Pathophysiology of Obesity and Dyslipidemia Flashcards
What is BMI? How is it measured?
Body Mass Index – relationship between a person’s height and weight
BMI = weight in KG/height in m^2
Can BMI diagnose body fatness and health?
No, it is used as a screening tool that can give us insight
What is Class I obesity in adults?
In adults, a BMI of 30.0 - 34.9 is class I obesity
What is obesity in children and adolescents?
BMI > sex-specific 95th percentile
Why is BMI not used for children under 2 years old?
Weight-for-length growth charts are used for them
Children can “outgrow” high BMI
There is no evidence for treating weight that is considered high in children under 2 years old (can be an important sign)
Is obesity a disease? What else can it be considered?
It was declared a disease
Some say it is a risk factor for other diseases
What are some examples of genetic problems that can lead to obesity?
Monogenetic causes (leptin gene mutations)
Prader-Willi Syndrome (Chromosome 15 defect) that causes constant hunger and uncontrollable eating
How significant are the obesity-related gene variants (SNPs) that have been found?
There is a link between these genes and obesity, but we must also take into account environmental factors.
Example: physical activity and/or a healthy diet can counteract the risk associated with variations in the FTO gene
Describe how gut microbiota affects obesity
There is decreased gut microbial diversity in obese people compared to lean people
There is a bi-directional relationship between diet and the microbiome
Describe the “thrifty gene” hypothesis of obesity
In times of fluctuating food availability, weight was gained when food was plentiful, and those energy stores were used when food was scarce
In the face of constant plentiful food supplies, this becomes maladaptive
What are some environmental factors that contribute to the pathophysiology/prevalence of obesity?
Abundance of foods filled with sugar, fat, and salt
Food industry that understands food desire and psychology (sweetened drinks, high fructose corn syrup)
Increased portion sizes
Proliferation of fast-food outlets
Food deserts (no fresh produce)
More sedentary occupations and lifestyles
What do adipocytes do?
Store fats (in the form of triglycerides)
Release triglycerides to be used for energy/fuel when needed
What happens to adipocytes under conditions of energy excess?
They proliferate (hyperplasia)
Hypertrophy occurs (a maladaptive response to energy excess!!)
What is adiposopathy? What happens in adiposopathy?
Combination of hypertrophy of adipocytes, visceral fat accumulation, and other markers. AKA “sick fat”
Adipocytes become so large that their diameter exceeds the diffusion limit of oxygen –> hypoxia
This can then result in necrosis, which attracts macrophages and promotes chronic inflammation
What are the two main patterns of fat deposition?
Primarily on the trunk –> central obesity // apple shape
Primary on the hips and limbs –> peripheral obesity // pear shape
What is ectopic fat? Why/how is it formed?
Fat store in, on, and around organs
If the capacity of adipocytes to store fat is exceeded, fat will be deposited elsewhere
What is visceral fat?
Internal abdominal fat
Intra-abdominal, mostly in the mesentery
Ectopic
What is subcutaneous fat?
Fat found under the skin
Which type of fat is hormonally active and more inflammation-promoting?
Visceral fat
What are adipose tissue’s endocrine functions?
Release cytokines that can promote insulin resistance, inflammation, hypertension, atherosclerosis, and thrombosis
Can also create conditions that promote obesity
What is leptin? What does it do?
Hormone that:
Increases satiety and energy expenditure
Increases insulin sensitivity
What happens to leptin in a state of obesity?
Increased/hypertrophied adipocytes can lead to overproduction of leptin –> leptin resistance
The body and brain fail to respond to leptin which affects satiety and energy expenditure
It is considered an overall pro-inflammatory cytokine
What is adiponectin? What does it do normally?
Normally stimulates the production of nitric oxide in the vasculature –> increases anti-atherogenic activities (considered anti-inflammatory)
What happens to adiponectin in obesity?
As fat mass increases, the amount of adiponectin decreases –> promoting atherogenesis
Hypertrophied adipocytes inhibit adiponectin gene transcription
What does resistin do?
Increases insulin resistance?
What is MMCP-1? What does it do?
Macrophage and Monocyte Chemoattractant Protein-1
Promotes inflammation by activating macrophages resident in adipose tissue
Also increase insulin resistance
What does TNF-alpha do?
Promotes inflammation and increases insulin resistance
What does plasminogen activator inhibitor-1?
Inhibits the breakdown of fibrin clots –> pro-thrombotic
What does IL-6 do?
Promotes inflammation
Increases insulin resistance
Increases hepatic lipid and glucose production
What is the RAAS system’s role in obesity?
Components of it such as Angiotensin II and aldosterone have been found in adipose tissue –> hypertension
What role do excess free fatty acids (FFA) have in obesity?
Overwhelm normal metabolic pathways –> toxic intermediates that interfere with normal insulin signaling and muscle glucose transporter functions
Contribute to insulin resistance
Attract macrophages –> inflammation
Describe dyslipidemia in obesity
Low HDL (“good cholesterol”)
High LDL (“bad cholesterol”) –> pro-atherogenic
Describe cardiovascular disease in obesity
Pro-inflammatory, prothrombotic and atherogenic
Increased waist circumference (indicator of visceral obesity) is a better measure of risk than BMI
Stroke in obesity
Prothrombotic and atherogenic
Sleep apnea in obesity
Increased upper airway pressure
Reduced chest compliance related to truncal fat deposition
Causes sleep deficit in patients which can result in decreased leptin and an increase in ghrelin (appetite stimulant)
What is NAFLD?
Non-alcoholic Fatty Liver Disease
Fat droplets accumulate in the liver cells, causing swelling and damage to the liver
How does obesity increase the risk of severe illness from COVID-19?
Linked to impaired immune function
Decreases lung capacity, makes ventilation more difficult
Obese children have a higher risk of developing _____
Diabetes
NAFLD in children
Has been reported in young toddlers
Is now the number one cause of chronic liver disease in children
7-%-80% of obese children have NAFLD or NASH (later progressive form)
What are some treatment options for obesity?
Diet - change eating habits
Increased physical activity
Counseling (trauma-informed treatment)
Medication
Surgery
What is metabolic syndrome (MetS)?
A constellation of signs that increases the risk of cardiovascular disease
(central obesity, dyslipidemia, increased BP, hyperglycemia)
How do you diagnose/define MetS?
At least 3 of the 5 characteristics:
- Large waist size (central obesity marker)
- Triglycerides > 150 mg/dL
- Decreased HDL
- High BP (>130/85 mm Hg)
- Fasting blood glucose > 100 mg/dL
Why should we care about MetS?
Indicates that the person is at high risk for cardiovascular disease, diabetes, dyslipidemia, and other diseases
Where does fat come from? (Glucose)
An intake of glucose greater than the body needs
Not-stored glucose (excess) is delivered to the liver and metabolized to acetyl CoA and used to synthesize triglycerides and cholesterol
The liver packages triglycerides and fatty acids into VLDL (a type of lipoprotein)
Adipose cells take up glucose via GLUT-4 and can use that to synthesize triglycerides as well
Where does fat come from? (Dietary fat)
Absorbed dietary fats, primarily in the form of triglycerides
Chylomicrons are synthesized in the GI tract and enter the GI lymph vessels, travel to the thoracic duct to enter the bloodstream
They travel in the circulation to deliver triglycerides to the tissues:
- Liver: uses triglycerides to synthesize other lipoproteins
- Adipose tissue: triglycerides broken down by lipoprotein lipase –> fatty acids diffuse into the adipocytes and triglycerides are synthesized
What is lipoprotein lipase? What does it do?
Sn enzyme found on vascular endothelial cells
Breaks down triglycerides from VLDLs and chylomicrons into FA that can diffuse into adipocytes and re-form into triglycerides with glycerol
Describe a lipoprotein’s general structure. How does its structure help it carry out its tasks?
Protein membrane surrounding a core of lipids
Non-polar/hydrophobic core of triglycerides and cholesterol esters surrounded by a hydrophilic shell of phospholipids
The shell allows for lipoproteins to travel in plasma
Transport cholesterol, triglycerides, and other lipids
What is a chylomicron?
Lipoprotein that carries triglycerides from dietary intake from the GI system to the liver and other tissues
What is VLDL?
A lipoprotein that primarily delivers triglycerides to tissues
What is LDL?
A lipoprotein that primarily delivers cholesterol to tissues.
Plays a role in atherogenesis in blood vessels
Known as “bad cholesterol”
What is HDL?
A lipoprotein that carries out “reverse cholesterol transport”
Brings cholesterol back to the liver
Known as “good cholesterol”
How is LDL-C recycled?
The LDL-C molecule and its receptor are endocytosed by the liver
The molecule is broken down by the liver and its receptor is returned back to the surface of the hepatocyte to take up more LDL-C from the blood
Describe a blood lipid panel of a person with Dyslipidemia
High triglycerides
High VLDL or LDL
Low HDL
How can dyslipidemia lead to insulin resistance? What does insulin resistance lead to?
Excess fatty acids circulating can lead to insulin resistance
Insulin resistance can then lead to inadequately suppressed glucagon secretion which can activate adipose tissue hormone-sensitive lipase and inhibit lipoprotein lipase, increasing VLDL levels
How does dietary cholesterol contribute to dyslipidemia?
It can vary from person to person
Overall, excess dietary cholesterol seems to contribute to dyslipidemia
50% of dietary cholesterol is absorbed, the rest is excreted
Contributes to about 5% of total serum cholesterol
Familial Hypercholesterolemia Summary
Monogenic, autosomal dominant disease
Mutation in the gene that codes for the LDL-C receptor that the liver uses to remove LDL-C from the bloodstream, resulting in reduced clearance of LDL-C in the circulation
May be first diagnosed when a very young person has a MI
