Pathophysiology and Determinants of Obesity Flashcards
1
Q
What where the two important findings of the Framingham Heart Study regarding obesity?
A
- Physical activity to reduce the risk of heart disease and obesity to increase the risk of heart disease.
- Obesity is a risk factor for heat failure.
2
Q
What is obesity?
A
- Health & life expectancy adversely affected by excess body fat.
3
Q
How do we measure obesity?
A
- BMI = body mass index.
- “It works for most people, most of the time.” BMJ, 2018
- Well correlated with other measurements of body fat
- Widely employed in obesity studies
- Body mass (kg)/height (m)2 BUT…BMI is a good population metric but not so good for individual
assessment. - Waist circumference, waist to hip ratio better as a metric of adiposity, visceral fat in individuals. Waist circumference provides additional information, regarding, CARDIOMETABOLIC risk.
4
Q
What are the issues with gathering data regarding obesity?
A
- Self-reported data differs significantly from measured data.
5
Q
What are the 5 A’s of Obesity managment?
A
- Ask.
- Asses.
- Advise.
- Agree.
- Assist.
6
Q
What are the classes of Obesity?
A
- BMI 25-29.9 kgm-2: Over-weight
- BMI 30-39.9 kgm-2: Obese
- BMI >40 kgm-2: Morbidly obese
7
Q
What are the stages of Obesity?
A
8
Q
What do the stages of obesity provide insight into?
A
- How obesity may be impacting the health of an individual.
9
Q
Do BMI and waist circumference correlate?
A
- BMI correlates significantly with waist circumference.
- In mean and women, with and without metabolic syndrome.
10
Q
Does BMI correlate with body fat?
A
- The correlation starts to break down at the extremes.
- BMI doesn’t correlate with body fat as well in women.
11
Q
What is the relationship between visceral adipose tissue and waist circumference?
A
- Much more closely related.
12
Q
What is a high BMI a risk for?
A
- High BMI: major risk factor for chronic diseases, including cardiovascular diseases, cancer &
diabetes. - e.g. 90% people diagnosed with type II diabetes are obese (WHO).
- WHO: 2014 >600 million adults obese.
13
Q
What are the risks associated with obesity?
A
- Increased adiposity and obesity are associated with worse health outcomes in a variety of systems.
- Most immediate risks are cardiovascular: increased risk of atherosclerosis, hypertension, and associated morbidities like MI, stroke and heart failure.
- Increased risk of certain cancers,such as liver, kidney, colorectal, and pancreatic cancer.
- Increased risk of metabolic syndrome including dyslipidemia, insulin resistance, type-2 diabetes.
- Higher risk of liver disease, such as fatty liver and cirrhosis.
- Harder time with conception in women who are obese or overweight.
- Higher risk of obstructive sleep apnea.
- Increased risk of osteoarthritis due to pressure on joints.
- Cardiovascular risks increase with visceral adiposity.
14
Q
What causes obesity?
A
- Energy imbalance between calories
consumed & calories expended. - Body fat = Stored energy.
- Obesity occurs when homeostatic
mechanisms controlling energy balance become disordered or overwhelmed. - Calories taken in exceeds energy output.
But…it’s not “just physics”…
15
Q
What are the other factors that cause obesity?
A
- Genetics
- Exposure to obesity and diabetes in utero
- Family Hx of obesity and MetS, genetic predisposition for T2D - polymorphisms - Socioeconomics
- Where do they live?
- What kind of food can they afford?
- What job do they do, do they have time to cook, exercise? - psychology
- Depression, emotional eating, eating disorders - Sex
5.Ethnicity
- Predisposition to different types of adiposity and metS
- Cultural considerations - Age
- Increased age, increased risk of MetS
16
Q
What is the current view on obesity?
A
- Susceptibility to obesity largely determined by genetic factors, expression is determined by environmental factors.
- Social, environmental, psychological and economic factors contribute to susceptibility.
- Type of food eaten can disturb energy homeostasis.
- e.g. mechanisms regulating appetite respond slower to fat than protein, may consume more.
- Quantity of food can disturb energy homeostasis.
- e.g. if previously obese, need less calories to maintain weight than if never been obese.
- Increased energy expenditure has positive role in reducing fat storage & adjusting energy balance.
17
Q
What are the root causes of weight gain?
A
18
Q
How does obesity occur?
A
- Disturbance of homeostatic mechanisms.
- Genetic influence.
- Food intake & activity levels.
- Social, cultural & psychological aspects.
19
Q
What are the societal determinants of obesity?
A
- Diet: Shift in the “western diet”
- high energy density, low nutritional value at most affordable price points.
- Increased cost and in some cases reduced availability of fresh, whole foods. - Activity:
- Decreased physical activity due to increasingly sedentary nature of work, increasing urbanization.
- “car cities”, food deserts.
- Social changes – long workdays, long commutes= ↓ time to prepare healthy food and exercise.
20
Q
What is the first line therapy for obesity?
A
- First line therapy: Lifestyle changes, i.e. diet and exercise.
- Next: pharmacotherapy.
21
Q
What are the environmental risks to obesity?
A
- Endocrine disrupting chemicals such as Bisphenol A (BPA) and phthalates can impact risk for obesity.
- One meta-analysis found that every 1ng/mL increase in urinary BPA contributed to an odds increase of 15% obesity in adults and 17% for children.
- A longitudinal study found that high-MW phthalates contributed to significant bodyfat and fat mass increase over 5 years in women, especially women who were normal or under weight.
22
Q
What are some medications that contribute to weight gain?
A
- Corticosteroids eg Predinsone: Induce insulin resistance and trigger visceral adiposity.
- Atypical antipsychotics eg Clozapine: 5HT2c antagonism. Decrease central serotonergic signaling and muscarinic signaling, as well as NPY activity – increase appetite.
- Older classes of antidepressants (TCA, MAOI) eg amitriptyline, phenelzine: 5HT2c antagonism. Decrease central serotonergic signaling – increase
appetite. - Some diabetes medications eg Insulin, glitazones: Insulin promotes nutrient “storage” – lipogenesis;
glitazones promote adipose tissue differentiation and water retention. - Some beta-blockers eg atenolol: Slow metabolism, impact insulin sensitivity due to effects on SNS.
- Some antihistamines: Histamine signalling can affect satiety signals – interruption will impact hunger and feeding signals and promote overfeeding.
23
Q
Describe the mechanism through which drugs increase appetite or energy storage.
A
24
Q
Describe the genetics of obesity.
A
- Polymorphisms have been identified that confer increased risk for obesity.
- Many are related to the mechanisms involved in regulation of energy homeostasis.
- FTO – fat mass and obesity associated gene, SNPs in this gene associated with increased BMI.
- May be ethnicity specific.
- Mutations to the leptin gene or its’ receptor.
- Severe early onset obesity.
- Melanocortin 4 receptor (MC4R) which binds the anorexigenic hormone alpha-MSH.
- Rapid weight gain at a very early age.
- Similar to type-2 diabetes, risk is typically polygenic and involves multiple genes and may involve added metabolic “hits”.
- Can be part of a larger genetic syndrome like Prader-Willi.
25
Q
Describe the homeostatic mechanisms controlling energy balance.
A
- Many people exposed to same dietary choices not obese.
- intrinsic homeostatic mechanisms.
- Centrally regulated.
- “gut-brain axis”.
- Strong genetic influence.
- defects in neuro-endocrine pathways that match food intake with expenditure.
- Common genetic variants in the general population: haplotype i.e multiple variants each with small impact on weight gain add up to an increased risk of obesity.
- Many of polymorphisms identified are in this pathway.
26
Q
What are the mechanisms controlling energy intake and expenditure?
A
- Nutrient status – has a meal just been consumed?
- Gut peptides like CCK and GLP-1.
- Afferent signaling from the vagus nerve. - What are current glucose levels?
- Insulin and glucagon can mediate these signals.
- Insulin crosses the BBB. - Energy stores – how much stored energy is available, eg adipose tissue deposits?
- Leptin is the marker of adipose tissue depots. - What kind of activity is required – will we need energy for this activity?
27
Q
How are the mechanisms controlling energy intake and expenditure regulated?
A
- Regulation at the hypothalamus – Sense and integrate peripheral signals to
regulate intake and expenditure. - Regulation at the hind-brain – input from the GI tract to terminate feeding.
- Complex systems controlling incentives – reward and motivation.
28
Q
Is adipose tissue an endocrine organ?
A
- Yes.
- Adipose tissue is the largest depot of fat storage.
- Also has secretory function.
- Adipocytokines modulate energy expenditure, insulin sensitivity, inflammation and more.
- Adipose tissue can be “healthy” or “unhealthy”.
29
Q
What is healthy adipose tissue?
A
- Promotion of a healthier adipose tissue phenotype is more metabolically favorable:
- Smaller adipocytes, better vascularization, less
inflammation/immune cell infiltration, insulin sensitive.
30
Q
What is unhealthy adipose tissue?
A
- Unhealthy adipose tissue more often seen in obesity and metabolic syndrome:
- Hypertrophic adipocytes, poor vascularization, pro-inflammatory, insulin resistance, dysregulated lipid metabolism.
31
Q
What is leptin?
A
- Leptin: product of ob gene.
- Signal of adipose tissue stores.
- “long term” signal of energy homeostasis:
- Reduces food intake & body weight.
- Produced by adipocytes – “adipokine”.
- Regulated by glucocorticoids, estrogens, insulin.q
- Production varies according to fat stores: increased fat stores = increase leptin.
32
Q
What can cause obesity in mice?
A
- Mice can become obese as a result of mutations.
33
Q
What are the mutations that lead to obesity in mice?
A
- ob (lack leptin).
- db (lack leptin receptor).
- tub (transcription factor).
34
Q
What happens when mice are homozygote (ob/ob,db/db)?
A
- eat excessively.
- low expenditure.
- Extreme adiposity.
- metabolic abnormalities.
- Used as a model for diet induce obesity and diabetes.
35
Q
How does leptin regulate body weight?
A
- Leptin enters CNS via saturable transporter.
- Acts on leptin receptors in 2 groups of neurons in arcuate nucleus (ARC) in hypothalamus.
36
Q
What are the two groups of neurons leptin acts on?
A
- 2 groups have opposing actions.
- Energy homeostasis depends on balance between actions of leptin (and other mediators) on these 2 groups of neurons.
- Leptin stimulates anorexigenic pathways (POMC and CART) and inhibits orexigenic (NPY and AGRP) pathways.
- Defects in POMC/MSH/melanocortin axis linked to obesity.
- e.g. mutation in melanocortin receptor linked to childhood obesity.
37
Q
Describe leptin regulation of energy balance and fat stores.
A
38
Q
Where is the ARC?
A
- The ARC is within the hypothalamus.
- communicates with the mesolimbic reward system and regions controlling hunger and satiety.
- Communicates information about metabolic fuel ability to other parts of the brain.
39
Q
Where else are leptin receptors found?
A
- Full-length leptin receptors are also found in the regions of the brain associated with reward
seeking. - Injection of leptin to the VTA suppresses food intake (food “wanting”).
- Deletion of leptin receptors in this region increases
hyperphagia.
40
Q
What background balances have to be taken into account when taking control of food intake?
A
- Regulation of energy balance occurs against background of
other factors that engage higher brain areas in control of
food intake. - e.g. Individuals who are susceptible to weight gain have a strong hedonic attraction to palatable foods.
- Mesolimbic “reward” system processes information about palatability of foods – translates “liking” to “wanting”.
- Humans evolutionary “wired” for sugar, salt and fat.
41
Q
What is leptin resistance?
A
- Previously thought obesity would be associated with lack of leptin – reduced anorexigenic benefits.
- In contrast, many obese patients have high levels of leptin “hyperleptinemia”.
- They have leptin resistance (analogous to insulin resistance associated with type 2 diabetes).
42
Q
What is the proposed mechanism of central leptin resistance?
A
- High fat diet/lipotoxicity could impair neuronal response to leptin via ER stress and
inflammation in the hypothalamus. - Inflammation associated with obesity: SOCS3 – leptin inducible suppressor of leptin signalling, upregulated by low-grade inflammation.
43
Q
What is saturable transport?
A
- Transporters can become “saturated” and limit transport across the BBB.
- This limits uptake when peptide is abundant.
- Therefor transport is more efficient at lower serum levels and reduced at high levels.
44
Q
What are gut peptides?
A
- Food intake also modulated by feedback loops in which signals transmitted from GI tract to CNS: Gut peptides.
45
Q
What is ghrelin?
A
- Peptide secreted by gastric mucosa.
- Plasma levels high during fasting, peak when expecting or requesting meal.
- Feeding causes immediate fall in levels.
- Decreases release of leptin & vice versa.
- –> decreased leptin signalling: increase food seeking behaviour
- “hunger” hormone.
- Stimulates food intake.
46
Q
What is CCK?
A
- Cholecystokinin (CCK).
- Secreted by mucosal cells in response to process of digesting food (esp. fat).
- Acts on CCKA receptors on afferent nerves (send signal back to CNS – hind brain) to inhibit food intake.
- Also activate CCKB receptors in brain – “satiety factor”.
- Mediates “short-term” inhibition of food intake – limits size of meals.
47
Q
What are PYY, OXM< and GLP-1?
A
- Peptide tyrosine tyrosine (PYY), Oxyntomodulin (OXM) &
Glucagon-like peptide (GLP-1). - “incretins” like GLP1 – mediate the “incretin effect”.
- Short-term satiety signals produced by cells of GI mucosa.
- GLP-1 also stimulates insulin release.
- Acts on afferent nerves and ARC.
- Released synchronously, plasma levels rise 5-10 min after starting to eat.
- plateau within 30-90 min & remain elevated for up to 6 hrs - delays time before feel hungry again.
- Rapid rise of circulating hormone levels signals a change in energy status to brain.
- Acts locally to enhance digestive processes.
- Lower levels in people with obesity and T2D.
48
Q
Describe the regulation of food intake and energy expenditure.
A
49
Q
Summary of mediators.
A
50
Q
How are these mechanisms disrupted in obesity and overnutrition?
A
- Individuals can have person-to-person variability in their susceptibility, due to variance in their homeostatic
mechanisms. - Eg polymorphisms in the pathways responsible for energy sensing and satiety that confer increased risk for obesity.
- Increased adiposity can lead to leptin resistance and impaired leptin signaling.
- Obesity increases the risk for insulin resistance and hyperinsulinemia.
- This disrupts homeostatic mechanisms.
- Triggers fuel “storage” mode
- People with obesity may have lower levels of endogenous GLP-1 leading to reduced short term satiety signals.
- Individuals may use medications that disrupt one of the mechanisms required for energy homeostasis putting
them at increased risk of obesity. - Obesity seems to dysregulate these pathways – overnutrition, glucotoxicity, lipotoxicity – causing a vicious cycle.
51
Q
Summary of obesity.
A
