Adiponectin

Adiponectin is a key adipokine predominantly secreted by white adipocytes that is important in enhancing insulin sensitivity, reducing inflammation, and protecting against atherosclerosis. 

Its levels, typically ranging from 3-30 μg/ml, are significant biomarkers for metabolic conditions such as Type 2 diabetes and metabolic syndrome. 

Adiponectin acts on various tissues, including the liver and skeletal muscle, through receptors AdipoR1 and AdipoR2, promoting glucose uptake and fatty acid oxidation.  

Factors like weight loss, caloric restriction, exercise, and certain nutraceuticals (e.g., resveratrol, berberine, omega-3 fatty acids) can increase adiponectin levels, improving metabolic health. 

Conversely, obesity, insulin resistance, inflammatory cytokines, and tissue hypoxia can reduce its levels. 

Understanding and regulating adiponectin is essential for managing obesity-related diseases and improving overall metabolic health.

What is Adiponectin?

Definition of Adiponectin, an Adipokine  [1., 8., 11.] 

Adiponectin is a 244 amino acid adipokine predominantly secreted by white adipocytes, and is the most abundant peptide hormone from these cells.  

It serves as a key biomarker for obesity-related diseases like metabolic syndrome, Type 2 diabetes, and atherosclerosis.  Adiponectin levels in plasma range from 3–30 μg/ml. 

Adiponectin is not only produced by white adipocytes but also by skeletal muscle cells, cardiac myocytes, and endothelial cells.  It acts on various tissues including the liver, skeletal muscle, and vasculature, promoting insulin sensitization and anti-inflammatory effects. 

Adiponectin exerts its functions through receptors AdipoR1 and AdipoR2, with AdipoR1 mainly found in skeletal muscle and AdipoR2 predominantly in the liver. T-cadherin serves as a non-signaling receptor.

In terms of clearance, adiponectin is primarily cleared by the liver, although it also binds to pancreatic beta cells and certain heart and kidney cells. This multifaceted role of adiponectin highlights its importance in regulating metabolic processes and underscores its potential as a target for treating related disorders.

What is an Adipokine? 

An adipokine is a type of cytokine (a cell-signaling protein) that is secreted by adipose (fat) tissue. 

Adipokines play crucial roles in regulating metabolic processes and are involved in a variety of physiological functions including appetite regulation, glucose and lipid metabolism, insulin sensitivity, inflammation, and immune responses. 

Examples of adipokines include adiponectin, leptin, resistin, and visfatin. These proteins can have both local (autocrine and paracrine) and systemic (endocrine) effects, influencing not only adipose tissue function but also the function of other organs and tissues throughout the body.

Adiponectin Function  [1., 8., 11., 12.]  

As an adipokine, adiponectin has several significant functions in the body:

Enhancing Insulin Sensitivity 

Adiponectin enhances insulin sensitivity by increasing glucose uptake and fatty acid oxidation in muscle cells and reducing hepatic glucose production. This helps lower blood glucose levels and improves overall metabolic health.

Anti-Inflammatory Actions 

It has anti-inflammatory properties, reducing the expression of inflammatory cytokines and promoting the polarization of macrophages towards an anti-inflammatory phenotype.  This reduces chronic inflammation associated with obesity and metabolic syndrome.

Anti-Atherogenic and Cardioprotective Properties

Adiponectin protects against the development of atherosclerosis by inhibiting the transformation of macrophages into lipid-laden foam cells, reducing vascular inflammation, and promoting endothelial function.

Adiponectin exerts additional protective effects on the cardiovascular system by enhancing the survival of cardiomyocytes, reducing myocardial infarction risk, and improving vascular function.  

Metabolic Regulation

Adiponectin regulates lipid metabolism by increasing the oxidation of fatty acids and reducing triglyceride content in tissues. This helps in maintaining lipid balance and preventing the accumulation of fat in non-adipose tissues.

Anti-Cancer and Apoptotic Effects  [6.] 

Adiponectin has been shown to influence cell proliferation and apoptosis, particularly in the context of cancer. 

Adiponectin, through its interaction with the AMP-activated protein kinase (AMPK) pathway, can inhibit cancer cell growth and induce apoptosis.  This process involves the upregulation of p21 and p53, which are crucial regulators of cell cycle arrest and apoptosis in colon cancer cells. 

Furthermore, adiponectin's tumor suppressor effects are mediated via the AKT and ERK signaling pathways in lung and pancreatic cancer cell lines, suggesting a broad anti-cancer activity across different types of cancer cells. 

However, a potential proliferative and antiapoptotic role of adiponectin may exist in certain contexts, indicating that the effects of adiponectin on cell proliferation and apoptosis might be cell type-specific and influenced by the surrounding microenvironment​​.

Conditions Associated with Low Adiponectin Levels

Cardiometabolic conditions including obesity, insulin resistance, atherosclerosis and metabolic syndrome have all been correlated with low levels of Adiponectin.  [8.] 

Additionally, the condition called lipodystrophy has also been associated with low adiponectin levels.  [8.] 

Lipodystrophy is a disorder characterized by abnormal or degenerative conditions of the body's adipose tissue, leading to a lack of fat storage in specific areas and sometimes an accumulation in others. This condition can be genetic or acquired and is often associated with metabolic disturbances including insulin resistance, diabetes, and dyslipidemia.  [11.] 

Adiponectin plays a crucial role in regulating glucose levels and fatty acid breakdown.  In lipodystrophy, adiponectin levels are typically low due to the reduced or dysfunctional adipose tissue. 

This decrease in adiponectin contributes to the metabolic complications seen in lipodystrophy patients, such as increased insulin resistance and cardiovascular risk.  Increasing adiponectin levels through therapeutic interventions may help mitigate these metabolic disturbances.

It should be noted that individuals with lower levels of adiponectin are up to 9 times more likely to develop type 2 diabetes.  [2.] 

Regulation of Adiponectin: What Increases Adiponectin?  [4., 9., 10., 12., 13.] 

Adiponectin is secreted by adipose tissue primarily in response to various metabolic signals.  Its secretion is generally stimulated by factors that promote insulin sensitivity and overall metabolic health. 

For instance, weight loss and caloric restriction have been shown to increase adiponectin levels, likely due to the reduction in adiposity and improvement in metabolic parameters.  Fish oil supplementation has shown to raise adiponectin levels by 14-60%, and fiber supplementation has been shown to raise adiponectin levels by up to 60-115%.  [10.] 

Additionally, certain medications such as thiazolidinediones (TZDs) that activate PPARγ, also enhance adiponectin secretion, contributing to their insulin-sensitizing effects.  [9.]

Exercise, particularly aerobic activity, is another positive regulator of adiponectin secretion, further linking physical activity to improved metabolic outcomes.  [10.] 

Conversely, adiponectin secretion is downregulated under conditions of metabolic stress and obesity.  [4., 12.] 

Increased adiposity, particularly central or visceral fat accumulation, is associated with reduced adiponectin levels.  This reduction is exacerbated by insulin resistance and hyperinsulinemia, common features of metabolic syndrome and type 2 diabetes. 

Inflammatory cytokines such as TNF-α, commonly elevated in obesity, also inhibit adiponectin production.  

Interestingly, tissue hypoxia seen in obesity can also reduce adiponectin levels.  Macrophage infiltration into adipose tissue is a significant marker of chronic inflammation in obesity. Adipose tissue hypoxia may inhibit macrophage departure, promoting infiltration. 

Additionally, hypoxia reduces adiponectin expression in adipocytes, contributing to insulin resistance.  The molecular mechanisms involve inhibition of adiponectin mRNA by hypoxia and TNF-α.  [13.] 

Moreover, certain pharmacological treatments like highly active antiretroviral therapy (HAART) for HIV have been shown to decrease adiponectin levels, potentially contributing to metabolic side effects. Overall, the regulation of adiponectin secretion reflects a balance between factors that enhance metabolic health and those that contribute to metabolic dysfunction.

Lab Testing for Adiponectin

Lab Testing, Sample Collection and Preparation

Adiponectin testing is typically performed with blood samples, which require a venipuncture.  

Overnight fasting is often required.  

Interpretation of Adiponectin Levels

Optimal Levels of Adiponectin

Optimal levels of adiponectin are on the higher end of the desired, or reference, range.  Individuals with higher BMI are expected to have lower levels of adiponectin, but these levels can be increased with certain dietary and lifestyle measures as discussed in this article.  

Reference values for adiponectin may vary depending on factors such as age, sex, and ethnicity, and should be interpreted in the context of the individual's clinical presentation and other relevant biomarkers. Additionally, the laboratory company used should be consulted.  

As an example, one laboratory company provides the following reference ranges for adiponectin in the blood samples from adults:  [7.] 

Male

BMI <25 kg/m2 2.3-15.2 ug/mL

BMI 25-30 kg/m2 2.1-16.7 ug/mL

BMI >30 kg/m2 2.2-12.9 ug/mL   

Female

BMI <25 kg/m2 2.9-30.4 ug/mL

BMI 25-30 kg/m2 2.5-26.8 ug/mL

BMI >30 kg/m2 3.9-21.8 ug/mL

Clinical Significance of Elevated Adiponectin Levels

Clinically, higher levels of adiponectin are considered desirable, as they are associated with better cardiometabolic health and lower risk of many chronic conditions.  

Clinical Significance of Low Adiponectin Levels

Low adiponectin levels are associated with a greater risk of obesity, cardiometabolic disease, and possibly cancer.  Individuals with low adiponectin levels should be counseled on the diet and lifestyle factors that have been associated with raising adiponectin levels, as discussed in this article.  

Related Biomarkers

Adiponectin is not the sole biomarker for metabolic and cardiovascular health; it is often evaluated in conjunction with other related biomarkers to provide a more comprehensive assessment of an individual's metabolic status and disease risk.

Leptin and the Leptin-to-Adiponectin Ratio

Leptin is another adipokine that plays a crucial role in regulating energy balance and metabolism.  

The ratio of leptin to adiponectin (the leptin-to-adiponectin ratio) has been proposed as a more informative marker of insulin resistance and metabolic dysfunction than either adiponectin or leptin alone. This ratio takes into account the opposing actions of these two adipokines, providing a more nuanced understanding of an individual's metabolic profile.

Inflammatory Markers

Chronic low-grade inflammation is closely linked to the development of metabolic disorders and cardiovascular disease, as well as lower adiponectin levels.

Biomarkers such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) are often evaluated in conjunction with adiponectin to assess the overall inflammatory status and its potential impact on metabolic health.

Insulin Resistance Markers

Insulin resistance is a key feature of many metabolic disorders, including type 2 diabetes and metabolic syndrome. 

Biomarkers such as fasting glucose, fasting insulin, and the homeostatic model assessment of insulin resistance (HOMA-IR) can provide valuable insights into an individual's insulin sensitivity and the potential interplay with adiponectin levels.

Adiponectin Supplements

In addition to dietary and lifestyle modifications, there is growing interest in the potential use of supplements to modulate adiponectin levels and improve metabolic health. 

While the evidence is still emerging, some studies have suggested that certain nutraceuticals, such as resveratrol, berberine, and omega-3 fatty acids, may have the ability to increase adiponectin production or enhance its signaling pathways.  [3., 5., 10.]

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