Prevention of what

Adipose tissue plays essential roles in maintaining lipid and glucose homeostasis. To date several types of adipose tissue have been identified, namely white, brown, and beige, that reside in various specific anatomical locations throughout the body. The cellular composition, secretome, and location of these adipose depots define their function in health and metabolic disease. In obesity, adipose tissue becomes dysfunctional, promoting a pro-inflammatory, hyperlipidemic and insulin resistant environment that contributes to type 2 diabetes mellitus (T2DM). Concurrently, similar features that result from adipose tissue dysfunction also promote cardiovascular disease (CVD) by mechanisms that can be augmented by T2DM. The mechanisms by which dysfunctional adipose tissue simultaneously promote T2DM and CVD, focusing on adipose tissue depot-specific adipokines, inflammatory profiles, and metabolism, will be the focus of this review. The impact that various T2DM and CVD treatment strategies have on adipose tissue function and body weight also will be discussed.

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Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease.

Irisin is a myokine that leads to increased energy expenditure by stimulating the 'browning' of white adipose tissue. In the first description of this hormone, increased levels of circulating irisin, which is cleaved from its precursor fibronectin type III domain-containing protein 5, were associated with improved glucose homeostasis by reducing insulin resistance. Consequently, several studies attempted to characterize the role of irisin in glucose regulation, but contradictory results have been reported, and even the existence of this hormone has been questioned. In this Review, we present the current knowledge on the physiology of irisin and its role in glucose homeostasis. We describe the mechanisms involved in the synthesis, secretion, circulation and regulation of irisin, and the controversies regarding the measurement of irisin. We also discuss the direct effects of irisin on glucose regulatory mechanisms in different organs, the indirect effects and interactions with other hormones, and the important open questions with regard to irisin in those organs. Finally, we present the results from animal interventional studies and from human clinical studies investigating the association of irisin with obesity, insulin resistance, type 2 diabetes mellitus and the metabolic syndrome.

Physiology and role of irisin in glucose homeostasis

There is compelling evidence to support an aetiological role for inflammation, oxidative and nitrosative stress (O&NS), and mitochondrial dysfunction in the pathophysiology of major neuropsychiatric disorders, including depression, schizophrenia, bipolar disorder, and Alzheimer's disease (AD). These may represent new pathways for therapy. Aspirin is a non-steroidal anti-inflammatory drug that is an irreversible inhibitor of both cyclooxygenase (COX)-1 and COX-2, It stimulates endogenous production of anti-inflammatory regulatory 'braking signals', including lipoxins, which dampen the inflammatory response and reduce levels of inflammatory biomarkers, including C-reactive protein, tumor necrosis factor-α and interleukin (IL)--6, but not negative immunoregulatory cytokines, such as IL-4 and IL-10. Aspirin can reduce oxidative stress and protect against oxidative damage. Early evidence suggests there are beneficial effects of aspirin in preclinical and clinical studies in mood disorders and schizophrenia, and epidemiological data suggests that high-dose aspirin is associated with a reduced risk of AD. Aspirin, one of the oldest agents in medicine, is a potential new therapy for a range of neuropsychiatric disorders, and may provide proof-of-principle support for the role of inflammation and O&NS in the pathophysiology of this diverse group of disorders.

http://dro.deakin.edu.au/eserv/DU:30052827/berk-aspirinareview-2013.pdf

Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness

Endothelial cells, as well as their major products nitric oxide (NO) and prostacyclin, play a key role in the regulation of vascular homeostasis. Diabetes mellitus is an important risk factor for cardiovascular disease. Diabetes-induced endothelial dysfunction is a critical and initiating factor in the genesis of diabetic vascular complications. The present review focuses on both large blood vessels and the microvasculature. The endothelial dysfunction in diabetic macrovascular complications is characterized by reduced NO bioavailability, poorly compensated for by increased production of prostacyclin and/or endothelium-dependent hyperpolarizations, and increased production or action of endothelium-derived vasoconstrictors. The endothelial dysfunction of microvascular complications is primarily characterized by decreased release of NO, enhanced oxidative stress, increased production of inflammatory factors, abnormal angiogenesis, and impaired endothelial repair. In addition, non-coding RNAs (microRNAs) have emerged as participating in numerous cellular processes. Thus, this reviews pays special attention to microRNAs and their modulatory role in diabetes-induced vascular dysfunction. Some therapeutic strategies for preventing and restoring diabetic endothelial dysfunction are also highlighted.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/1753-0407.12521

Macro- and microvascular endothelial dysfunction in diabetes

Sodium glucose co-transporter-2 inhibitors (SGLT2i) have favorable cardiovascular outcomes in diabetic patients. However, whether SGLT2i can improve obesity-related cardiac dysfunction is unknown. Sestrin2 is a novel stress-inducible protein that regulates AMPK-mTOR and suppresses oxidative damage. The aim of this study was to determine whether empagliflozin (EMPA) improves obesity-related cardiac dysfunction via regulating Sestrin2-mediated pathways in diet-induced obesity. C57BL/6J mice and Sestrin2 knockout mice were fed a high-fat diet (HFD) for 12 weeks and then treated with or without EMPA (10 mg/kg) for 8 weeks. Treating HFD-fed C57BL/6J mice with EMPA reduced body weight, whole-body fat, and improved metabolic disorders. Furthermore, EMPA improved myocardial hypertrophy/fibrosis and cardiac function, and reduced cardiac fat accumulation and mitochondria injury. Additionally, EMPA significantly augmented Sestrin2 levels, increased AMPK and eNOS phosphorylation, but inhibited Akt and mTOR phosphorylation. These beneficial effects were partially attenuated in HFD-fed Sestrin2 knockout mice. Intriguingly, EMPA treatment enhanced the Nrf2/HO-1-mediated oxidative stress response, suggesting antioxidant and anti-inflammatory activity. Thus, EMPA improved obesity-related cardiac dysfunction via regulating Sestrin2-mediated AMPK-mTOR signaling and maintaining redox homeostasis. These findings provide a novel mechanism for the cardiovascular protection of SGLT2i in obesity.

https://diabetes.diabetesjournals.org/content/diabetes/69/6/1292.full.pdf

Empagliflozin Ameliorates Obesity-Related Cardiac Dysfunction by Regulating Sestrin2-Mediated AMPK-mTOR Signaling and Redox Homeostasis in High-Fat Diet-Induced Obese Mice.

Irisin is a novel hormone secreted by myocytes. Lower levels of irisin are independently associated with endothelial dysfunction in obese subjects. The objective of this study was to explore whether irisin exerts a direct vascular protective effect on endothelial function in high-fat-diet-induced obese mice. Male C57BL/6 mice were given chow or a high-fat diet with or without treatment with irisin. Aortic endothelial function was determined by measuring endothelium-dependent vasodilatation (EDV). Nitric oxide (NO) in the aorta was determined. The effect of irisin on the levels of AMP-activated protein kinase (AMPK), Akt, and endothelial NO synthase (eNOS) phosphorylation in endothelial cells was determined. Human umbilical vein endothelial cells were used to study the role of irisin in the AMPK-eNOS pathway. Acetylcholine-stimulated EDV was significantly lower in obese mice compared with control mice. Treatment of obese mice with irisin significantly enhanced EDV and improved endothelial function. This beneficial effect of irisin was partly attenuated in the presence of inhibitors of AMPK, Akt, and eNOS. Treatment of obese mice with irisin enhanced NO production and phosphorylation of AMPK, Akt, and eNOS in endothelial cells. These factors were also enhanced by irisin in human umbilical vein endothelial cells in vitro. Suppression of AMPK expression by small interfering RNA blocked irisin-induced eNOS and Akt phosphorylation and NO production. We have provided the first evidence that irisin improves endothelial function in aortas of high-fat-diet-induced obese mice. The mechanism for this protective effect is related to the activation of the AMPK-eNOS signaling pathway.

Irisin improves endothelial function in obese mice through the AMPK-eNOS pathway

Nucleotide-binding oligomerization domain-Like Receptor with a Pyrin domain 3 (NLRP3) inflammasome was emerged as a marker of metabolic dysregulation. We revealed that age-related Sirtuin-1 (SIRT1) modulates cardiac metabolism that medicated inflammatory response during ischemia and reperfusion (I/R) stress. We hypothesize that SIRT1 attenuates NLRP3 inflammasome-dependent inflammation and pyroptosis during myocardial I/R through metabolic modulation. C57BL/6J wild type (WT) mice, inducible cardiomyocyte specific SIRT1 knockout (icSIRT1 KO) and inducible cardiomyocyte specific PDH E1α knockout (icPDH E1α KO) mice were subjected to ligation and release of left anterior descending coronary artery for in vivo regional I/R models. The echocardiography measurement demonstrated that SIRT1 agonist SRT1720 (30 μg/g) improved cardiac systolic function during 45 min of ischemia and 6 h of reperfusion in C57BL/6J WT mice. The biochemical analysis showed that I/R triggered activation of cardiac pyruvate dehydrogenase (PDH), while SIRT1 agonist SRT1720 inhibited I/R-induced PDH activity and reduced production of reactive oxygen species (ROS) during myocardial I/R. Moreover, SRT1720 regulates PDH-related glucose oxidative metabolism to reduce NLRP3 inflammasome activation and pyroptosis in an Akt signaling dependent manner during I/R. Furthermore, an impaired Akt signaling was observed in icSIRT1 KO versus SIRT1fox/flox mice under I/R stress. Intriguingly, we observed lower levels of ROS generation, decreased NLRP3 levels and less pyroptosis occurred in the icPDH E1α KO versus PDH E1αflox/flox hearts during I/R. Taken together, the results indicate that SIRT1 agonism can inhibit activation of NLRP3 inflammasome via Akt-dependent metabolic regulation during ischemic insults by I/R.

SIRT1 agonism modulates cardiac NLRP3 inflammasome through pyruvate dehydrogenase during ischemia and reperfusion.

SummaryObjective
Irisin has been shown to turn white adipocytes into brown-like adipocytes, which is emerging as an appealing therapeutic target for obesity. The objective of the study was to determine whether circulating irisin levels are related to endothelial dysfunction in obese subjects.

Design
A total of 41 nonhypertensive, nondiabetic obese subjects and 40 age- and sex-matched lean healthy control were involved in this study. Clinical characteristics, blood biochemistry, circulating irisin and adiponectin of the subjects were measured. Endothelium-dependent vasodilation (EDV) and endothelial-independent vasodilation (EIV) were determined using high-resolution ultrasound.

Results
Circulating irisin and adiponectin were significantly lower in obese subjects compared with lean healthy control (P < 0·05). Endothelial function was impaired in obese subjects (maximum EDV: 8·95 ± 3·46% vs 14·56 ± 3·90%, P < 0·05). Bivariate correlation analysis revealed that circulating irisin was positively correlated with EDV(r = 0·388, P < 0·01) and negatively correlated with BMI (r = −0·281, P < 0·05), waist circumference (r = −0·298, P < 0·01), free fatty acid (FFA) (r = −0·289, P < 0·01), high-sensitivity C-reactive protein (hs-CRP) (r = −0·244, P < 0·05) and malondialdehyde (r = −0·258, P < 0·05). Multiple regression analysis revealed that circulating irisin, adiponectin, FFA and BMI were independently associated with EDV after adjusting for covariates (R2 = 0·457, F = 8·766, P = 0·000).

Conclusions
Circulating irisin level was decreased in nonhypertensive, nondiabetic obese subjects compared with lean healthy control. Lower levels of irisin are independently associated with endothelial dysfunction. Therefore, irisin may be involved in the regulation of endothelial function in obesity.

Fang Han

Papers

Empagliflozin Ameliorates Obesity-Related Cardiac Dysfunction by Regulating Sestrin2-Mediated AMPK-mTOR Signaling and Redox Homeostasis in High-Fat Diet-Induced Obese Mice.

Irisin improves endothelial function in obese mice through the AMPK-eNOS pathway

SIRT1 agonism modulates cardiac NLRP3 inflammasome through pyruvate dehydrogenase during ischemia and reperfusion.

The relationship between circulating irisin levels and endothelial function in lean and obese subjects

Irisin improves perivascular adipose tissue dysfunction via regulation of the heme oxygenase-1/adiponectin axis in diet-induced obese mice