26: Obesity & 28: Metabolic Syndrome (share objectives) Flashcards
Definition - Learn how obesity is defined and measured.
Global obesity = BMI = kg/m^2
- > 25 overweight
- > 30 obese I
- > 35 obese II
- > 40 severe obese
Regional obesity:
- waist circumference–visceral or abdominal fat
- waist to height ratio
- body shape index
In prehistory, metabolism in the human body was shaped between the winter & summer seasons. In summer, food is abundant & serum glucose is high–so energy supply is more than what is needed. Therefore, we store excess energy in the form of lipids in white adipose tissuesince blood glucose is high. In winter, food becomes limited; therefore, the storing mechanism is very important to be able to mobilize fat stores in winter. Evolution has stored the ability to store energy in summer & mobilize this energy in winter.
Unlimited food supply + sedentary lifestyle + optimal temperature (air conditioning) = obesity, & obesity leads to metabolic syndrome.
Scope & causes - Appreciate the scope and causes of the obesity problem. Why is obesity a problem?
Causes of obesity:
- Environment: nutritional abundance & sedentary lifestyle
- Genetic: polygenic (no single gene determines obesity)
Obesity is a big problem–it is an epidemic & it is an economic burden.
90% of people who lose weight via dieting gain it back.
Complications - Appreciate the complications of obesity (and especially of visceral adiposity).
It is a risk factor for many other clinical conditions:
- psychological stress
- obstructive sleep apnea
- joint disease, gallbladder disease, reproductive disorders, & 20% of cancer death
- CARDIOVASCULAR DISEASE
- Type 2 DIABETES***
Approaches - Appreciate the different approaches to the obesity problem within the medical profession.
Obesity is not a strictly biological problem, if it were, we would be able to correct it.
The lipostat hypothesis – Understand the concept of lipostat and its implications for the generally poor long-term success of weight-loss diets.
Lipostats work like thermostats, keeping weight around a set point.
Lipostats have 3 components:
- Signal = leptin. Leptin is a hormone-like protein released by adipose.
- Sensor (brain) = leptin receptors in hypothalamus
- Effectors (brain): storage–effector controls feeding & energy expenditure. Effectors are in hypothalmus.
- Orexigenic effector promotes feeding
- Anorexigenic effector suppresses feeding
However, in obesity, the over-nutrition can increase the set point. Or lipostat resetting can lead to obesity.
Know how leptin acts to control appetite and energy expenditure.
Leptin inhibits orexigenic (feeding) neurons & stimulates anorexigenic neurons. Hence, Leptin action suppresses appetite and burns fat stored in adipose tissue.
Leptin deficient mice (ob/ob genotype) & people behave as if starved so they have an increase in weight & body fat. ob gene is expressed in adipocytes only. Injections of leptin into ob/ob mice decrease feeding, increase energy expenditure & decrease body weight = effects are reversible.
db/db genotype mice do not produce leptin receptors. db gene is expressed in hypothalamus = brain region that controls feeding. Product of db = membrane receptor.
@ a stable weight leptin makes it so food intake = energy expenditure
When decrease in body fat, leptin decreases (since from fat) & food intake > energy expenditure
When there is an increase in body fat, leptin increases & energy expenditure > food intake
In obesity* body fat increases, leptin increases, set point is raised, & food intake = energy expenditure
Therefore, once a person has become obese, the lipostat is reset, which robustly defends the obese state & resists weight loss. In other words, the lipostat defends the reset body weight in obesity.
What causes lipostat resseting? Overnutrition over a long period of time.
Can we pharmacologically control the lipostat?
Know how ghrelin acts to control appetite and energy expenditure.
Ghrelin is produced by empty stomach (when starved). It is an appetite stimulant.
Appreciate the importance and implications of leptin resistance.
Possible issues in the leptin regulatory loop that could be involved in obesity:
- Leptin deficiency is a rare genetic ilness.
- Leptin is produced but cannot leave adipocyte
- Leptin resistance – leptin levels are normal but brain is not sensitive to leptin anymore. This is most likely. This is the main factor contributing to obesity.
As people have more body fat, leptin levels are higher! Therefore, chronic over-nutrition could affect the ER & give mitochondrial damage which can make hypothalamic neurons resistant to leptin so they cannot sense it anymore which leads to obesity. Thus, clinical trial with leptin do not help, since levels already high in obese people.
Brown fat tissue, membrane uncoupling and adaptive thermogenesis - Appreciate the importance of UCP1 in brown fat tissue for energy dissipation and expenditure.
Adaptive thermogenisis = shivering thermogenisis in response to cold. It is subject to hormonal regulation & it involves uncoupling proteins in the mitochondrial inner membrane.
Adaptive thermogenisis is promoted by brown fat. White fat is for storage. Brown fat is rich in mitochondria & can generate heat using ATP. White fat cells can almost be turned into brown fat cell in a process called browing by increasing the number of mitochondria, there are called beige fat cells.
Complexes 1, 3, & 4 pump proteins out of mitochondrial inner membrane & create a proton electrochemical gradient. Protons then go down & give energy to ATP synthase to make ATP.
20 - 25% of the proton gradient is lost & not coupled with ATP synthesis–this is called uncoupling. There are uncoupling proteins in the membrane like UCP1 (uncoupling protein 1). A proton can go through UCP1 & out of inner membrane without being coupled to ATP synthesis. Dinitrophenol is also an uncoupler.
UCP 1 promotes re-entry of protons into the mitochondrial matrix which generates heat. It is an acid-proton symporter. This occurs in brown fat (not abundant in adults, more in kids). Amount of brown fatty tissue correlates inversley with BMI–so high brown fat = low BMI = skinny. It allows leaking of protons from mitochondrial intermembrane space into the matrix.
Activators of UCP1 that increase uncoupling:
- fatty acids
- B3-adrenergic receptors stimulate lypolysis & FA release = transcription factor (unsuccessful)
- Thyroid hormone receptor = transcription factor (unsuccessful)
- PPARy
- Exercise increases the browning of fat! This increases the number of mitochondria in the fat & increases the amount of uncoupling. Turns white fat into beige fat.
Appreciate key endocrine functions of adipose tissue.
Adipose tissue has endocrine function with leptin.
Leptin is one of the most important adipose-derived hormones.
Know the hallmarks of the Metabolic Syndrome.
Metabolic syndrome is a cluster of pre-clinical metabolic changes associated with obestity. Obesity causes metabolic syndrome & metabolic syndrome causes type 2 diabetes. Metabolic syndrome is sometimes called pre diabetes.
Metabolic syndrome has interplay between adipocytes, muscle, liver, & brain.
Risk factors for insulin resistance & metabolic syndrome = obesity, mitochondrial damage, nutritional factors, visceral fat.
Know how insulin resistance is manifested in skeletal muscle, liver and adipose tissue.
In normal people: the pancreas releases insulin which reduces blood glucose. Insulin signal is sensed by skeletal muscle & the muscle takes up glucose–skeletal muscle consumes 90% of glucose in body. Liver senses insulin also & it begins glycogen synthesis & reduces gluconeogenisis.
In obese people, something is released in white adipose tissue that inhibits insulin signaling in muscle or liver. It impairs the utilization of glucose. The culprits are 1) NEFA (non esterified fatty acids) & 2) cytokines. So excessive adipocyte releases these in high quantities & inhibits insulin signaling.
Hallmarks of metabolic syndrome:
- visceral obesity
- hyperglycemia
- insulin resistance
- dyslipidemia (TG goes up & HDL goes down)
- Hypertension
Hyperglycemia, insulin resistance, & dyslipidemia (TG goes up & HDL goes down) cause B-cell damage & type 2 diabetes.
Mechanism of insulin resistance - Understand the lipotoxicity and low-grade inflammation theories of insulin resistance.
Insulin resistance is the failure of blood glucose levels to decline, despite the presence of elevated levels of insulin. Insulin resistance is measured by glucose tolerance test (measuring rate of clearance of glucose @ defined insulin level) & fasting insulin level.
There is insulin resistance in adipose. Consequences are decreased glucose uptake, decreased LP lipase, decreased TG storage, decreased adiponectin & increased lipolysis (NEFA) & increased cytokines. There is decrease glucose uptake & decrease glycogenisis & liver.
Adipose tissue is an endocrine organ. It releases Leptin & Adiponectin. Adiponectin is high in normal people but low in obese people. In normal people there are higher amount of macrophages.
NEFA (DAG) is increased in obesity & increases FFA from adipocytes & decreases Adiponectin. Increased cytokines cause systemic inflammation.
There are 2 mechanisms of insulin resistance:
1) Lipotoxicity theory = excessive adipose tissue & reduced adiponectin leads to increased NEFA (DAG)
2) Low-grade systemic inflamation theory = excessive adipose tissue leads to increased cytokines
Both cause insulin dependent glucose disposal.
Exercise – Appreciate the importance of exercise and its underlying biological mechanisms for treating obesity and Metabolic Syndrome.
Browning of white adipose is induced by EXERCISE, by a peptide myokine called Arisine. Arisine converts white fat into brown via browning & then UCP 1 expression goes up & increases energy expenditure & glucose homeostasis by making body sensitive to insulin again.
Drug targets - Become aware of some targets for discovery of drugs to treat obesity and Metabolic Syndrome.
First drug used was dinitrophenol uncoupler. It pokes hole in mitochondrial inner membrane & dissapates the gradient. But it was withdrawn with servere side effects. Amphetamines were once used to treat obesity.
Important recent drugs that are currently used:
- Lorcaserin
- Qsymia/ Belviq = phenterminine + topiramate = appetite supressant which affects hypothalamic signaling
Therapeutic stratedies of treating metabolic syndrome & type 2 diabetes:
- Increasing AMPK by Metformin
- Remodel lipid metabolism & decrease circulating NEFA (increase PPAR transcription factors by drug Fibrate). Make cells more insulin sensitive.
- Remodeling adipogenisis by shifting visceral to non-abdominal fat (subcutaneous fat). Drugs pioglitazone or Thiazolididinedione.
- Increase energy expenditure by browning white fat or by uncoupling muscle mitochondria (he likes this one)–turning white fat into brown fat. Browning of white adipose is induced by EXERCISE, by a peptide myokine called Arisine. Arisine converts white fat into brown via browning & then UCP 1 expression goes up & increases energy expenditure & glucose homeostasis by making body sensitive to insulin again.
