ADBR3

The ADRB3 gene encodes the beta-3 adrenergic receptor (β3-AR), a key receptor involved in the regulation of lipolysis and thermogenesis in adipose tissue. 

β3-AR, primarily found in brown and white adipocytes, mediates the activation of adenylate cyclase through catecholamines, particularly norepinephrine, which triggers the cAMP-PKA signaling pathway. 

This pathway regulates crucial processes such as lipolysis and thermogenesis, making β3-AR a significant player in energy metabolism.

Variations in the ADRB3 gene, such as the Trp64Arg polymorphism, have been linked to obesity, metabolic alterations, and changes in body composition. 

This polymorphism affects the receptor's function, leading to differences in adipokine levels and lipid metabolism, and is considered a genetic risk factor for conditions like coronary artery disease (CAD). 

Understanding the role and variations of ADRB3 is essential for developing targeted therapies for obesity and metabolic disorders.

What is ADBR3?

The ADRB3 gene encodes the beta-3 adrenergic receptor, a key member of the beta adrenergic receptor family.  It mediates the activation of adenylate cyclase by catecholamines through G proteins.

ADBR3 is one member of a class of beta-adrenergic receptors which also include beta-1 and beta-2 adrenergic receptors. Each has slightly different functions in mediating adrenergic activity, and beta-1 and beta-2 receptors overall have a stronger relationship with epinephrine than does the beta-3 adrenergic receptor.

Beta-adrenergic receptors are part of a larger class of adrenergic receptors, which include 3 alpha-1 adrenergic receptors, 3 alpha-2 adrenergic receptors, and 3 beta adrenergic receptors. [14.] 

Location of the ADBR3 Protein

This receptor is primarily found in adipose tissue, although it is also expressed pervasively in the body including the lymph nodes, the placenta, the urinary bladder and gallbladder, the prostate, brain, heart and blood vessels, and the appendix. [1., 12.] 

Physiology of the ADBR3 Protein [12.] 

The catecholamines epinephrine and norpeinephrine bind to ADBR3, which mediates the activation of adenylate cyclase through G proteins, leading to various physiological effects. [2.] 

While it is accepted that epinephrine binds to ADBR3, norepinephrine is recognized as the primary stimulator of ADBR3 in adipose tissue. [13.] 

Specifically, norepinephrine released by sympathetic nerve endings trigger ADBR3 activation in adipocytes. This activation initiates the cAMP-PKA signaling pathway, which regulates processes like lipolysis and thermogenesis in adipose tissue. [13.] 

The β3-adrenergic receptor (β3-AR) is predominantly expressed in brown and white adipocytes and is crucial for brown adipose tissue (BAT) activation. [13.] 

ADBR3 in Health and Disease

ADBR3 in Obesity, Lipolysis and Thermogenesis

Obesity is associated with decreased beta-adrenergic receptor (beta-AR) mediated lipolysis and lipid oxidation. [6.]

ADBR3 plays a critical role in regulating lipolysis and thermogenesis through catecholamine signaling. Research findings suggest that targeting ALK7 can enhance beta-adrenergic signaling and catecholamine sensitivity, offering potential therapeutic strategies for obesity by leveraging the body's natural lipolytic and thermogenic pathways. [6.]

Thermogenic Fat as a Target for Obesity and Metabolic Health

Thermogenic fat, comprising brown and beige adipocytes, are essential regulating energy balance and metabolic health. 

Brown and beige fat cells share similar properties, including the ability to generate heat through thermogenesis, but they also exhibit distinct features, such as their origins and regulatory mechanisms.

Brown Adipose Tissue (BAT) 

Brown adipocytes, found in brown adipose tissue (BAT), are specialized for thermogenesis. 

They are densely packed with mitochondria and exhibit a multilocular lipid droplet organization, enhancing their ability to combust glucose and fatty acids for heat production. [15.] 

Activation of BAT is primarily mediated through the sympathetic nervous system (SNS), which releases norepinephrine that binds to the β3-adrenergic receptor (ADBR3) on brown adipocytes. [15.] 

This activation initiates a cascade of intracellular events leading to the upregulation of thermogenic proteins like uncoupling protein 1 (UCP1), which facilitates heat generation by dissipating the proton gradient in mitochondria. [15.] 

Beige Adipocytes

Beige adipocytes, found within white adipose tissue (WAT), can be induced to adopt thermogenic properties similar to brown adipocytes. [15.] 

Beige fat cells are highly plastic and can interconvert between a thermogenic beige state and a storage-oriented white state in response to environmental stimuli, such as cold exposure or pharmacological agents targeting ADBR3. [15.] 

This plasticity and the ability to respond dynamically to external signals highlight the potential of beige adipocytes in therapeutic strategies against obesity.

White Adipose Tissue (WAT)

In contrast to brown and beige fat, white adipocytes are primarily involved in energy storage. 

They expand by accumulating triglycerides and can contribute to obesity and metabolic diseases when present in excess. [15.] 

However, under certain conditions, white adipocytes can transdifferentiate into beige adipocytes, thereby gaining thermogenic capabilities. [15.] 

ADBR3 and Thermogenic Activation

The β3-adrenergic receptor (ADBR3) is a key player in the activation of thermogenic fat. [15.] 

Although it is found in other tissues, it is primarily expressed in adipose tissue and is crucial for the lipolysis and thermogenesis processes. [1., 12., 15.]

Activation of ADBR3 by catecholamines triggers a signaling pathway involving cyclic AMP (cAMP) and protein kinase A (PKA), leading to the upregulation of UCP1 and enhanced thermogenic activity.

ADBR3 in the Brain [12.] 

In the context of the central nervous system, norepinephrine release via activation of central ADBR3 likely located in the locus coeruleus is discussed in relation to its potential antidepressant effects. 

ADBR3 has been implicated in the generation of neuropathic pain as the mediator of ATP release from dorsal root ganglia neurons upon norepinephrine stimulation, highlighting its broader involvement in catecholamine-mediated physiological responses. [12.] 

ADBR3 in the Heart [14.] 

The human heart contains beta-1, beta-2, and beta-3 adrenergic receptors, with beta-1 and beta-2 receptors expressed at a 70:30 ratio. 

Stimulation of beta-1 and beta-2 receptors enhances cardiac contractility (positive inotropic effect), heart rate (positive chronotropic effect), relaxation rate (lusitropic effect), and impulse conduction through the atrioventricular node (positive dromotropic effect). 

In contrast, beta-3 receptors are mostly inactive under normal conditions but, when stimulated, produce a negative inotropic effect through the nitric oxide synthase pathway, acting as a "safety valve" during intense adrenergic stimulation.

Body Mass Index Quantitative Trait Locus 11 (BMIQ11) [4., 9.] 

Body Mass Index Quantitative Trait Locus 11 (BMIQ11) is a genetic factor that influences body mass index, a measure of body fat based on height and weight. 

This quantitative trait locus is linked to mutations or variations in the ADRB3 gene, which encodes the β3-adrenergic receptor. 

The ADRB3 gene plays a crucial role in regulating lipolysis and thermogenesis, processes that are essential for energy metabolism and fat storage. Variations in the ADRB3 gene associated with BMIQ11 may contribute to an increased susceptibility to obesity. 

BMIQ11 is part of a broader spectrum of genetic factors influencing body weight and metabolism, and it is associated with other conditions such as leptin deficiency or dysfunction, prediabetes syndrome, and type 2 diabetes mellitus. 

The condition may affect various metabolic processes including glucose tolerance, insulin sensitivity, and adipose tissue development. 

BMIQ11 is likely associated with symptoms such as increased body weight, obesity (potentially metabolically benign), and related metabolic disturbances. 

BMIQ11 represents a complex genetic influence on BMI, likely involving interactions with other genes and environmental factors, highlighting the intricate nature of genetic contributions to body weight regulation.

Leptin Deficiency or Dysfunction [5., 10.] 

Dysfunction in ADBR3 signaling or impaired SNS outflow could potentially lead to dysregulation of leptin levels, contributing to metabolic disorders such as obesity and insulin resistance. 

The β3-adrenergic receptor (ADBR3) is primarily expressed in adipose tissues and affects the regulation of metabolic processes, including lipolysis and thermogenesis.

Increased sympathetic nervous system (SNS) outflow, which activates ADBR3, inhibits leptin production in adipose tissue.

β-adrenergic receptors have a well-established role in modulating leptin levels: previous research has shown that activation of β-adrenergic receptors, particularly ADBR3, suppresses leptin gene expression and protein levels.

In obesity, there's often a state of leptin resistance, where high leptin levels fail to suppress appetite effectively. [7.]  ADRB3 activation can potentially counteract this by reducing leptin levels and increasing fat burning. However, in obesity, ADRB3 expression and function may be impaired, contributing to metabolic dysfunction.

Genetic Alterations in the ADBR3 Gene

The gene for the ADBR3 protein may contain alterations or mutations that cause increase or decrease of function of the ADBR3 protein.  

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Specific SNPs Associated with Alterations in ADBR3 Function

rs4994 (Trp64Arg) [11.] 

This is one of the most studied polymorphisms in the ADRB3 gene. It's associated with obesity risk, metabolic alterations, and potentially impacts cardiorespiratory fitness.

The Trp64Arg polymorphism in the ADRB3 gene has notable effects on body composition, cardiorespiratory fitness, and physical activity levels.

In contrast, the Trp64Trp genotype is associated with higher adiposity and better cardiorespiratory fitness, while the Arg allele is linked to a leaner body type.

One large meta-analysis demonstrated an association of the Trp64Arg polymorphism in the ADRB3 gene with plasma adipokines and lipid levels: a comprehensive analysis was conducted, including 22 studies (5527 subjects) for adipokines and 121 studies (54,059 subjects) for lipids. [8.] 

The C allele carriers (Trp64Arg) showed higher leptin and lower adiponectin levels, along with elevated triglycerides (TG) and total cholesterol (TC) and reduced high-density lipoprotein cholesterol (HDL-C). [8.] 

Subgroup analyses highlighted significant associations in obese Asian women. [8.] 

These results suggest the Trp64Arg polymorphism, vs. the Trp64Trp variant, may be a genetic risk factor for coronary artery disease (CAD), mediated by its influence on adipokines and lipid levels. [8.] 

Further research needs to be done to confirm the overall health and metabolic effects of each of these alleles.

Rs1892818 

The CC version of this SNP has been associated with coronary artery disease risk, while in Han Chinese populations, the CT genotype of rs1892818 appeared to be a protective factor for coronary artery disease. [16.] 

Laboratory Testing for ADBR3

Genetic testing for single nucleotide polymorphisms (SNPs) typically involves obtaining a sample of DNA which can be extracted from blood, saliva, or cheek swabs. 

The sample may be taken in a lab, in the case of a blood sample.  Alternatively, a saliva or cheek swab sample may be taken from the comfort of home.  

Test Preparation

Prior to undergoing genetic testing, it's important to consult with a healthcare provider or genetic counselor to understand the purpose, potential outcomes, and implications of the test.  This consultation may involve discussing medical history, family history, and any specific concerns or questions. 

Additionally, individuals may be advised to refrain from eating, drinking, or chewing gum for a short period before providing a sample to ensure the accuracy of the test results.  Following sample collection, the DNA is processed in a laboratory where it undergoes analysis to identify specific genetic variations or SNPs. 

Once the testing is complete, individuals will typically receive their results along with interpretation and recommendations from a healthcare professional. 

It's crucial to approach genetic testing with proper understanding and consideration of its implications for one's health and well-being.

Patient-Centric Approaches

A patient-centered approach to SNP genetic testing emphasizes individualized medicine, tailoring healthcare decisions and interventions based on an individual's unique genetic makeup.

When that is combined with the individual’s health status and health history, preferences, and values, a truly individualized plan for care is possible. 

By integrating SNP testing into clinical practice, healthcare providers can offer personalized risk assessment, disease prevention strategies, and treatment plans that optimize patient outcomes and well-being. 

Genetic testing empowers a deeper understanding of genetic factors contributing to disease susceptibility, drug response variability, and overall health, empowering patients to actively participate in their care decisions. 

Furthermore, individualized medicine recognizes the importance of considering socioeconomic, cultural, and environmental factors alongside genetic information to deliver holistic and culturally sensitive care that aligns with patients' goals and preferences. 

Through collaborative decision-making and shared decision-making processes, patients and providers can make informed choices about SNP testing, treatment options, and lifestyle modifications, promoting patient autonomy, engagement, and satisfaction in their healthcare journey.

Genetic Panels and Combinations

Integrating multiple biomarkers into panels or combinations enhances the predictive power and clinical utility of pharmacogenomic testing. Biomarker panels comprising a variety of transporter proteins and enzymes including drug metabolizing enzymes offer comprehensive insights into individual drug response variability and treatment outcomes. 

Combining genetic SNP testing associated with drug transport, metabolism, and pharmacodynamics enables personalized medicine approaches tailored to individual patient characteristics and genetic profiles.

ADBR3 Related Biomarkers

While ADBR3 is a valuable biomarker on its own, alterations in this gene may signify the need for closer assessment of metabolic factors alongside healthy diet and lifestyle interventions.  

Insulin and Glucose Levels

Insulin and glucose levels are critical markers in metabolic health, particularly in conditions such as obesity and diabetes. 

Since ADBR3 is involved in regulating energy expenditure and fat metabolism, its activity is linked to insulin sensitivity and glucose homeostasis. Monitoring insulin and glucose levels in conjunction with ADBR3 can enhance the understanding of metabolic dysfunctions. 

Lipid Panel

ADRB3 variants, particularly the Trp64Arg polymorphism, have been associated with altered lipid profiles and obesity risk. Combining ADRB3 testing with lipid panels can help better stratify patients for metabolic and cardiovascular risk and guide more targeted interventions. 

ApoB

ADRB3 variants have been associated with metabolic disorders and obesity risk, while ApoB is a well-established marker for cardiovascular disease risk. Testing both could provide a more comprehensive picture of a patient's cardiovascular and metabolic health.

Frequently Asked Questions (FAQs) about ADBR3

The FAQ section addresses common questions and concerns about ADBR3, providing clear and concise answers for better understanding. Whether you're interested in its significance, testing, or health implications, this section covers essential information you need to know.

What Is ADBR3?

ADBR3 stands for adrenoceptor beta 3 (β3-adrenergic receptor), a protein encoded by the ADRB3 gene. This receptor is involved in the regulation of fat breakdown (lipolysis) and thermogenesis in brown and white adipose tissues.

Why Is ADBR3 Important?

ADBR3 is important because it plays a critical role in energy balance, fat metabolism, and thermogenesis. 

It is involved in the body's response to catecholamines like adrenaline and noradrenaline, which are hormones that, among many other things, trigger the breakdown of fats and the production of heat in response to cold or stress.

What Is the Function of ADBR3?

The primary function of ADBR3 is to mediate the effects of catecholamines on adipose tissue. 

When activated, ADBR3 stimulates lipolysis, the breakdown of triglycerides into free fatty acids, and glycerol. It also promotes thermogenesis, the production of heat, particularly in brown adipose tissue, which helps regulate body temperature and energy expenditure.

What Are Normal Levels of ADBR3 Activity?

Normal levels of ADBR3 activity can vary based on factors such as age, sex, genetic background, and overall health. 

Functionality is being established through research studies and should be interpreted by a healthcare provider in the context of the patient's health status and medical history.

What Can Cause Elevated Levels of ADBR3 Activity?

Elevated levels of ADBR3 activity can be associated with increased sympathetic nervous system activity, often triggered by stress, cold exposure, or certain medications. 

Genetic variations in the ADRB3 gene can also influence the receptor's activity, potentially leading to differences in fat metabolism and energy expenditure.

What Can Cause Low Levels of ADBR3 Activity?

Low levels of ADBR3 activity may result from genetic mutations, reduced sympathetic nervous system activity, or conditions that impair receptor function. 

Decreased ADBR3 activity can affect the body's ability to regulate fat metabolism and thermogenesis, potentially contributing to obesity and metabolic disorders.

What Are the Symptoms of Abnormal ADBR3 Activity?

Symptoms of abnormal ADBR3 activity depend on whether the activity is elevated or reduced. 

High ADBR3 activity may lead to increased fat breakdown and heat production, which can result in weight loss and increased energy expenditure. 

Low ADBR3 activity can lead to weight gain, reduced energy expenditure, and difficulty maintaining body temperature in response to cold.

How Are Abnormal Levels of ADBR3 Activity Treated?

Treatment for abnormal levels of ADBR3 activity depends on the underlying cause. 

Lifestyle interventions such as diet and exercise are foundational to help regulate body weight and metabolism. 

In some cases, medications that influence sympathetic nervous system activity or receptor function may be considered. It is important to consult with a healthcare provider for an accurate diagnosis and appropriate treatment plan.

Why Might a Doctor Order an ADBR3 Test?

A doctor might order an ADBR3 test to investigate issues related to energy metabolism, obesity, or metabolic disorders. Testing may help determine the role of ADBR3 in a patient's metabolic profile and guide personalized treatment strategies.

Is the ADBR3 Test Safe?

Yes, the ADBR3 test is safe. The procedure typically involves collecting a blood, saliva, or cheek swab sample; a blood sample which may cause minor discomfort or bruising at the site of collection. The molecular analysis of gene expression or receptor activity poses no risk to the patient.

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