Sex differences in the regulation of porcine coronary artery tone by perivascular adipose tissue: a role of adiponectin?

Background and Purpose- As there is sexual dimorphism in the regulation of vascular tone, the aim of this present study was to determine whether there are sex differences in perivascular adipose tissue (PVAT) - mediated regulation of the porcine coronary artery (PCA) tone. Experimental Approach- Isometric tension recording system was used to record changes in tone in PCAs. Western blot analysis was performed to examine the expression of adiponectin in PVAT and adiponectin receptors (adipo 1 receptor and adipo 2 receptor) and adiponectin binding protein (APPL1) in PCA. The level of adiponectin released from PVAT was measured using ELISA. Key Results- In the presence of adherent PVAT, contractions to the thromboxane mimetic U46619 and endothelin-1 were significantly reduced in PCAs from females, but not males. In PCAs pre-contracted with U46619, re-addition of PVAT caused relaxation in PCAs from females, but not males. This relaxant response in females was attenuated by combined inhibition of NO synthase (with L-NAME) and cyclooxygenase (with indomethacin). Pre-incubation with an anti-adiponectin antibody abolished the relaxant effects of PVAT. The adiponectin receptor agonist (adipoRon) produced a greater relaxation in PCAs from females compared to males. However, there was no difference in either expression or release of adiponectin from PVAT between sexes. Similarly, there was no difference in expression of adiponectin receptors or the adiponectin receptor adaptor protein APPL1 in PCAs. Conclusion and Implications- These findings demonstrate a clear sex difference in the regulation of coronary artery tone in response to adiponectin receptor stimulation, which may underlie the anticontractile effects of PVAT in females

The role of adiponectin receptors in the regulation of synaptic transmission in the hippocampus

In the last two decades adiponectin, member of the adipokines family, gained attention because of its unique antidiabetic effects. However, the presence in the brain of adiponectin receptors and adiponectin itself raised interest because of the possible association with neuropsychiatric diseases. Indeed, clinical studies found altered concentration of adiponectin both in plasma and cerebrospinal fluid in seeveral pathologies including depression, multiple sclerosis, Alzheimer’s disease and stroke. Moreover, recent preclinical studies also suggest its involvement in different physiological functions. Despite this evidence very few studies attempted to elucidate the functional role of adiponectin at the synapse.To address this question, here we investigated the effect of Adiporon, an agonist of both adiponectin receptors on synaptic transmission and LTP at Schaffer-collateral CA1 pathway. Surprisingly, increasing concentration of Adiporon correlated with lower CA1-LTP levels and paired-pulse ratio, whereas basal transmission was always preserved. Collectively, our data show that the adiponectin system, beyond its involvement in metabolic diseases, plays also a critical role in synaptic activity thereby representing a putative target for the treatment of synaptic pathologies

Future glucose-lowering drugs for type 2 diabetes

The multivariable and progressive natural history of type 2 diabetes limits the effectiveness of available glucose-lowering drugs. Constraints imposed by comorbidities (notably cardiovascular disease and renal impairment) and the need to avoid hypoglycaemia, weight gain, and drug interactions further complicate the treatment process. These challenges have prompted the development of new formulations and delivery methods for existing drugs alongside research into novel pharmacological entities. Advances in incretin-based therapies include a miniature implantable osmotic pump to give continuous delivery of a glucagon-like peptide-1 receptor agonist for 6-12 months and once-weekly tablets of dipeptidyl peptidase-4 inhibitors. Hybrid molecules that combine the properties of selected incretins and other peptides are at early stages of development, and proof of concept has been shown for small non-peptide molecules to activate glucagon-like peptide-1 receptors. Additional sodium-glucose co-transporter inhibitors are progressing in development as well as possible new insulin-releasing biological agents and small-molecule inhibitors of glucagon action. Adiponectin receptor agonists, selective peroxisome proliferator-activated receptor modulators, cellular glucocorticoid inhibitors, and analogues of fibroblast growth factor 21 are being considered as potential new approaches to glucose lowering. Compounds that can enhance insulin receptor and post-receptor signalling cascades or directly promote selected pathways of glucose metabolism have suggested opportunities for future treatments. However, pharmacological interventions that are able to restore normal β-cell function and β-cell mass, normalise insulin action, and fully correct glucose homoeostasis are a distant vision

Global Mapping of Cell Type–Specific Open Chromatin by FAIRE-seq Reveals the Regulatory Role of the NFI Family in Adipocyte Differentiation

Identification of regulatory elements within the genome is crucial for understanding the mechanisms that govern cell type–specific gene expression. We generated genome-wide maps of open chromatin sites in 3T3-L1 adipocytes (on day 0 and day 8 of differentiation) and NIH-3T3 fibroblasts using formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq). FAIRE peaks at the promoter were associated with active transcription and histone modifications of H3K4me3 and H3K27ac. Non-promoter FAIRE peaks were characterized by H3K4me1+/me3-, the signature of enhancers, and were largely located in distal regions. The non-promoter FAIRE peaks showed dynamic change during differentiation, while the promoter FAIRE peaks were relatively constant. Functionally, the adipocyte- and preadipocyte-specific non-promoter FAIRE peaks were, respectively, associated with genes up-regulated and down-regulated by differentiation. Genes highly up-regulated during differentiation were associated with multiple clustered adipocyte-specific FAIRE peaks. Among the adipocyte-specific FAIRE peaks, 45.3% and 11.7% overlapped binding sites for, respectively, PPARγ and C/EBPα, the master regulators of adipocyte differentiation. Computational motif analyses of the adipocyte-specific FAIRE peaks revealed enrichment of a binding motif for nuclear family I (NFI) transcription factors. Indeed, ChIP assay showed that NFI occupy the adipocyte-specific FAIRE peaks and/or the PPARγ binding sites near PPARγ, C/EBPα, and aP2 genes. Overexpression of NFIA in 3T3-L1 cells resulted in robust induction of these genes and lipid droplet formation without differentiation stimulus. Overexpression of dominant-negative NFIA or siRNA–mediated knockdown of NFIA or NFIB significantly suppressed both induction of genes and lipid accumulation during differentiation, suggesting a physiological function of these factors in the adipogenic program. Together, our study demonstrates the utility of FAIRE-seq in providing a global view of cell type–specific regulatory elements in the genome and in identifying transcriptional regulators of adipocyte differentiation

Perspective of Small-Molecule AdipoR Agonist for Type 2 Diabetes and Short Life in Obesity

Obesity associated with unhealthy diet and lack of exercise is shown to contribute to the onset and/or aggravation of the metabolic syndrome and diabetes, thus placing affected individuals at increased risk of cardiovascular disease and cancer. Plasma adiponectin levels are decreased in obesity, which causes insulin resistance and diabetes. Therefore, we identified adiponectin receptors (AdipoRs) as the therapeutic target. It was suggested that, similarly to caloric restriction and exercise, activation of the AdipoRs may have the potential not only to improve lifestyle-related diseases but to contribute to prolonged the shortened lifespan on a high caloric unhealthy diet. To this end, we have identified "AdipoRon" as an adiponectin receptor agonist. Indeed, AdipoRon ameliorated diabetes associated with obesity as well as to increase exercise endurance, thus prolonging shortened lifespan of obese mice fed on a high fat diet. Additionally, we have recently determined the crystal structures of the human AdipoRs. The seven-transmembrane helices of AdipoRs are structurally distinct from those of G-protein coupled receptors. It is expected that these findings will contribute not only to the elucidation of the AdipoR-related signal transduction but to the development and optimization of AdipoR-targeted therapeutics for obesity-related diseases such as diabetes

5-Hydroxytryptamine 2A receptor signaling cascade modulates adiponectin and plasminogen activator inhibitor 1 expression in adipose tissue

AbstractKnowledge of the regulatory factors associated with down-regulation of adiponectin gene expression and up-regulation of PAI-1 gene expression is crucial to understand the pathophysiological basis of obesity and metabolic diseases, and could establish new treatment strategies for these conditions. We showed that expression of 5-HT2A receptors was up-regulated in hypertrophic 3T3-L1 adipocytes, which exhibited decreased expression of adiponectin and increased expression of PAI-1. 5-HT2A receptor antagonists and suppression of 5-HT2A receptor gene expression enhanced adiponectin expression. Activation of Gq negatively regulated adiponectin expression, and inhibition of mitogen-activated protein kinase reversed the Gq-induced effect. Moreover, the 5-HT2A receptor blockade reduced PAI-1 expression. These findings indicate that antagonism of 5-HT2A receptors in adipocytes could improve the obesity-linked decreases in adiponectin expression and increases in PAI-1 expression