Obesity and Insulin Resistance Quiz

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Questions and Answers

What is a consequence of insulin resistance in relation to lipid deposition?

Decreased TAG storage in skeletal muscle

Correlated increased lipid deposition in skeletal muscle and liver (correct)

Reduction of ectopic lipid deposition

Improved sensitivity to inflammatory cytokines

How does obesity affect plasma adiponectin levels?

Plasma adiponectin levels remain unchanged

Plasma adiponectin levels decrease as obesity progresses (correct)

Obesity leads to increased adiponectin production

Adiponectin has no correlation with obesity

Which of the following factors is NOT associated with hypertension?

Decreased blood vessel elasticity

Increased adiponectin secretion (correct)

Abdominal obesity

Increased BMI

What impact does leptin have on insulin sensitivity in cases of obesity?

Leptin resistance seen in obesity limits its ability to improve insulin sensitivity Signup and view all the answers

Which statement accurately describes the role of inflammatory cytokines in obesity?

They can lead to arterial stiffness and influence smooth muscle cells Signup and view all the answers

What is hyperplasia in adipocytes?

Increase in cell number Signup and view all the answers

What is a consequence of adipocyte hypertrophy?

Increased recruitment of macrophages Signup and view all the answers

Which of the following is a proinflammatory adipokine secreted by infiltrating macrophages?

TNF-α Signup and view all the answers

What effect does adiponectin have on the body?

Has anti-inflammatory effects Signup and view all the answers

What is a reason for leptin resistance in obese individuals?

Malfunction in crossing the blood-brain barrier Signup and view all the answers

How does leptin affect appetite?

Decreases appetite Signup and view all the answers

Which statement about leptin is correct?

Leptin secretion reflects body fat levels Signup and view all the answers

Which adipokine is linked to hypertension and cardiovascular disease?

Leptin Signup and view all the answers

What effect does leptin administration have on the immune response?

Enhances the immune response Signup and view all the answers

Which of the following is a consequence of high levels of adiponectin?

Decreased risk of cardiovascular problems Signup and view all the answers

What is primarily indicated by the presence of crown-like structures (CLS) in adipose tissue?

Macrophage infiltration around necrotic adipocytes Signup and view all the answers

Which cytokine is considered anti-inflammatory and decreased in obesity?

IL-10 Signup and view all the answers

What leads to the recruitment of immune cells during obesity-related inflammation?

Hypoxia in the expanding adipose tissue Signup and view all the answers

Which factor contributes to insulin resistance in obesity?

All of the above Signup and view all the answers

What is the role of pro-inflammatory cytokines like leptin and TNF-α in obesity?

They promote inflammation in adipose tissue Signup and view all the answers

What can increase levels of adiponectin?

Weight loss Signup and view all the answers

What is the primary function of brown adipose tissue (BAT) in adults after cold acclimation?

To produce heat through thermogenesis Signup and view all the answers

Which of the following accurately describes the difference in adipocyte structure between brown and white adipose tissue?

Brown adipocytes contain numerous smaller lipid droplets and more capillaries Signup and view all the answers

What is the role of PPARγ in adipose tissue development?

To facilitate the differentiation of stem cells into adipocytes Signup and view all the answers

How does stimulation by noradrenaline affect brown adipose tissue?

It activates lipolysis and fatty acid oxidation Signup and view all the answers

Which statement best describes the prevalence of brown adipose tissue in humans as they age?

It decreases as humans age Signup and view all the answers

What determines the 'brown' appearance of brown adipose tissue?

More iron-containing mitochondria Signup and view all the answers

What is the function of UCP1 (thermogenin) in brown adipose tissue?

It dissipates the proton gradient to produce heat Signup and view all the answers

Which of the following best describes pre-adipocytes?

They appear similar to stem cells yet are committed to an adipocyte lineage Signup and view all the answers

How do inflammatory cytokines contribute to hypertension?

By increasing reactive oxygen species and decreasing nitric oxide Signup and view all the answers

What effect does adiponectin have on blood pressure regulation?

Increases nitric oxide production Signup and view all the answers

Which statement reflects the relationship between leptin and hypertension?

Leptin stimulates the sympathetic nervous system Signup and view all the answers

Which component of the renin-angiotensin system does adipose tissue produce most abundantly in obesity?

Angiotensinogen Signup and view all the answers

What role does angiotensin II play in blood pressure regulation?

It stimulates aldosterone production from the adrenal cortex Signup and view all the answers

Which of the following is a consequence of altered adipokine secretion in obesity?

Favoring of metastasis in cancer Signup and view all the answers

How does obesity influence cancer risk according to the content provided?

It increases the aggression of tumors Signup and view all the answers

What is one way that reactive oxygen species (ROS) affect nitric oxide levels in the context of hypertension?

They lead to the depletion of nitric oxide Signup and view all the answers

What is the role of leptin in cancer progression?

Encourages angiogenesis Signup and view all the answers

How does adiponectin affect cancer risk?

Promotes anti-angiogenic effects Signup and view all the answers

Which characteristic is associated with tumors that have increased leptin receptor levels?

Poor prognosis Signup and view all the answers

What is the significance of neovascularization in tumor development?

Facilitates metastatic spread Signup and view all the answers

What phenomenon occurs during adipocyte hypertrophy?

Release of pro-inflammatory cytokines Signup and view all the answers

What impact does inflammation have on cancer progression?

Enhances aggression and metastasis Signup and view all the answers

In the context of obesity, what change occurs in adipocyte secretory profiles?

Alterations due to nutritional status Signup and view all the answers

What does hypoadiponectinemia indicate in cancer patients?

Aggressive disease phenotype Signup and view all the answers

Study Notes

Endocrine Aspects of Obesity

Obesity is the most common nutrition-related disorder in the western world and developing nations
It reduces life expectancy due to increased risk of associated diseases.
Adipose tissue was previously seen as an energy source with large amounts of triacylglycerol.
Adipose tissue is now recognised as an important endocrine tissue.
Its secretory profile is disturbed in obesity.

Aim

To understand the roles of adipose secretion of cytokines and hormones in the development of insulin resistance, metabolic syndrome, inflammation, hypertension, cardiovascular disease, and cancer.

Objectives

Explain the risks associated with obesity
Describe examples of how mouse models of obesity have improved understanding of appetite and energy expenditure control
Appreciate the importance of adipose tissue, illustrated by lipodystrophies
Understand the potential importance of subcutaneous and visceral adipose tissue in metabolic syndrome
Understand how adipocyte behavior changes during adipogenesis and hypertrophy.
Explain the contributions of adipokines (leptin, adiponectin and inflammatory cytokines) to insulin resistance, hypertension, cardiovascular disease, and cancer.

Risks of Obesity

Obesity with BMI ≥ 30 kg/m² is associated with increased risk of type II diabetes, hyperinsulinemia, glucose intolerance, hypertension and stroke, coronary heart disease, and some cancers (breast, endometrial, ovarian, gall bladder, colon).

Metabolic Syndrome

Metabolic syndrome is a group of five risk factors that increase the likelihood of developing type 2 diabetes, heart disease, and stroke.
Risk factors include increased blood pressure (> 130/85 mmHg), high blood sugar levels (insulin resistance), excess fat around the waist, high triglyceride levels, and low levels of good cholesterol (HDL).

Genetic Mouse Models of Obesity

Much of current knowledge comes from preclinical research on laboratory mice and rats.
These models mimic aspects of human conditions, including complex gene-environment interactions and over-consumption of calories.

Genetic Mouse Models Detail

The Lethal yellow mutant mouse (AY): Unable to inhibit feeding.
The Obese mouse (ob/ob): Does not express leptin.
The Diabetic mouse (db/db): Does not express the leptin receptor.
The Fat mouse (fat/fat): Obesity develops slowly, not prone to diabetes, has hyper(pro)insulinemia but not hyperglycemia.

Lethal Yellow Mutant Mouse (AY) Details

Carries a lethal gene (mutant agouti gene Av) causing death in homozygous individuals.
Causes ectopic expression of agouti protein, normally expressed by follicular melanocytes, altering pigment production.
Ectopic expression chronically antagonizes hypothalamic neurons (inhibiting feeding), disabling feeding inhibition.
Exhibits: yellow coat color, obesity, hyperleptinemia, insulin resistance, type II DM, tumor susceptibility.

The Obese Mouse (ob/ob) Details

Gains weight rapidly, becoming three times the size of control mice.
Lacks expression of leptin.
Leptin acts in the hypothalamus to depress appetite and affect insulin signaling.
Leptin absence causes insulin resistance.
This mouse model exhibits T2DM: develops high blood sugar despite high insulin levels.
Leptin administration reduces weight in these mice, plus those with obesity due to leptin deficiency.

The Diabetic Obese Mouse (db/db) Details

Large/obese with increased fat deposition and hyperglycemia.
Does not express leptin receptor.
Its phenotype is identical to the obese mouse. Letipin administration is ineffective.

Diet-Induced Obesity

Some animal studies use specific diets to induce obesity, such as high-fat diets (58% of Kcal from fat) and cafeteria diets (high-salt, high-fat, low-fiber, energy dense, palatable foods).
Mice fed high-fat diets show impaired glucose tolerance (early-stage type 2 diabetes), increased weight gain, modest hyperglycemia, and insulin resistance.
Cafeteria-fed mice exhibit greater weight gain, worse hyperglycemia, higher plasma FFA levels, more infiltrating macrophages, and significantly altered pancreatic islets.

Traditional View of Adipose Tissue

Adipose tissue stores energy for later use.
Insulin stimulates glucose uptake for TAG synthesis, storing TAG in large droplets.
Low insulin/adrenaline ratio during fasting or exercise stimulates TAG lipolysis.
Released NEFAs enter the plasma as fuel for other tissues.

Insulin Signaling in Adipocytes

PI-3-K Pathway: Mediates immediate responses to insulin (e.g., Glut-4 translocation, glycogenesis, lipolysis inhibition). Shown as less active in insulin resistance.
MAPK Pathway: Mediates insulin's proliferative effects, unaffected by insulin resistance.

Brown Adipose Tissue

Primary function is thermoregulation through non-shivering thermogenesis.
Found in almost all mammals. Abundant in newborns and hibernating mammals, active in adult after cold acclimation.
Its prevalence decreases with age.
Adipocytes contain smaller multilocular TAG droplets and numerous iron-containing mitochondria giving it a brown appearance.
High capillary density supplies tissue with oxygen, nutrients and distributes heat throughout the body.

Brown Adipose Tissue mechanism

BAT is highly innervated by the sympathetic nervous system (SNS).
Noradrenaline stimulation activates lipolysis and fatty acid oxidation.
Proton gradient generated by electron transport chain dissipated via UCP1 (thermogenin), generating heat.

Adipose Tissue Development

PPARY (peroxisome proliferator-activated receptor-gamma) is a transcription factor needed for adipocyte differentiation, and adipogenesis.
Stem cells differentiate into adipocytes.
Pre-adipocytes express enzymes and receptors enabling lipid synthesis and insulin responsiveness; don't produce adipokines (except leptin); committed to adipocyte lineage.

Adipose Tissue development detail

PPARY is essential for adipocyte differentiation and adipogenesis.
Stem cells are pluripotent, capable of differentiating into various cell types.
Mature adipocytes express enzymes for lipid transport, synthesis, and have receptors and sensitivity to insulin.
Express adipokines: leptin, adiponectin, chemerin

Lipodystrophies

Disorders involving loss of adipose tissue from particular anatomical regions, genetic or acquired.
Affected patients often display aspects of metabolic syndrome; insulin resistance, dyslipidemia, and hypertension.
Symptoms sometimes relieved by administration of adipocytokines (leptin or adiponectin).

Familial Partial Lipodystrophy 3

Progressive loss of adipose tissue from extremities during puberty.
Etiology: PPARY gene mutation.
Clinical features: hypertriglyceridemia, low HDL, increased TAG deposition in the liver, severe insulin resistance, and resultant diabetes.

Distribution of Adipose Tissue

Two important depots:
Subcutaneous adipose tissue: Largest depot, protective.
Visceral adipose tissue: Most harmful.
Adipose tissue includes adipocytes, immune cells, and vascular tissue.
Adipokines are secreted by adipose tissue depots.

Visceral Adipose Tissue (VAT)

Excess VAT may indicate the subcutaneous fat's energy-sink capacity has been exceeded.
VAT is "hyperlipolytic," sensitive to adrenaline, and resistant to insulin signaling.
VAT products drain into the portal vein to the liver influencing liver metabolism (increased VLDL and glucose production).

Abdominal Adiposity

Waist circumference (or waist-to-hip ratio) is a simple indicator but cannot distinguish between abdominal subcutaneous fat and VAT.
CT scans provide more accurate discrimination of abdominal subcutaneous fat and VAT.
Exercise improves VAT and metabolic health, liposuction of subcutaneous fat does not.
Removal of VAT and glitazones (thiazolidinediones) can improve glucose and insulin levels.

Adipocyte Size

Hyperplasia: Increase in cell number, considered relatively healthy, increasing TAG storage capacity. Adipokines produced during hyperplasia are anti-inflammatory and insulin-sensitizing.
Hypertrophy: Increase in cell size, associated with problems. Adipokines are pro-inflammatory and insulin-desensitizing. Hypertrophy causes more cell death and macrophage recruitment, leading to inflammation.

Adipokines

Adipose tissue secretes over 50 adipokines, most of which are pro-inflammatory.
Obese individuals exhibit altered adipokine secretion patterns.

Adipokine Detail: Leptin

Secreted by mature adipocytes, reflecting body fat content; concentrated in hypothalamic feeding centers.
Leptin secretion fluctuates, increasing with overfeeding and decreasing with fasting in response to insulin.
Function: decreases appetite, increases energy expenditure, and has a pro-inflammatory effect.

Leptin Resistance

Obese individuals may have high leptin levels despite leptin resistance.
Impaired leptin transport across the blood-brain barrier, resulting in low leptin levels in the cerebrospinal fluid compared to plasma levels.
Downstream signaling issues may also contribute to leptin resistance.

Leptin's Other Effects

Plays a role in immunity, impacting immune system development.
Acts as a chemoattractant for macrophages, influencing inflammation.

Adiponectin

Acts as an anti-inflammatory cytokine; it inhibits TNF-α secretion by macrophages and facilitates insulin sensitivity of adipose tissue.
Low Adiponectin levels are associated with obesity, hyperinsulinemia, insulin resistance, and an increased risk for type 2 diabetes in the future.
Adiponectin levels increase with weight loss, exercise, and some synthetic ligands.

Inflammation in Obesity

Obesity is correlated with mild, persistent inflammation.
High levels of inflammation markers, like C-reactive protein, IL-6, IL-8, IL-1B, and TNF-α are observed in obese individuals.
The immune response is stimulated by immune cell recruitment and maturation. Weight loss leads to decreased inflammation marker levels.
Mechanism: Hypoxia in expanding adipose tissue causes adipocyte death, prompting macrophage infiltration and pro-inflammatory cytokine secretion.

Inflammation Mechanisms

Adipocyte death increases with adipocyte size, causing macrophage clustering around necrotic adipocytes.
This forms “crown-like” structures (CLS).
Pro-inflammatory cytokines in obesity: Leptin, Angiotensin, IL-6.
Anti-inflammatory cytokines: Adiponectin, IL-10.

Insulin Resistance

Inadequate response to normal insulin levels; elevated insulin levels required to maintain normal blood sugar levels.
Long-term, insulin resistance can result in pancreatic beta-cell failure and type 2 diabetes.
Inhibition of insulin signaling pathway by proinflammatory cytokines or phosphorylation in the signalling pathway leads to insulin resistance.
Insulin resistance correlates with lipid deposition in skeletal muscle and liver (ectopic lipid deposition).
TAG storage spills over into VAT, skeletal muscle, and liver.

Adiponectin and Insulin Resistance

Plasma adiponectin levels decrease with increasing obesity, correlating with insulin resistance and type 2 diabetes.
Conversely, decreased obesity correlates with increased adiponectin levels, leading to improved insulin sensitivity.

Hypertension

High blood pressure is a risk factor for cardiovascular disease (CVD).
Hypertension is correlated with obesity (increased BMI and abdominal obesity).
Weight loss can reduce hypertension.

Hypertension Mechanisms

Adipokine secretion is altered (e.g., leptin and adiponectin), impacting endothelial cells lining blood vessels, smooth muscle cells, and the renin-angiotensin system (RAS).
Inflammatory cytokines can act as vasoconstrictors or vasodilators influencing blood pressure regulation.
Decreasing NO production, increasing ROS, and stimulating vascular cell proliferation can cause vasoconstriction and contribute to hypertension.
Increased angiotensinogen production contributes as well.

Hypertension & CVD: Leptin/Adiponectin

Leptin can lead to increasing blood pressure due to stimulation of pro-inflammatory cytokines, SNS, and smooth muscle cell proliferation in obesity.
Adiponectin, on the other hand, regulates blood pressure by increasing NO, decreasing smooth muscle cell (SMC) proliferation, and reducing oxidative stress, thus potentially helping to lower blood pressure in obesity when levels are high.
Lower adiponectin levels correlate with hypertension in obesity.

Hypertension and RAS

The renin-angiotensin system (RAS) regulates blood pressure and balance.
Adipose tissue expresses RAS-components.
Angiotensin II stimulates adrenal cortex to produce aldosterone, regulating blood pressure through salt and water homeostasis.
More angiotensinogen is produced in obesity, notably by visceral adipocytes, contributing to hypertension in metabolic syndrome.

Obesity and Cancer

Obesity is linked with altered adipokine secretion and increased risk for some cancers.
Obesity increases risk of tumor aggression, greater metastasis numbers, and reduced chemotherapy/treatment efficacy & recurrence/mortality rates.

Adipokines and Cancer

Altered adipokine secretion, in particular leptin/adiponectin levels, can contribute to:
Neovascularization: Altered adipokines can act as growth factors, supporting cancer cell proliferation and angiogenesis (new blood vessel formation).
Adipose tissue produces substances that favor metastasis (e.g., Hepatocyte Growth Factor).
Metastasis: Adipose Tissue appears to promote metastasis through the production of factors such as HGF.

Plasma Leptin/Adiponectin and Cancer

Leptin: increased in cancer patients; promotes angiogenesis, inhibits apoptosis.
Tumors with more leptin receptors correlate with poor prognosis.
Adiponectin: Decreased in cancer patients; inhibits cell growth, promotes apoptosis, and inhibits angiogenesis. Low levels correlate with increased cancer risk and progression, suggesting that hypoadiponectinemia may indicate an aggressive cancer phenotype; inflammation is also correlated.
Exercise during/after cancer treatment may improve survival rates.

Summary of Adipose Tissue and Endocrine Role in Obesity

Adipocytes store TAG but are endocrine tissues that alter whole-body metabolism during obesity.
Adipocyte secretion patterns are affected by nutritional status, location, size, and other signaling molecules.
Hypertrophy rather than hyperplasia stimulates pro-inflammatory cytokine secretion, contributing to insulin resistance in obesity.
Altered adipokine secretion patterns are a significant factor contributing to many metabolic problems associated with Obesity and Metabolic Syndrome.

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Description

Test your knowledge on the physiological effects of obesity, insulin resistance, and their relationship with adipokines. Explore how these factors influence lipid deposition, appetite regulation, and inflammatory responses in the body. This quiz covers various aspects of obesity-related metabolic changes and the role of adipose tissue.