Insights Into the Controversial Aspects of Adiponectin in Cardiometabolic Disorders

Abstract

In 2016, the World Health Organization estimated that more than 1.9 billion adults were overweight or obese. This impressive number shows that weight excess is pandemic. Overweight and obesity are closely associated with a high risk of comorbidities, such as insulin resistance and its most important outcomes, including metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Adiponectin has emerged as a salutary adipocytokine, with insulin-sensitizing, anti-inflammatory, and cardiovascular protective properties. However, under metabolically unfavorable conditions, visceral adipose tissue-derived inflammatory cytokines might reduce the transcription of the adiponectin gene and consequently its circulating levels. Low circulating levels of adiponectin are negatively associated with various conditions, such as insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease. In contrast, several recent clinical trials and meta-analyses have reported high circulating adiponectin levels positively associated with cardiovascular mortality and all-cause mortality. These results are biologically intriguing and counterintuitive, and came to be termed “the adiponectin paradox”. Adiponectin paradox is frequently associated with adiponectin resistance, a concept related with the downregulation of adiponectin receptors in insulin-resistant states. We review this contradiction between the apparent role of adiponectin as a health promoter and the recent evidence from Mendelian randomization studies indicating that circulating adiponectin levels are an unexpected predictor of increased morbidity and mortality rates in several clinical conditions. We also critically review the therapeutic perspective of synthetic peptide adiponectin receptors agonist that has been postulated as a promising alternative for the treatment of metabolic syndrome and type 2 diabetes mellitus.

What Are the Clinical and Systemic Results of Periodontitis Treatment in Obese Individuals?

“…Obesity is characterized by an excessive accumulation of body fat [ 16 ]. World Health Organization (WHO) and the National Institutes of Health determine obesity by using the body mass index (BMI), obtained as a ratio given by weight (in kg)/height (in m 2 ) that classifies several categories.…”

“…This correlation is corroborated by the intracellular crosstalk with insulin pathways since adiponectin directly interacts with insulin receptor substrates 1 and 2 (IRS1/2). This binding evokes downstream activation of PI3K, a major component of the insulin pathway [ 16 ], ameliorating the insulin response and triggering anti-inflammatory pathways in peripheral tissues (Fig. 1a ).…”

“…The downregulation of the adiponectin pathway results in oxidative stress and activation of NFκ-B (Fig. 1b ) [ 16 ]. In addition, the low-grade inflammation observed in obese individuals is a result of augmented expression of inflammatory cytokines, by visceral adipose tissue [ 9 ].…”

The prognostic role of RBP-4 and adiponectin in patients with peripheral arterial disease undergoing lower limb endovascular revascularization

“…Contrary to the other adipokines, its levels are lower in obesity, and it exerts an anti-inflammatory, insulin-sensitizing and anti-atherogenic effect. Although initial in vitro studies had firmly established the cardio-protective role of adiponectin, human studies have been contradictory [ 14 ]. Low levels of adiponectin have been associated with higher incidence of PAD [ 15 , 16 ], along with an increased risk of MACE in patients with symptomatic PAD [ 17 ].…”

Circulating Adiponectin and Its Association with Metabolic Traits and Type 2 Diabetes: Gene-Diet Interactions Focusing on Selected Gene Variants and at the Genome-Wide Level in High-Cardiovascular Risk Mediterranean Subjects

“…Given the interest that adiponectin has aroused, there is a large number of studies that have analyzed its associations with various adiposity parameters, insulin resistance, plasma lipid levels, inflammatory markers, type 2 diabetes risk and atherosclerosis biomarkers [13][14][15][16][17][18]. Although the results of several studies may differ, there is strong consistency in observing that adiponectin appears to increase insulin sensitivity by improving glucose and lipid metabolisms.…”