AVE0991, a nonpeptide angiotensin 1-7 receptor agonist, improves glucose metabolism in the skeletal muscle of obese zucker rats : possible involvement of prooxidant/antioxidant mechanisms

Angiotensin 1-7 (Ang 1-7) enhances insulin signaling and glucose transport activity in the skeletal muscle. The aim of our study was to evaluate the effect of AVE0991, a nonpeptide Mas receptor agonist, on the metabolic parameters, expression of RAS components and markers of oxidative stress, and insulin signaling in the skeletal morbidly obese rats. 33-week-old male obese Zucker rats were treated with vehicle and AVE0991 (0.5 mg/kg BW/day) via osmotic minipumps for two weeks. Gene expressions were determined by qPCR and/or Western blot analysis in musculus quadriceps. The enzymatic activities were detected flourometrically (aminopeptidase A) or by colorimetric assay kit (protein tyrosine phosphatase 1B). Administration of AVE0991 enhanced insulin signaling cascade in the skeletal muscle, reflected by improved whole-body glucose tolerance. It has been shown that reactive oxygen species (ROS) have insulin-mimetic action in muscle. The expression of renin receptor, transcription factor PLZF, and prooxidant genes was upregulated by AVE0991 accompanied by elevated expression of genes coding enzymes with antioxidant action. Our results show that AVE0991 administration activates genes involved in both ROS generation and clearance establishing a new prooxidant/antioxidant balance on a higher level, which might contribute to the improved insulin signaling pathway and glucose tolerance of obese Zucker rats

GPR180 is a component of TGFβ signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1

Activation of thermogenic brown and beige adipocytes is considered as a strategy to improve metabolic control. Here, we identify GPR180 as a receptor regulating brown and beige adipocyte function and whole-body glucose homeostasis, whose expression in humans is associated with improved metabolic control. We demonstrate that GPR180 is not a GPCR but a component of the TGF beta signalling pathway and regulates the activity of the TGF beta receptor complex through SMAD3 phosphorylation. In addition, using genetic and pharmacological tools, we provide evidence that GPR180 is required to manifest Collagen triple helix repeat containing 1 (CTHRC1) action to regulate brown and beige adipocyte activity and glucose homeostasis. In this work, we show that CTHRC1/GPR180 signalling integrates into the TGF beta signalling as an alternative axis to fine-tune and achieve low-grade activation of the pathway to prevent pathophysiological response while contributing to control of glucose and energy metabolism.Activation of thermogenic adipocytes is a strategy to combat metabolic diseases. Here the authors report that GPR180 is a component of TGF beta signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1, and contributes to the regulation of glucose and energy metabolism

BATLAS: Deconvoluting Brown Adipose Tissue

Recruitment and activation of thermogenic adipocytes have received increasing attention as a strategy to improve systemic metabolic control. The analysis of brown and brite adipocytes is complicated by the complexity of adipose tissue biopsies. Here, we provide an in-depth analysis of pure brown, brite, and white adipocyte transcriptomes. By combining mouse and human transcriptome data, we identify a gene signature that can classify brown and white adipocytes in mice and men. Using a machine-learning-based cell deconvolution approach, we develop an algorithm proficient in calculating the brown adipocyte content in complex human and mouse biopsies. Applying this algorithm, we can show in a human weight loss study that brown adipose tissue (BAT) content is associated with energy expenditure and the propensity to lose weight. This online available tool can be used for in-depth characterization of complex adipose tissue samples and may support the development of therapeutic strategies to increase energy expenditure in humans

Obesity- and age-related alterations in FAT/CD36 translocation and lipin-1 subcellular localization in skeletal muscle of the Zucker rats

Fatty acid (FA) uptake and/or intramuscular triglyceride (TG) accumulation in skeletal muscle are increased in obesity, type 2 diabetes and aging. FA translocase (FAT/CD36) translocation, lipin-1 subcellular localization and nuclear factor kappa B (NF-kappa B) p65 protein content in quadriceps muscle of young and old obese Zuckerfa/fa rats and their lean controls were analyzed by immunoblot to define obesity- and aging-related alterations in FA uptake, their subsequent metabolic fate and potential to activate pro-inflammatory signaling. As expected, obesity increased FAT/CD36 content in plasma membrane in quadriceps muscle of fa/fa rats. Aging increased cytosolic lipin-1 content in both, obese rats and their lean controls. Also, old obese rats had decreased level of nuclear extract lipin-lcompared to that in old lean rats. Neither obesity nor age altered NF-kappa B p65 protein content in cytosol and nuclear extract of quadriceps muscle suggesting that obesity/aging-induced changes in FA handling are not accompanied by NF-kappa B-mediated inflammation. Increase in plasma membrane FAT/CD36 content in obese rats and failure in lipin-1 export to nucleus with progression of obesity, implying an increase in FA uptake and their different channeling into lipid intermediates synthesis pathway in old fa/fa rats versus FA usage in lean rats of the same age

Enantioselective Total Syntheses of Cassane Furanoditerpenoids and their Stimulation of Cellular Respiration in Brown Adipocytes

We report the first and enantioselective total syntheses of (+)-1-deacetylcaesalmin C, (+)-δ-caesalpin, (+)-norcaesalpinin MC, and (+)-norcaesalpinin P. Salient features of the synthetic strategy are exo-selective intramolecular Diels–Alder reaction of a furanoquinone monoketal and subsequent chemoselective reduction of the resulting pentacyclic furfuryl ketal furnishing a keystone intermediate. The latter enables access to the collection of natural products through implementation of stereoselective oxidations. Having accessed the cassane furanoditerpenoids, we unveil previously unknown bioactivity: (+)-1-Deacetylcaesalmin C stimulates respiration in brown adipocytes, which has been suggested to play a central role in treatment of obesity

Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril

Lactacystin is a proteasome inhibitor that interferes with several factors involved in heart remodelling. The aim of this study was to investigate whether the chronic administration of lactacystin induces hypertension and heart remodelling and whether these changes can be modified by captopril or melatonin. In addition, the lactacystin-model was compared with NG-nitro-l-arginine-methyl ester (L-NAME)- and continuous light-induced hypertension. Six groups of three-month-old male Wistar rats (11 per group) were treated for six weeks as follows: control (vehicle), L-NAME (40 mg/kg/day), continuous light (24 h/day), lactacystin (5 mg/kg/day) alone, and lactacystin with captopril (100 mg/kg/day), or melatonin (10 mg/kg/day). Lactacystin treatment increased systolic blood pressure (SBP) and induced fibrosis of the left ventricle (LV), as observed in L-NAME-hypertension and continuous light-hypertension. LV weight and the cross-sectional area of the aorta were increased only in L-NAME-induced hypertension. The level of oxidative load was preserved or reduced in all three models of hypertension. Nitric oxide synthase (NOS) activity in the LV and kidney was unchanged in the lactacystin group. Nuclear factor-kappa B (NF-κB) protein expression in the LV was increased in all treated groups in the cytoplasm, however, in neither group in the nucleus. Although melatonin had no effect on SBP, only this indolamine (but not captopril) reduced the concentration of insoluble and total collagen in the LV and stimulated the NO-pathway in the lactacystin group. We conclude that chronic administration of lactacystin represents a novel model of hypertension with collagenous rebuilding of the LV, convenient for testing antihypertensive drugs or agents exerting a cardiovascular benefit beyond blood pressure reduction

BATLAS: Deconvoluting Brown Adipose Tissue

Recruitment and activation of thermogenic adipocytes have received increasing attention as a strategy to improve systemic metabolic control. The analysis of brown and brite adipocytes is complicated by the complexity of adipose tissue biopsies. Here, we provide an in-depth analysis of pure brown, brite, and white adipocyte transcriptomes. By combining mouse and human transcriptome data, we identify a gene signature that can classify brown and white adipocytes in mice and men. Using a machine-learning-based cell deconvolution approach, we develop an algorithm proficient in calculating the brown adipocyte content in complex human and mouse biopsies. Applying this algorithm, we can show in a human weight loss study that brown adipose tissue (BAT) content is associated with energy expenditure and the propensity to lose weight. This online available tool can be used for in-depth characterization of complex adipose tissue samples and may support the development of therapeutic strategies to increase energy expenditure in humans