Roles of oxidative stress, adiponectin, and nuclear hormone receptors in obesity-associated insulin resistance and cardiovascular risk

Abstract

Obesity leads to the development of type 2 diabetes mellitus, which is a strong risk factor for cardiovascular disease. A better understanding of the molecular basis of obesity will lead to the establishment of effective prevention strategies for cardiovascular diseases. Adipocytes have been shown to generate a variety of endocrine factors termed adipokines/adipocytokines. Obesity-associated changes to these adipocytokines contribute to the development of cardiovascular diseases. Adiponectin, which is one of the most well-characterized adipocytokines, is produced exclusively by adipocytes and exerts insulin-sensitizing and anti-atherogenic effects. Obese subjects have lower levels of circulating adiponectin, and this is recognized as one of the factors involved in obesity-induced insulin resistance and atherosclerosis. Another pathophysiological feature of obesity may involve the low-grade chronic inflammation in adipose tissue. This inflammatory process increases oxidative stress in adipose tissue, which may affect remote organs, leading to the development of diabetes, hypertension, and atherosclerosis. Nuclear hormone receptors (NRs) regulate the transcription of the target genes in response to binding with their ligands, which include metabolic and nutritional substrates. Among the various NRs, peroxisome proliferator-activated receptor γ promotes the transcription of adiponectin and antioxidative enzymes, whereas mineralocorticoid receptor mediates the effects of aldosterone and glucocorticoid to induce oxidative stress in adipocytes. It is hypothesized that both play crucial roles in the pathophysiology of obesity-associated insulin resistance and cardiovascular diseases. Thus, reduced adiponectin and increased oxidative stress play pathological roles in obesity-associated insulin resistance to increase the cardiovascular disease risk, and various NRs may be involved in this pathogenesis.

Decreased baroreflex sensitivity is linked to sympathovagal imbalance, body fat mass and altered cardiometabolic profile in pre-obesity and obesity

“…Further, pro-inflammatory state has been reported to increase the CV risk [14]. Other CV risks such as dyslipidemia, insulin resistance and oxidative stress have also been reported in obesity [15,16]. Recently, baroreflex sensitivity (BRS) has been established as a sensitive marker for the assessment of CV risks in health and disease [17].…”

Impact of Pioglitazone on Macrophage Dynamics in Adipose Tissues of Cecal Ligation and Puncture-Treated Mice

“…PPARγ is related to adipocyte differentiation, and PPARγ agonists are commonly used as insulin sensitizers to treat type II diabetic patients with insulin resistance. 20) Several studies have suggested that PPARγ agonists which up-regulate adiponectin production via activation of nuclear PPARγ 21,22) may have protective effects on the cardiovascular system by ameliorating endothelial dysfunction and vascular inflammation.…”

Beneficial Effects of Incretin-Based Therapy on Glycemic Control, Adipokines, Insulin Sensitivity Parameters and Weight Loss in Overweight or Obese Patients With Newly Diagnosed Type 2 Diabetes: A Prospective Study

“…Overweight and obesity are widely believed to contribute to the development of several metabolic complications, including insulin resistance and T2DM [1,2]. However, the pathophysiological link between obesity and insulin resistance remains to be elucidated, but several recent studies indicate a central role for adipose tissue and its endocrine dysfunction.…”