT FROM AUTHOR]

We demonstrated previously that inhibition of endothelial nitric oxide synthase (NOS), using pharmacological inhibitors, attenuated the ionomycin- and ATP-induced increases in microvessel permeability (Am J Physiol Heart Circ Physiol 272: H176-H185, 1997). Recently, the scaffolding domain of caveolin-1 (CAV) has been implicated as a negative regulator of endothelial NOS (eNOS). To examine the role of CAV-eNOS interaction in regulation of permeability in intact microvessels, the effect of internalized CAV on the platelet-activating factor (PAF)-induced permeability increase was investigated in rat mesenteric venular microvessels. Internalization of CAV was achieved by perfusion of individual vessels using a fusion peptide of CAV with Antennapedia homeodomain (AP-CAV) and visualized by fluorescence imaging and electron microscopy. Changes in microvessel permeability were evaluated by measuring hydraulic conductivity (L[sub p]) in individually perfused microvessels. We found that the PAF (10 nM)-induced L[sub p] increase was significantly attenuated from 6.0 ± 0.9 (n = 7) to 2.0 ± 0.3 (n = 5) times control after microvessels were perfused with 10 µM AP-CAV for 2 h. The magnitude of this reduction is comparable with that of the inhibitory effect of N[sup ω]-monomethyl-L-arginine on the PAF-induced L[sub p] increase. In contrast, perfusion with 10 µM AP alone for 2 h modified neither basal L[sub p] nor the vessel response to PAF. These results indicate that CAV plays an important role in regulation of microvessel permeability. The inhibitory action of CAV on permeability increase might be attributed to its direct inactivation of eNOS. In addition, this study established a method for studying protein-protein interaction-induced functional changes in intact microvessels and demonstrated AP as an efficient vector for translocation of peptide across the cell membrane in vivo. [ABSTRACT FROM AUTHOR]

The current obesity pandemic results from a physiological imbalance in which energy intake chronically exceeds energy expenditure (EE), and prevention and treatment strategies remain generally ineffective. Approaches designed to increase EE have been informed by decades of experiments in rodent models designed to stimulate adaptive thermogenesis, a long-term increase in metabolism, primarily induced by chronic cold exposure. At the cellular level, thermogenesis is achieved through increased rates of futile cycling, which are observed in several systems, most notably the regulated uncoupling of oxidative phosphorylation from ATP generation by uncoupling protein 1, a tissue-specific protein present in mitochondria of brown adipose tissue (BAT). Physiological activation of BAT and other organ thermogenesis occurs through β-adrenergic receptors (AR), and considerable effort over the past 5 decades has been directed toward developing AR agonists capable of safely achieving a net negative energy balance while avoiding unwanted cardiovascular side effects. Recent discoveries of other BAT futile cycles based on creatine and succinate have provided additional targets. Complicating the current and developing pharmacological-, cold-, and exercise-based methods to increase EE is the emerging evidence for strong physiological drives toward restoring lost weight over the long term. Future studies will need to address technical challenges such as how to accurately measure individual tissue thermogenesis in humans; how to safely activate BAT and other organ thermogenesis; and how to sustain a negative energy balance over many years of treatment. [ABSTRACT FROM AUTHOR]