Obesity PathophysiologyandDyslipidemia

What about dietary cholesterol?

- About 50% of dietary cholesterol is absorbed; remainder is excreted. - Dietary cholesterol is thought to contribute about 5% to total serum cholesterol. - Contribution of dietary cholesterol to dyslipidemia - particularly elevated LDL-C -- can vary from person to person, but overall, excess dietary cholesterol seems to contribute to dyslipidemia. *As we will see, drugs that block absorption of dietary cholesterol do decrease LDL-C levels.

Where does fat come from, anyway?

1. Intake of glucose greater than body needs: - Liver uses some glucose for immediate needs and stores some in the form of glycogen. - Most of the remaining glucose delivered to the liver is metabolized to acetyl CoA and is used to synthesize triglyceride and cholesterol. The liver packages triglycerides and fatty acids into VLDL, a type of lipoprotein. - Adipose cells take up glucose via GLUT4, and use it for their own energy needs, but also to synthesize triglycerides.

Metabolic Syndrome = at least 3 of the following 5 characteristics

1. Male waist size > 102 cm (40 in.) marker of Female waist size > 88 cm (35 in.) central obesity 2. Triglycerides ≥ 150 mg/dL 3. Male HDL ("good cholesterol") < 40 mg/dL Female HDL < 50 mg/dL 4. Blood pressure ≥ 130/85 mm Hg (HTN) 5. Fasting serum glucose ≥ 100 mg/dL

Where does fat come from, Cont.

2. Absorbed dietary fats, primarily in the form of triglycerides. Lipoproteins known as chylomicrons - composed largely of triglycerides -- are synthesized in the GI tract and enter the GI lymph vessels, travel to the thoracic duct to enter the bloodstream. Chylomicrons travel in the circulation to deliver triglycerides to the tissues, especially - The liver, which uses triglycerides, along with cholesterol, to synthesize other lipoproteins. - Adipose tissue, where triglycerides are broken down by lipoprotein lipase --> fatty acids diffuse into the adipocytes and triglycerides are resynthesized.

Epidemiology of Obesity

According to the World Health Organization, there were > 1.9 billion adults worldwide who were overweight in 2016, > 650 million of whom were obese. - 39% of adults aged 18 years and over were overweight in 2016, and 13% were obese. - Most of the world's population lives in countries where overweight and obesity kills more people than underweight, although both may co-exist in the same country. - 41 million children under the age of 5 were overweight or obese in 2016. --> This includes high, middle and low-income countries, especially in urban areas. The worldwide prevalence of obesity nearly tripled between 1975 and 2016.

Is Obesity a Disease?

AMA declared it is a disease in 2013. Still controversial. - Some say it is simply a risk factor for other diseases.

Epidemiology of Obesity

According to US National Health and Nutrition Examination (NHANES) data, 69.5% of adult Americans 20 years or older were classified as either overweight or obese as of 2016. -3 9.6% of Americans were classified as obese as of 2016. - Compare this to 15% of Americans who were classified as obese in the 1976-1980 survey. - 7.7% of Americans classified as obese had BMI ≥ 40 Approximately 18.5% of children & adolescents (ages 2-19) in the US were classified as obese as of 2016; 5.6% were classified as "severely obese".

Pathophys - adipose tissue

Adipose tissue (white)*: - Hyperplasia versus hypertrophy of cells - Subcutaneous versus visceral Adipocytes and adipose tissue are key to understanding both the pathophysiology and many of the sequelae of obesity Adipocytes: - store fats, in the form of triglycerides. - release triglycerides (in broken-down form) to be used for energy/fuel when needed. Under conditions of energy excess (energy intake > energy need), adipocytes can either: - Proliferate (increase in number; i.e., hyperplasia); or - Hypertrophy. Hypertrophy is considered a maladaptive response to energy excess.

Pathophysiology, continued - Hormones

Adipose tissue produces multiple hormones and cytokines that promote insulin resistance, inflammation, hypertension, atherosclerosis and thrombosis [effx of adipsopathoy] and also create the conditions that promote the development and maintenance of obesity: Leptin: Main function is to increase satiety and energy expenditure. It also increases insulin sensitivity. However, under conditions of increased and/or hypertrophied adipocytes, too much leptin is produced --> "leptin resistance", where the brain and body fail to respond to leptin as they should. Adiponectin: Normally increases nitric oxide in the vasculature, which then increases the anti-atherogenic activities of the vascular endothelium (helps prevent atherogenesis). But as fat mass increases, the amount of adiponectin decreases, thus promoting atherogenesis. - Hypertrophied adipocytes play a role, as their large size --> induction of transcription factors that increase transcription of genes coding for angiogenic growth factors and that inhibit adiponectin gene transcription . *Atherogenesis = the formation of subintimal lipid-containing plaques (atheromas) in the lining of arteries. We will discuss this more in the cardiac lectures. Resistin: Increases insulin resistance. Macrophage and Monocyte Chemoattractant Protein-1 (MMCP-1): Promotes inflammation by activating macrophages resident in adipose tissue. Also increases insulin resistance.

Pathophysiology, cont- Adipose Tissue Endocrine Functions

Adipose tissue: It's way more than organ cushioning or an energy storage locker! - Endocrine functions: release cytokines/adipokines - Receptors for those same cytokines and other hormones provide a feedback mechanism.

In 2013-2016, 36.6% of adults consumed fast food on a given day

Age 20-39 eats the highest % of fast food. Most common meal eaten as fast food is lunch (43.7%), followed by dinner (42.0%), then breakfast (22.7%) and snacks (22.6%). Notice those figures add up to well over 100% -- what does that mean? "Food deserts" in inner cities, where there are no grocery stores selling fresh produce. More sedentary occupations and lifestyles (computers, smartphones, video gaming)

Clinical Manifestations and Sequelae

All-cause mortality is increased at both ends of the BMI spectrum (too little weight or too much weight), but rises especially fast as BMI ↑ over 35.

Definition of BMI and Obesity

BMI = Body Mass Index - Relationship between a person's height and weight BMI = body weight in kilograms/(height in meters)^2 Important to keep in mind, per the CDC: "At an individual level, BMI can be used as a screening tool but is not diagnostic of the body fatness or the health of an individual. A trained healthcare provider should perform appropriate health assessments in order to evaluate an individual's health status and risks."

LDL-C is recycled via receptors on hepatocytes

Both the LDL-C molecule and its receptor are endocytosed by the liver. The LDL-C 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.

Cont.

CONT: Adipose tissue produces multiple hormones and cytokines that promote insulin resistance, inflammation, hypertension, atherosclerosis and thrombosis and also create the conditions that promote the development and maintenance of obesity: TNF-α: promotes inflammation and increases insulin resistance. Plasminogen Activator Inhibitor-1: inhibits the breakdown of fibrin clots --> pro-thrombotic IL-6: promotes inflammation, increases insulin resistance and increases hepatic lipid and glucose production. Components of the RAAS system, especially Angiotensin II and aldosterone, have been identified in adipose tissue --> hypertension

Clinical Manifestations Sequelae Obesity in Children Treatment

Central or peripheral obesity - or both Dyslipidemia, including hypertriglyceridemia accompanied by low HDL (the "good cholesterol"), and smaller, denser LDL (the "bad cholesterol") particles that are more pro-atherogenic. Cardiovascular disease (pro-inflammatory, prothrombotic and atherogenic)

Epidemiology, continued

Certain populations have a greater predisposition to obesity: - Members of the Pima Indian tribe, as well as other Native American tribes - Pacific Islanders - African Americans - Latinos (especially those from Mexico and Puerto Rico) A greater percentage of women than men are obese. - Transwomen/DMAB who initiate estrogen hormone therapy tend to have an increase in total body fat and a decrease in lean body mass; the opposite happens in transmen/DFAB who initiate testosterone hormone therapy. The prevalence of obesity increases with advancing age until after age 60 and then begins to decline.

Obese children

Children who are obese: Have ↑risk of developing diabetes. Obese adolescents have > risk than those with adult-onset obesity. Obese adolescents have > risk of becoming obese adults. - Recent evidence indicates an obese 2-year-old has a 75% chance of being an obese adult. Develop NAFLD. - Has been reported in very young toddlers. - Is now the Number One cause of chronic liver disease in children. - Among obese children, 70-80% of them have NAFLD or its later progressive form, NASH Can have early evidence of atherosclerosis. 50% of severely obese adolescents have Metabolic Syndrome (discussed next)

Types of Lipoproteins

Chylomicrons carry triglycerides from dietary intake from the GI system to the liver and other tissues. VLDL primarily delivers triglycerides to tissues; made by liver LDL primarily delivers cholesterol to tissues. It plays a major role in atherogenesis in blood vessels. That's why it is called the "bad cholesterol"; made by liver but liver also has LDL-C receptor to take it out of the blood and back into the liver to prevent atherogenesis in blood - Considered "bad" cholesterol because it can migrate into the tunica intima layer of cardiovascular arteries and cause an inflammatory reaction. HDL carries out "reverse cholesterol transport" and brings cholesterol back to the liver. That's why it is called the "good cholesterol".

Pathophysiology of Obesity

Complex interaction of genetics, environment and metabolism: Genetic problems include - Monogenetic causes of obesity, such as mutations in the gene that codes for leptin - Prader-Willi Syndrome, a defect of Chromosome 15, which causes constant hunger and uncontrollable eating, among other clinical manifestations. *Photo: The ob/ob mouse on the left cannot produce leptin. It eats constantly. ob/ob mice are used in research on obesity, metabolic syndrome and diabetes.

Pathophysiology, continued

Currently, there are many other candidate genes suspected of playing a role in obesity. "Common obesity" is considered to be polygenic, with complex epigenetic influences. *Fig. 1 Loci associated with obesity-related phenotypes. In almost every human chromosome was found a locus linked to predisposition to obesity-phenotype (BMI, abdominal fat, fat percentage or extreme obesity).

Treatment of obesity

Diet - change eating habits Increased physical activity Counseling Medications Surgery

Why LDL Cholesterol is the "Bad" Cholesterol - More in the Cardiovascular Lecture

Don't worry about details. Don't look at pic Just know LDL is bad cholesterol because of X and causes plaque buildup etc

Dyslipidemia concepts

Dyslipidemia: Abnormal blood lipid panel consisting of: - High triglycerides and/or - High VLDL or LDL and/or - Low HDL - Term often used interchangeably with "hyperlipidemia", especially since we usually focus on elevated LDL and triglycerides

Pathophysiology, continued (evnt'al)

Environmental factors include: An abundance of foods filled with sugar, fat and salt and a food industry with an understanding of food desire and psychology. - Trend of increased calories from soda and sweetened fruit drinks. - Trend of increased use of high fructose corn syrup. Increased portion sizes, including "super sizing". Proliferation of fast food outlets, especially since the 1970s

Dyslipidemia concepts

Excess fatty acids can circulate, contributing to insulin resistance (hence getting type 2 diabetes is due to being "fatter" and thus you develop an insulin resistance) Insulin resistance - which can lead to inadequately-suppressed glucagon secretion -- may activate adipose tissue hormone-sensitive lipase (postabsorptive) and inhibit lipoprotein lipase (absorptive), increasing circulating VLDL levels - Hormone sensitive lipase promotes the lipolysis of triglycerides in adipose tissue into glycerol and free fatty acids, which are released into the bloodstream and taken up by the liver. ---> Compare this to lipoprotein lipase, which breaks down triglycerides from VLDLs and chylomicrons --> fatty acids that can diffuse into adipocytes and re-form triglycerides (with glycerol) *Once glycerol and free fatty acids are delivered to the liver, the liver can use (1) glycerol to perform gluconeogenesis and (2) free fatty acids to re-synthesize triglycerides and package them into VLDLs. The liver can also use fatty acids for fuel during times of carbohydrate deprivation --> formation of ketone bodies.

Before you grab that sugary drink...

Fructose is part of the disaccharide sucrose (table sugar = one glucose + one fructose). It is used in many commercially produced foods (as high-fructose corn syrup) and is much more likely to be converted to fat than glucose. In other words, fructose's biochemical metabolic pathway preferentially leads to lipogenesis.

Other theories of obesity pathophysiology

Gut microbiota: - Don't need to know. "Thrifty gene" hypothesis: - In times of fluctuating food availability, weight was gained when food was plentiful and then those energy stores were used when food was scarce. - In the face of constant plentiful food supplies, this becomes maladaptive. - See photo

Lipoproteins - packaged lipids for delivery throughout the body

HDL would sink the fastest in water; it has the highest density Chylomicron would float because it has more fat and fat floats

Pathophysiology, cont.

Hypertrophied adipocytes release lots of free fatty acids (FFAs). - Excess FFAs overwhelm normal metabolic pathways --> toxic intermediates that interfere with normal insulin signaling and muscle glucose transporter (GLUT4) functions. - Excess FFAs contribute to insulin resistance. - Excess FFAs also attract macrophages --> macrophages release TNF-α --> increased inflammation Basically your visceral fat cells can get so sick they hypertrophy and become necrotic and explode and inflammation occurs making macrophages and TNFa to worsen the inflammation and all of this makes you insulin resistant

Pathophys - adipose tissue

Hypertrophy of adipocytes, in combination with visceral fat accumulation, and other markers, is called adiposopathy, or "sick fat". - Adipocytes can become so large that their diameter exceeds the diffusion limit of oxygen, resulting in localized hypoxia. This may --> necrosis (sometimes apoptosis), which attracts macrophages and promotes chronic inflammation. The person will become visibly "fatter". 2 main patterns of fat deposition: - Primarily on the trunk, known as "central obesity" --> apple shape - Primarily on the hips and limbs, known as "peripheral obesity" --> pear shape If the capacity of adipocytes to store fat is exceeded, fat will be deposited elsewhere, including in, on and around lean organs including the heart, kidneys and liver. - Fat stored in, on and around organs is known as ectopic fat.

Pathophysiology, continued

In 2007, researchers using GWAS identified the first obesity-related gene variants (SNPs) in the FTO gene; often called the "fat mass and obesity-associated" gene. These gene variants are fairly common (remember the definition of SNPs), and people who have one of the variants have a 20 to 30 percent higher risk of obesity than people who do not. Genetics is not destiny, however. Some studies have found that physical activity and/or a healthy diet can counteract the risk associated with variations in the FTO gene.

Epidemiology, continued

In general, the southern and midwestern states have higher rates of obesity than the rest of the US. The trend of obesity in the US has been relentlessly upward.

Lipoproteins - General Structure

Lipoprotein = Any of a number of complex molecules that consist of a protein membrane surrounding a core of lipids. - Lipoproteins transport cholesterol, triglycerides and other lipids - Generalized structure of a non-polar (hydrophobic) core of triglycerides and cholesterol esters surrounded by a hydrophilic shell of phospholipids, non-esterified cholesterol and apoproteins. - The hydrophilic shell allows lipoproteins to travel in plasma.

The role of lipoprotein lipase

Lipoprotein lipase - enzyme found on vascular endothelial cells throughout the body, particularly in adipose tissue, breaks down triglycerides (in absorptive state) from VLDLs and chylomicrons into fatty acids that can diffuse into the adipocyte and re-form triglycerides with glycerol. Notice also that the adipocyte can uptake glucose, which feeds into the pathway for the synthesis of triglycerides.

Review: Familial Hypercholesterolemia

Most common form is: - Monogenic - Autosomal dominant - Mutation in the gene that codes for the LDL-C receptor that the liver uses to remove LDL-C from the bloodstream Results in: - Reduced clearance of LDL-C from circulation --> high levels of plasma LDL-C from birth - Increased uptake of oxidized LDL into coronary arterial intima, increased foam cell formation, increased atherosclerotic plaque formation - Coronary artery calcification can be seen in patients as young as 11 years old. May first be diagnosed when a very young person has a myocardial infarction.

Metabolic Syndrome

Normal-weight people can have MetS; obesity (as measured by waist size) is just one marker. Approximately 34% of adult Americans are estimated to have MetS. Why should we care about MetS? This bird will die before a person.

Triglyceride structure and synthesis

Not sure if we need to know this chat

Wait! So Glucose Becomes Lipids? Yep. Who knew? Our patients need to know!

Notice how lipolysis (shown here as tissue triglyceride hydrolysis), as well as glucose metabolism, generates Acetyl CoA.

Definition, continued

Obesity (adults) = BMI ≥ 30 - BMI ≥ 25.0 but ≤ 29.9 is classified as "overweight" - BMI ≥ 30.0 but ≤ 34.9 is considered "Class I obesity" - BMI ≥ 35.0 but ≤ 39.9 is considered "Class II obesity" - BMI ≥ 40.0 is considered "Class III obesity" (you will sometimes hear it referred to as "severe obesity", "morbid obesity" or "extreme obesity") - BMI ≥ 50 is sometimes called "super morbid obesity", but there is no general consensus about the term *You do not need to memorize all the classes of obesity and their associated BMIs. I do expect you to know that a BMI of at least 30.0 is considered "obesity".

Definition, continued

Obesity (children and adolescents, 2-20 years) = (BMI) ≥ sex-specific 95th percentile on CDC BMI-for-age growth charts. - BMI > 85th and <95th percentiles is classified as "overweight" - BMI > 99th percentile is "severe" or "morbid" obesity - "Extreme obesity" in children and adolescents = = BMI ≥ 120% sex-specific 95th percentile *Don't need to know chart; pay attention to bolded terms here

Metabolic Syndrome

Obesity is closely related to Metabolic Syndrome (MetS), but is not the same thing as MetS MetS is a constellation of signs (central obesity, dyslipidemia, increased BP and hyperglycemia) that increases the risk of cardiovascular disease. MetS does not have a standard definition. A widely-used definition defines a person as having MetS if they have 3 or more of the following 5 characteristics:

Clinical Manifestations and Sequelae

Sleep apnea (increased upper airway pressure, reduced chest compliance related to truncal fat deposition). - causes sleep deficit in patients --> ↓leptin and ↑grehlin, a hormone produced by the stomach which stimulates appetite. Gallbladder disease/gallstones, primarily from an accumulation of cholesterol. Increased joint stress, resulting in osteoarthritis and joint dysfunction Nonalcoholic Fatty Liver Disease (NAFLD); fat droplets accumulate in the liver cells, causing swelling and damage to the liver. Estimated that up to one-third of the US population has NAFLD; 90% of morbidly obese people have it. We will cover NAFLD in detail during the Liver lecture, so for now, just know that NAFLD is a potential sequela of obesity. More on NAFLD in the liver diseases lecture.

Clinical Manifestations and Sequelae

Stroke (prothrombotic and atherogenic) Insulin resistance or frank diabetes (multiple hormones and cytokines released by adipocytes, plus excess FFAs, promote insulin resistance). Hypertension (increased Angiotensin II and aldosterone, decreased NO) Cancer *Don't need to memorize

Surgical Treament for Obesity:Metabolic/Bariatric Surgery

There are other types of metabolic/bariatric surgery. These are the 3 most common types you will see in your patients. a | The abdominal gastric band is an inflatable silicone band placed just below the gastro-oesophageal junction to create a small gastric pouch with a narrow stoma. A subcutaneous port, which allows adjustment of the tightness, is attached to the band. Frequent follow-up is essential to achieve the optimal band tightness for each patient. This procedure is technically easy, but weight loss is less than with other bariatric procedures. b | The sleeve gastrectomy involves placement of a staple line along the greater curvature of the stomach, followed by the removal of the closed stomach. This produces an elongation from the oesophago-gastric junction to the pylorus. This procedure is now among the most widely performed, and the weight loss is comparable to the Roux-en-Y gastric bypass. Good amount of weight loss, less complications. c | The Roux-en-Y gastric bypass involves laparoscopic division of the jejunum approximately 50 cm from the ligament of Treitz, and the proximal end of the jejunum is anastomosed to the distal part of the jejunum about 150 cm below the site of transection, producing a jejunojejunostomy. The resultant 150 cm Roux limb of the proximal jejunum is brought up and anastomosed to the small proximal gastric pouch, providing a volume of about 15-30 ml. This procedure is more technically demanding, but competes with the sleeve gastrectomy. Most weight loss, more complications.

Visceral adipose tissue

Visceral adipose tissue is pro-inflammatory; inc pro-inflamm adopkines (cytokines), IL-, TNF, etc Subcutaneous adipose tissue is anti-inflammatory

Pathophysiology, cont - Visceral vs. Subcutaneous Fat

Visceral: internal abdominal fat - Intra-abdominal, mostly in the mesentery, plus - Ectopic = fat stored around organs Central obesity ("apple") is often a strong indicator of underlying visceral fat. Subcutaneous: found under the skin. In general, visceral adipose tissue is more hormonally active and more inflammation-promoting than subcutaneous fat.

Metabolic Syndrome Origins of Fat Lipoproteins Dyslipidemia

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