Circadian dysfunction in adipose tissue: Chronotherapy in metabolic diseases

Essential for survival and reproduction, the circadian timing system (CTS) regulates adaptation to cyclical changes such as the light/dark cycle, temperature change, and food availability. The regulation of energy homeostasis possesses rhythmic properties that correspond to constantly fluctuating needs for energy production and consumption. Adipose tissue is mainly responsible for energy storage and, thus, operates as one of the principal components of energy homeostasis regulation. In accordance with its roles in energy homeostasis, alterations in adipose tissue's physiological processes are associated with numerous pathologies, such as obesity and type 2 diabetes. These alterations also include changes in circadian rhythm. In the current review, we aim to summarize the current knowledge regarding the circadian rhythmicity of adipogenesis, lipolysis, adipokine secretion, browning, and non-shivering thermogenesis in adipose tissue and to evaluate possible links between those alterations and metabolic diseases. Based on this evaluation, potential therapeutic approaches, as well as clock genes as potential therapeutic targets, are also discussed in the context of chronotherapy

SIÇANLARDA OLUŞTURULAN TİP-2 DİYABET MODELİNDE PİOGLİTAZONUN PERİVASKÜLER ADİPOZ DOKUDA (PVAD) ENDOPLAZMİK RETİKULUM (ER) STRESİ VE OTOFAJİ ÜZERİNE OLAN ETKİLERİNİN İNCELENMESİ

Amaç: Damarların etrafında bulunan lokal adipoz doku katmanı olan PVAD’ın kardiyovasküler sistem fizyolojisinde önemli rol oynadığı bilinmektedir. Tip-2 diyabette görülen PVAD disfonksiyonu neticesinde PVAD’ın antikontraktil etkisi ortadan kalkmakta ve PVAD’dan salınan adipokin kompozisyonu değişmektedir. Çalışmamızda tip-2 diyabette gözlenen PVAD disfonksiyonunda ER stres ve otofajinin rolünün araştırılması ve klinikte sıklıkla kullanılan bir oral antidiyabetik olan pioglitazonun etkisinin incelenmesi amaçlanmıştır.Gereç-Yöntem: Wistar sıçanlar 4 hafta süresince yüksek yağlı diyet ile beslenmiş ve 4 hafta sonunda 35 mg/kg streptozotosin intraperitoneal olarak uygulanmıştır. Diyabet grubunda olmayan sıçanlar ise normal yem ile beslenmiş ve streptozotosinin çözücüsü sitrat tamponu intraperitoneal olarak uygulanmıştır. Diyabet doğrulamasını takiben 4 hafta beklenmiş ve daha sonra 6 hafta boyunca 20 mg/kg pioglitazon oral olarak uygulanmıştır. Kontrol grubuna ise pioglitazonu süspande etmek için kullanılan metilselüloz verilmiştir. 6 hafta sonunda sıçanlar sakrifiye edilmiş ve torasik PVAD’ları izole edilmiştir. İzole edilen PVAD’larda ER stres ile ilişkili ATF4, CHOP, GRP78 ile otofaji ile ilişkili LC3-II, p62, Beclin mRNA düzeyleri PCR yöntemiyle ölçülmüştür.Bulgular: Diyabete bağlı olarak PVAD’da ER stres ile ilişkili gen ekspresyonlarında artış gözlenmiştir. Bunun yanı sıra kontrol gruplarında pioglitazon uygulamasına bağlı olarak ER stresin arttığı görülmüştür. Diyabet grubunda pioglitazon uygulamasına bağlı olarak GRP78 gen ekspresyonu anlamı düzeyde yükselmiştir. Otofaji ile ilişkili genlerden LC3-II ve Beclin ekspresyon düzeyleri diyabete bağlı olarak artmış ve diyabetik grupta pioglitazon uygulamasına bağlı olarak azalmıştır. p62 mRNA düzeyi ise pioglitazon uygulamasına bağlı olarak hem kontrol hem de diyabet grubunda artmıştır.Sonuç: Tip-2 diyabete bağlı olarak ER stres ve otofaji ile ilişkili olan gen ekspresyonlarında artış gözlenmiştir. Pioglitazon uygulamasının ise genel olarak ER stresi artırırken otofajiyi azalttığı tespit edilmiştir. Bulgularımız diyabet koşulunda gerçekleşen PVAD disfonksiyonunun mekanizmasının ve pioglitazonun etkisinin anlaşılmasına katkı sunmaktadır.Bu çalışma TÜBİTAK (Proje No:217S209) tarafından desteklenmiştir. Anahtar Kelimeler: Perivasküler Adipoz Doku, Pioglitazon, Tip-II Diyabet, ER stres, Otofaj

The assessment of the relaxant effect of S-nitrosoglutathione on isolated human saphenous vein

S-nitrosothiols (RSNOs) are thought to represent the circulating reservoir of nitric oxide (NO). S-nitrosoglutathione (GSNO) is an endogenous S-nitrosothiol which suggested to be a potent vasodilator with a prolonged relaxant effect compared to the current NO donors that clinically used. There are limited studies about its vascular effects on human vessels while no data is available on its mechanism of action. In this study, we aimed to investigate the acute effect of GSNO on human saphenous vein rings as well as the possible underlying mechanisms. Isolated human saphenous veins obtained from coronary artery bypass surgery, were mounted in an organ bath system, aerated with %5CO2 + %95o 2 at 37o C with a resting tension of 2g. The effect of GSNO (10-8 -10-4 M) were studied in a concentration-dependent manner on rings precontracted submaximally with phenylephrine (3x10-5 M). In order to analyse its mechanism of action, the effects of GSNO were studied in the absence and presence of NO synthase inhibitor, L-NAME (10-4 M, 30min), soluble guanylyl cyclase (sGC) inhibitor, ODQ (10-5 M, 30min) or a selective inhibitor of ATP-sensitive K+ channels (KATP), glibenclamide (10-5 M, 30min). GSNO produced concentration-dependent relaxant effects on precontracted human saphenous veins (Emax: 102,40±1,37%). The prominent relaxant influence of GSNO was not altered in the presence of the inhibitor of NO synthase or KATP channels. While, a significant decrease was observed with ODQ (ODQ-Emax: 43,73±8,61%; Control-Emax:108,4±4,76%, p<0.001, n=5) Our results indicate that acute relaxant effects of GSNO in isolated human saphenous vein were neither mediated by KATP channel activation nor endogenous NO. Whereas, the activation of sGC pathway is likely be involved in this response. A better understanding of the mechanism regulating the vasorelaxant effect of GSNO and its possible role as a new antispasmodic agent for bypass graft spasms will provide us new therapeutic opportunities. Keywords: S-nitrosoglutathione, nitric oxide, coronary artery bypass graft, human saphenous vei

The assessment of the relaxant effect of S-nitrosoglutathione on isolated human saphenous vein

S-nitrosothiols (RSNOs) are thought to represent the circulating reservoir of nitric oxide (NO). S-nitrosoglutathione (GSNO) is an endogenous S-nitrosothiol which suggested to be a potent vasodilator with a prolonged relaxant effect compared to the current NO donors that clinically used. There are limited studies about its vascular effects on human vessels while no data is available on its mechanism of action. In this study, we aimed to investigate the acute effect of GSNO on human saphenous vein rings as well as the possible underlying mechanisms. Isolated human saphenous veins obtained from coronary artery bypass surgery, were mounted in an organ bath system, aerated with %5CO2 + %95o 2 at 37o C with a resting tension of 2g. The effect of GSNO (10-8 -10-4 M) were studied in a concentration-dependent manner on rings precontracted submaximally with phenylephrine (3x10-5 M). In order to analyse its mechanism of action, the effects of GSNO were studied in the absence and presence of NO synthase inhibitor, L-NAME (10-4 M, 30min), soluble guanylyl cyclase (sGC) inhibitor, ODQ (10-5 M, 30min) or a selective inhibitor of ATP-sensitive K+ channels (KATP), glibenclamide (10-5 M, 30min). GSNO produced concentration-dependent relaxant effects on precontracted human saphenous veins (Emax: 102,40±1,37%). The prominent relaxant influence of GSNO was not altered in the presence of the inhibitor of NO synthase or KATP channels. While, a significant decrease was observed with ODQ (ODQ-Emax: 43,73±8,61%; Control-Emax:108,4±4,76%, p<0.001, n=5) Our results indicate that acute relaxant effects of GSNO in isolated human saphenous vein were neither mediated by KATP channel activation nor endogenous NO. Whereas, the activation of sGC pathway is likely be involved in this response. A better understanding of the mechanism regulating the vasorelaxant effect of GSNO and its possible role as a new antispasmodic agent for bypass graft spasms will provide us new therapeutic opportunities. Keywords: S-nitrosoglutathione, nitric oxide, coronary artery bypass graft, human saphenous vei