Obesity, Diabetes and Nutrition Flashcards
1
Q
What are the main trends regarding obesity in the developed and developing world?
A
- Since the 1970s it has been reported as increasing
- This increase was first seen in developed countries due to the rise of both the fast food industry and white collar jobs with low physical activity but is now seen in developing countries also
- Globally the prevalence of overweight is 35% and there are over 500 million obese adults
- Developing countries face a double burden of both under and over nutrition
2
Q
How is BMI calculated and categorised?
A
BMI= weight (kg)/ height (m) squared <18.5= underweight 18.5-24.9 = normal weight 25-29.9 = overweight >30 = obese (class increases with each 5 BMI points)q >40 = morbidly obese
- BMI is a crude measure that can be altered by high muscle density etc. however it can identify is someone might need to follow up with a medical practitioner
3
Q
Describe the prevalence of obesity in Japan and how it is managed?
A
- Japan has relatively low levels of obesity in comparison to other developed nations
- In Japan there is ‘Metabo’ Law which mandates that older citizens have to go for waistline checks and health check ups with doctors and deal with any weight issues
4
Q
What is the priority in addressing obesity in childhood?
A
- Educating parents is the priority
- Children eat what is provided to them, so it society’s responsibility to educate them
- Parents bad lifestyle is often passed onto children
- Childhood obesity is strongly linked to adult obesity
5
Q
How are socioeconimic status and obesity linked in low and middle income countries?
A
- Positive association with socioeconomic status and obesity
- People with higher socio-economic status are more likely to live in urban settings, be more likely to drive, have greater access to more food and less likely to have a job involving manual labour
6
Q
What are the health consequences of obesity?
A
- Increased weight increases the risk of many diseases including: diabetes, CVD, sleep apnoea, cancer, gallbladder disease, osteoarthritis and depression
7
Q
How can the economic costs of obesity be calculated?
A
- Obesity has almost as much of an economic impact as smoking and armed violence, war and terrorism
- These costs in Australia are covered 34.3% by the federal government and 29.4% by individuals
Direct costs:
- Medical costs to treat associated medical conditions
Indirect costs:
- Reduction in productivity and size of workforce
8
Q
How do changes in the global food system drive obesity?
A
- The increased availability of more processed food which is more affordable and better marketed is a key driver of obesity
- A key issue is that highest calorie foods tend to be the least expensive which targets the socioeconomically disadvantaged
9
Q
What action has the UN general assembly taken on tackling issues with nutrition?
A
- The UN general assembly has called on governments to set national targets for 2025 to address malnutrition (including under and over nutrition)
10
Q
How can a social network influence obesity?
A
- Studies have shown that an individual is more likely to be obese if individuals in close social contact with them are also overweight/obese
- Therefore social networks could be used as a platform for improving education about healthy lifestyle and reducing obesity
11
Q
What are the main causes of obesity?
A
- Complex and multifactorial including:
1. Genetics/epigenetics
2. Lifestyle eating/exercise patterns
3. Socioeconomic status
4. Psychological factors
5. Cultural background
6. Age
7. Hormonal, metabolic and physiological factors
8. Sleep disturbances
12
Q
Describe the monogenic mutation that causes obesity:
A
- Monogenic mutations that cause obesity are very rare
- Mutation of the obese (ob) gene results in profound obesity
- It is thought the mutation prevents the production of leptin from adipose tissue causing: uncontrolled hunger and low energy expenditure (low BMR and body temp)
- Congenital deficiency of leptin in humans causes extreme childhood obesity
13
Q
Describe the features of the ‘set-point’ of body weight:
A
- There is an innate setpoint of weight in animals and humans
- It is more evident in humans
- Determined by genetics and environment: mutations of other genes does not affect it
- Occurs in mice despite changing baseline
- Set point in human ONLY OCCURS IN ADULTS (it is not established until after puberty)
- It is very difficult to lower the set point once it has been established in adulthood
- It is important to intervene prior to puberty
14
Q
How is the set point maintained by counterregulatory mechanisms?
A
- The set point is maintained through counterregulatory mechanisms
- In response to weight loss there is a long-term homeostatic drive to increase body weight (still present after 2 years)
- In response to weight gain the counterregulatory mechnanisms are generally fairly acute (occur for a few months before body adapts to increased weight)
15
Q
What were the two gene variants that matched with different phenotypes associated with obesity?
A
- FTO: Fat mass and oesity associated gene (SNP)
- MC4-R
16
Q
Describe how FTO was discovered and its effect when mutated in mice:
A
FTO= fat mass and obesity associated gene
- It was discovered via a GWAS study that showed that when individuals had 2 variant (SNP) versions of the gene they were 1.67x more likely to be obese
- It is the most commonly associated gene with any index of increased body weight
- It is NOT a monogenic cause of obesity however
Overexpression of FTO in mice:
- Increased body weight
- Drastically increased fat mass
- Increased food intake
- Increased preference of higher calorie foods
- Reduced physical activity and energy expenditure and impaired browning of white adipose tissue
17
Q
What variants of FTO are seen in humans?
A
- There are numerous variants of FTO in humans
- 89 genetic variants within introns 1 and 2 of FTO have been associated with BMI
- These FTO genetic variants increase the copy number of the gene and increase the propensity to become obese
- GWAS studies have identified nearly 10,000 SNPs however 90% of these are in non-coding regions
18
Q
What is metabolic syndrome?
A
- Metabolic syndrome (MetS) represents a combination of cardiovascular risk determinants including:
- Obesity (especially central adiposity)
- Glucose intolerance and insuline resistance
- Dyslipidaemia (hypertriglyceridaemia, increased FFAs and decreased HDL)
- Hypertension
MetS is associated with clinical manifestations such as PCOS, atherosclerosis and NAFLD
MetS is diagnosed by:
- An accumulation of visceral fat (waist circumference)
- 2 or more of the following: increased fasting blood glucose, increased BP and altered serum lipids
19
Q
Describe the spectrum of non-alcoholic fatty liver disease:
A
- Healthy liver becomes fatty liver (NAFLD):
- Due to obesity when body has to store fat in ectopic tissue
- This causes hepatic steatosis with lipid accumulation in the liver
- Reversible - NAFLD develops into non-alcoholic steatohepatitis (NASH)
- A liver immune response causes oxidative stress, mitochondrial dysfunction, cytokine production and release, adipocytokine imbalance and stellate cell activation
- NASH is characterised by increased lipid deposition, immune infiltraiton and fibrosis/scarring - If left un-treated NASH can develop into cirrhosis (scarring) and carcinoma
- Non-reversible
- NASH progresses and fibrosis occurs and can lead to cirrhosis where hepatocytes are replaced by scar tissue
20
Q
How are NAFLD and NASH diagnosed?
A
- Measuring liver function via blood testing:
- Can measure bilirubin, ALT and ALS
- Elevated bilirubin indicates a type of steatosis - Can measure liver stiffness
- Increased stiffness is a sign of fibrosis - Biopsy of liver tissue:
- Histological analysis is the only way to distinguish between NAFLD and NASH
21
Q
Describe the general principles of glucose homeostasis and the role of insulin:
A
- When a person has fasted, their blood glucose is approximately 5mM
- After eating a typical meal, blood glucose will rise to 7mM
- After a meal peripheral tissues take up glucose from circulation and within 1-2 hours the blood glucose levels will go back down to 5mM
Role of insulin:
- When blood glucose levels rise after a meal, the pancreas responds by increasing secretion of insulin
1. Insulin shuts down hepatic glucose output
2. Insulin acts on skeletal muscle to increase glucose uptake
3. Insulin acts on adipose tissue to increase glucose uptake
22
Q
What is Diabetes?
A
- A chronic condition in which the body cannot properly use glucose due to either:
- The pancreas not producing enough insulin (type 1)
- The body being unable to effectively use and respond to the insulin produced (type 2)
- Diabetes is characterised by the abnormal buildup of glucose in the blood and can have serious complications
- Many individuals have high blood glucose levels and high insulin resistance, but not high enough to be diagnosed with type 2 diabetes
23
Q
Describe the pathological progression of type 2 diabetes:
A
- Healthy people with normal glucose tolerance (GT) tend to have low levels of insulin secretion, high insulin sensitivity and low levels of plasma glucose
- When an individual becomes obese and has impaired glucose tolerance, the peripheral insulin sensitivity will decrease
- A secondary response following a decrease in peripheral insulin sensitivity is a rapid rise in insulin secretion from the pancreas (which will initially keep plasma glucose stable)
- As peripheral tissues become further impaired and cannot take up more glucose, the pancreas will reach a tipping point and then there will be a rapid reduction in insulin secretion
- The reduction in insulin secretion causes a rapid increase in plasma glucose levels
24
Q
How is diabetes diagnosed?
A
- It is estimated that 1/3 of people with diabetes do not know they have it
- It is diagnosed using:
- Fasting blood glucose
- Normal <5.5
- If over 7 on more than one occasion shows diabetes - Oral glucose tolerance test:
- 75g glucose drink consumed
- 2 hours later blood sample
- Blood glucose >11.1 = diabetes
25
Describe the epidemiology of diabetes in Australia:
- 90% of people with diabetes have T2D
- 10% of people with diabetes have T1D
- Between 2007/8 and now proportion of people with diabetes has increased from 4.4% to 7%
- 92% of diabetics are 45 years and older
- The proportion of diabetics across Australia is quite similar expect NT (high level of diabetes due to Indigenous population)
26
Describe the heritability of type 2 diabetes:
- A person with T2D most likely has an inherited predisposition for developing the disease
- Estimates of the additive genetic heritability of T2D range from 25-40%
- GWAS studies have shown that there are 40-60 independent SNPs associated with an increased risk of T2D
- 12 T2D susceptability loci have been identified
- Variants in the TCF7L2 (transcription factor associated with cancer progression) gene appear to be associated with the highest risk of developing T2D
- These risk alleles often ct through beta-cell dysfunction (rather than peripheral insulin resistance), indicating that peripheral insulin resistance is environmentally driven
- Most genetic associations are quite modest leading researchers to believe that the increased risk of diabetes in offspring of parents with diabetes is largely due to shared environmental/lifestyle factors
27
How is type 2 diabetes associated with obesity?
- Diabetes prevalence increased with increased body weight
- There is a negative correlation between insulin sensitivity and body fat/VAT
- Obese people require a greater level of insulin for peripheral glucose uptake to occur, and this peripheral glucose uptake is diminshed
- Obese people require more plasma insulin and take longer for hepatic glucose production to decrease by a given amount (and this decrease is not as much)
28
How is insulin sensitivity assessed in the lab?
Done using a hyperinsulinemic-euglycemic clamp:
- Subject is cannulated
- Insulin is infused at a high set rate
- Glucose is infused at a variable rate
- Blood glucose is measured- depending on insulin sensitivity, more or less glucose will need to be infused to keep blood glucose at a steady rate (someone with reduced insulin sensitivity would require less glucose infusion to become euglycaemic)
- A tracer (radioactively labelled glucose molecule) can also be infused to look at the disposal of glucose into different tissues (mainly done in mice
29
Describe the common progression of T2D:
1. Insulin resistance
2. Beta cell compensation (increased insulin secretion)
3. Beta cell failure (decreased insulin secretion)
30
What is insulin resistance and what occurs physiologically in the body?
- Insulin resistance is when cells in the body become less sensitive to the effects of insulin
- Results in:
1. Impaired glucose uptake
2. Impaired suppression of hepatic glucose production
3. Reduced anti-lipolytic effect
4. Reduced insulin signal transduction
5. Blunted suppression of feeding
31
What is the effect of IR/T2D on skeletal muscle glucose uptake?
- Skeletal muscle glucose uptake should increase dramatically after a meal
- In IR/T2D the capacity for glucose uptake after a meal dramatically decreases
32
Describe insulin resistance at a molecular level:
1. Insulin receptors are on the surface of many cells (including skeletal muscle)
2. Activation of insulin receptors by insulin leads to the activation of the insulin signalling cascade -> activation of AKT -> increased glycogen synthesis, decreased gluconeogenesis and lipolysis -> GLUT4 transporters moved to the membrane
3. In obesity there is increased plasma circulation of FFAs
4. The intermediates produced in the storage of fats e.g. ceramide, inhibit the activity of AKT interfere with insulin signalling and therefore glucose uptake
5. Cytokines from adipocytes and macrophages also interfere with the insulin signalling cascade and can lead to further expression of pro-inflammatory markers by the tissue itself
33
What happens in obesity to cause insulin resistance?
1. Lipotoxicity
- The intermediates produced in the storage of fats interfere with insulin signalling and thus glucose uptake
- E.g. ceramide inhibits the activity of AKT
2. Inflammation (low-grade)
3. Altered endocrine signals
e. g. changes in ghrelin and leptin
4. Mitochondrial dysfunction
- Obese people tend to have less mitochondria as well as mitochondria that are smaller and less functional
- This causes a decreased capacity to 'clear' lipids and well as an increased production of reactive oxygen species
34
Describe the 'adipose-centric' view of obesity and insulin resistance:
- This view is that:
1. Adipose tissue stores are important in regulating how much fatty acids are released into circulation
2. In obesity there is an increase in circulating FFA, cholesterol and lipoproteins
3. More circulating fats results in more fat deposition in adipose tissue, as well as the liver and skeletal muscle (which leads to insulin resistance
4. In obesity there is greater inflammation in adipose tissue which released cytokines that negatively affect metabolic health in peripheral tissues
35
Describe in detail how lipotoxocity causes insulin resistance:
- Lipotoxicity and ectopic fat deposition:
- In an obese individual there is a very high level of circulating FFAs
- These FFAs are taken up into tissues and stored (ectopic fat storage)
- When generating triglycerides for the storage of FFAs, the intermediates e.g. ceramide, interfere with insulin signalling and can cause the cell to become insulin resistant
36
Describe in detail how low grade inflammation causes insulin resistance:
- In obesity there is low grade inflammation in adipose tissue causing the release of cytokines such as TNF-a, IL-6, IL1-B
- These cytokines enter circulation and cause impairments in insulin signalling and metabolic health in peripheral tissues such as muscle and liver
37
Describe in detail how obesity alters endocrine function and caused insulin resistance:
- Due to the interspersed blood vessels in adipose tissue, it is very easy for adipose tissue to release hormones and cytokines into circulation (adipose secretome)
- The factors released by adipose tissue can affect insulin sensitivity, inflammation, growth of new blood vessels, food intake and energy expenditure
38
Describe in detail how mitochondria become dysfunction in diabetes and insulin resistance:
- In obese individuals there is reduced mitochondrial number, size and activity
- There is also reduced fatty acid oxidation proteins
- This mitochondrial dysfunction in insulin resistance is a major issue especially in skeletal muscle as this is the main tissue that must take up excess blood glucose
- There is also reduced B-oxidation of fatty acids in these cells which contributes to further fat storage and lipotoxicity
39
Describe the typical response to insulin in a healthy skeletal muscle cell:
1. Insulin binds the insulin receptor and initiates a signalling cascade
2. This leads to the movement of GLUT4 to the plasma membrane which allows glucose uptake into the tissue
3. Glucose is rapidly oxidised via glycolysis to form ATP and some is stored as glycogen- with the help of functional mitochondria
4. FFAs from circulation are taken up and a large proportion are oxidised in the mitochondria (which a small amount being stores as TAGs)- with the help of functional mitochondria
40
Describe the typical response to insulin in a T2D skeletal muscle cell:
1. Insulin binds to the insulin receptor and initiates a signaling cascade
2. Due to the large increase in circulating FFAs there is a drastic increase in the uptake of FFAs into the peripheral tissues
3. There is a decreased capacity of mitochondria in obese individuals to oxidise these fats and dispose of them so therefore lots of these fats go into storage
4. The storage of FFAs into TAGs produces lots of lipid intermediates which interfere with insulin signalling
5. This results in less translocation of GLUT4 to the plasma membrane which results in less glucose uptake in peripheral tissues
6. Mitochondrial dysfunction also means that mitochondria are not able to effectively oxidise FFAs which results in a greater production of ROS, leading to increased oxididative stress which can also interfere with various parts of the insulin signalling cascade
41
What are the main complications of diabetes?
- Decreased life expectancy
- Increased risk for many diseases e.g.
1. CVD (postprandial hyperglycaemia is a powerful predictor for CVD)
2. Diabetic retinopathy
3. Neuropathy
4. Diabetic retinopathy
- Most of these complications are the result of chronic hyperglycamia which induces multiple mechanisms leading to cellular changes causing microvascular complications
42
What are the treatment goals for type 2 diabetes?
- The goal of medications in T2D is to improve glycaemic control which is often measured by glycated hemoglobin (HbA1c)
- HbA1c is an indication of average plasma glucose over a prolonged period (1-3 months)
- The HbA1c target it <7%
- Tight glycaemic control early in the diabetes process is desirable and likely to yield the greatest benefit for the prevention of microvascular/macrovascular complications as well as overall mortality
- Attaining tight glycaemic control in advanced disease yield little if any benefit for macrovacular disease but may be effective in retarding the progression of microvascular disease
43
How do lifestyle changes help treat diabetes?
- Rationale to is to manage diabetes mainly by counteracting the adiposity effect
1. Increase energy expenditure and decrease energy intake to reduce fat mass
2. Reduce fatty acid delivery to peripheral tissues and reduce inflammation
3. Enhance skeletal muscle oxidative capacity (mitochondrial function)
4. Reduce lipid storage in muscle and liver
- The culmination of these effects is to reduce the stress and interference in the insulin signalling pathway and thus reduce insulin resistance
- Studies show that lifestyle intervention is effective at reducing the incidence of T2D by 30%
- The effectiveness of lifestyle changes in treating diabetes improves with age
44
How is metformin used to treat diabetes?
- Metformin is a biguanide class of drugs
- The frontline therapy uses to treat T2D
- Has an excellent safety profile and few side effects (only side effects short term GI symptoms and long term B12 deficiency)
- Prevents the progression of impaired glucose tolerance to T2D:
- Metformin is a mitochondrial uncoupler that increases free AMP in cells, this increases the phosphorylation and activation of AMPK
- Meformin is more effective in younger people and people who are more obese
Skeletal muscle effects:
1. AMPK upregulation increases GLUT4 translocation
2. AMPK activation improves fatty acid oxidation (reduces lipid storage)
Liver (most dominant effects):
1. AMPK activates SHP and decreases gluconeogenesis and thus reduces hepatic glucose production
2. AMPK causes a long term decrease in the expression of SREBP-1 and thus cause a reduction in expression of genes involves in lipid synthesis
3. Results in decreases hepatic FA and VLDL synthesis, increases hepatic FA oxidation, reduces hepatic steatosis and increases liver insulin sensitivity
45
How are sulfonylureas used to treat diabetes?
- These drugs increases insulin secretion by the B-cells of the pancreas
- Prior to metformin they were the first choice drug for T2D
- Not effective in T1D
- Often used in combination with metformin
- Not as effective as metformin, but still causes a decrease in many end point including microvascular disease, CVD and mortality
Mechanism:
- Sulfonyureas act by binding and blocking ATP dependent K+ channels on the cell membrane of B-cells (mimicing what normally happens when blood glucose increases)
- This inhibits the hyperpolarising effects of potassium causing the membrane to become positive which opens voltage gated calcium channels
- The rise in intracellular calcium causes an increases fusion of insulin granules with the cell membrane and thus its secretion
46
What are the complications of sulfonylureas?
- It may induce hypoglycaemia as a result of excess insulin production and release (if given in a high dose or if the person is fasting)
- It can cause weight gain
- Cannot be used in pregnancy
- Cannot be used in people with renal/liver failure due to high risks of hypoglycaemia
47
How are GLP-1 agonists (exenatide) used to treat diabetes?
- Exenatide is a synthetic version of exedin-4, a blood glucose lowering hormone found in the saliva of the Gila monster
- Extenatide acts as an insulin mimic, and can increase the amount of insulin released from B-cells (even before blood glucose is raised)
- The biological properties re similar to human glucagon-like peptide 1 (a regulator of glucose metabolism and insulin secretion
- Exenatide raises insulin levels quickly (in 10 minutes), before they subside over the next hour or two
- Used as an adjunct therapy for glycemic control: e.g. used with metformin and sulfonylureas
Mechanisms of action:
1. Increases insulin response to a meal
2. Reduces glucagon secretion and HGP
3. Slows gastric emptying and decreases appearance of meal derived glucose
4. Reduces appetite mildly (some weight loss effects)
48
Is exenatide better used in combination with metformin or sulfonylureas?
- Exenatide (increases insulin secretion) is best used in combination with metformin (an insulin sensitizer) rather than sulfonyureas (increases insulin secretion) to avoid side effects such as hypoglycaemia and to increase efficacy
49
What are the complications of GLP-1 agonists (exenatide)?
- The complications are GI in nature including: heartburn, belching, diarrhoea, indigestion, nausea and vomiting (lasting several days-weeks)
- Can cause acute pancreatitis
- Potential thyroid cancer risk
- Requires daily/weekly injections
- Not PBS funded as a dual therapy with metformin unless the person is intolerant to sulfonyureas
50
What are the most common triple therapies for managing T2D?
- Metformin, sulfonyureas and exantide
| - Metformin, sulfonyureas and insulin
51
What does the neuroendocrine regulation of energy homeostasis refer to?
- The neuroendocrine regulation of energy homeostasis refers to how peripheral hormones and nutrients inform the brain about avaliable energy levels and affect mechanisms that control body weight
52
What endocrine factors control food intake:
1. Appetite stimulators:
- Ghrelin
2. Appetite inhibitors:
- Leptin
- Insulin
- GLP-1
- CCK
- PYY
3. Metabolites:
- Glucose
- Free fatty acids
53
What are the 3 factors released by neurons in the arcuate nucleus that control food intake?
- Both of these neurons (NPY and POMC) act on PVN neurons)
1. Neuropeptin Y:
- Produced by NPY cells
- Most potent orexigen (appetite stimulant)
- Increases food intake by acting at Y1 and Y5 neurons
2. Agouti-related peptide (AgRP)
- Co-produced by 90% of NPY cells
- Appetite stimulator
- Increases food intake by antagonising the effect of aMSH at MC4R receptors (acts as an antagonist at MC4R to promote hunger)
3. POMC neurons:
- Appetite inhibitor
- Produces melanocortins (primarily aMSH)
- aMSH acts as an agonist at MC4R
- Very important in controlling body weight by inhibiting food intake
- The vast majority of monogenic mutations that cause severe obesity are found in this melanocortin pathway
- in states of negative energy balance AgRP binds to MC4R as an inverse agonist and blocks the effects of aMSH
54
How can NPY neurons act on POMC neurons?
- The effects of NPY/AgRP can have paracrine effects on adjacent POMC cells in the arcuate nucleus by shutting of the production of aMSH
- They do this by signalling through GABA which is inhibitory (this GABA signalling also projects to the PVN and inhibits satiety neurons there)
55
What are the rapid signals controlling food intake?
AgRP/NPY neurons:
- NPY acts on orexigenic neurons to activate them and increase food intake
- GABA acts on satiety neurons to inhibit them and increase food intake
Glutamate neurons:
- Activate the satiety neurons in the PVN and decrease food intake
56
What are the slow signals controlling food intake?
AgRP/NPY neurons:
- AgRP acts an an antagonist to block the effect of aMSH on MC4R on satiety neurons
- Aims to increase food intake
POMC neurons:
- Produce aMSH which acts as an agonist to activate MC4R on satiety neurons
- Aims to decrease food intake
57
What occurs if AgRP/NPY neurons are ablated?
- Essential for survival
- Genetic ablation of AgRP/NPY results in starvation and death
- Animals lose a signifant amount have weight, have a significantly reduced food intake and a decreased survival rate
- Therefore AgRP is a profound long-term stimulator of food intake and is essential to drive hunger
58
What occurs if POMC neurons are ablated?
- POMC cells prevent obesity and diabetes
- Genetic ablation of POMC increases food intake, increases body weight and causes a reduced glucose tolerance (POMC neurons are important in glucose metabolism in the periphery)
- Glucose intolerance occurs due to the combined effect of lack of POMC and an increase in body weight
59
Describe the first order neuronal signalling principle with regards to control of body weight:
- The arcuate nucleus has a leaky blood brain barrier due to fenestrations on the capillaries
- Therefore the ARC is the first site of action for the control of body weight as endocrine factor e.g. ghrelin and leptin can act on it easily
- The presence of tanacytes that send projections into the parenchyma and determine the transport of factors across the BBB determine the what factors the ARC will be exposed to:
1. In a fasted state, the ARC will be primarily exposed to ghrelin and fatty acids to trigger hunger
2. In a fed state, the ARC neurons will be primarily exposed to leptin and glucose to trigger satiety
- The signals from the ARC neurons are then relayed to second order neurons (e.g. PVN neurons with MC4R) and these secondary neurons then go on to regulate food intake, energy expenditure and other metabolic functions
60
How do leptin and insulin act on ARC neurons?
- Leptin and insulin (both satiety factors) act at both NPY/AgRP neurons by inhibiting them and at POMC neurons by activating them
- In obesity, leptin saturates the brain and then no longer exerts an effect so it will not inhibit AgRP/NPY or activate POMC in those individuals (leptin resistance)
61
How does ghrelin act on ARC neurons?
- Ghrelin is a factor that promotes increased food intake, adiposity, blood glucose and growth hormone
- It is increases in plasma during negative energy balance (fasting) and designed to drive this to neutral energy balance
- Ghrelin acts ONLY at NPY/AgRP neurons and activates them
- However NPY/AgRP neurons can inhibit POMC neurons via GABA so ghrelin is able to indirectly act on POMC
62
What other hypothalamic nuclei are involved in the control of body weight?
- Aside from the primary site (arcuate nucleus) and the secondary site (paraventricular nucleus) there are other nuclei involved such as the:
1. Ventromedial hypothalamus (VMH)
- VMH is a satiety centre
2. Dorsomedial hypothlamus (DMH)
3. Lateral hypothalamus (LH)
- Feeding centre
- Therefore neurons in the ARC communicate with these neurons in addition to the PVN
63
Describe in detail the circuitry in the hypothalamus which controls body weight:
1. ARC is the first order area
2. ARC projects to the PVN:
- NPY/AgRP neurons secrete NPY which acts at Y1 and Y5 receptors of orexigenic neurons (fast)
- activated by ghrelin
- inhibited by leptin and insulin
- POMC neurons secrete aMSH which are agonists of the MC4R of satiety neurons (slow)
- Activated by leptin and insulin
- Activated by PYY and GLP1
- Indirectly (via GABA) inhibited by NPY/AgRP neurons and thus ghrelin
- NPY/AgRP neurons secrete AgRP which acts as an antagonist of MC4R of satiety neurons (slow)
- activated by ghrelin
- inhibited by leptin and insulin
- NPY/AgRP neurons secrete GABA which inhibits both POMC neurons in the ARC and satiety neurons in the PVN
3. ARC neurons also project to the ventromedial hypothalamus (VMH)
4. Leptin acts directly in the VMH by activating BDNF neurons to reduce food intake
5. ARC neurons also project to the LH
- aMSH inhibits neurons that produce orexin and melanin concentrating hormone in the LH to decrease food intake
64
How do the gut hormones: ghrelin, GLP1, PYY and CCK regulate food intake?
1. Ghrelin:
- Increases food intake by activating NPY/AgRP neurons in the ARC
2. PYY and GLP1
- Decrease food intake by activating POMC neurons in the ARC and via the brainstem (vagal afferents)
3. CKK:
- Decreases food intake by acting on the brain stem (vagal afferents)
65
What happens to the levels of neuroendocrine hormones/peptides that control food intake during a meal?
- Leptin and insulin provide long-term feedback signals regarding the levels of adiposity
1. Ghrelin starts to increase prior to the onset of a meal and then decreases after the meal- acute mediator
2. Insulin and gut peptides (GLP1, CCK, PYY) increase during a meal to terminate it- acute mediators
66
What happens to the neuroendocrine hormones/gut peptides after fasting?
- In response to any weight loss there is a resetting of hunger drive:
1. Increased ghrelin
2. Decreased PYY, GLP-1 and CCK
3. Decreased leptin
4. Decreased insulin
- All of these feedback to the hypothalamus to cause:
- Increased AgRP
- Increased NPY
- Decreased POMC activaton (aMSH)
- These mechanisms persist in the long term and contribute to the difficulty of weight loss- these mechanisms increase hunger drive and also decrease energy expenditure
67
What are the 4 means of energy expenditure?
1. Basal metabolic rate
2. Exercise and physical activity
3. NEAT (non-exercise adaptive thermogenesis)
4. Adaptive thermogenesis
68
What is basal metabolic rate?
- BMR is the energy expended at rest i.e. the energy required to maintain basic cell and organ function
- Accounts for 70% of total daily energy expenditure
- BMR is positively correlated to lean body mass (males have an increased BMR compared to females driven by increased lean body mass)
- BMR decreases with aging
- The resting energy expenditure is 60% determined by heart, kidneys, liver and brain and 20% contributed to by skeletal muscle
69
How does exercise impact energy expenditure?
- Exercise increases energy expenditure significantly, specifically due to the metabolic demands of working skeletal muscle
- During exercise there is also a decrease in the energy expenditure of other muscles such as smooth muscle
- How beneficial exercise is for weight loss/maintenance is largely determined by genetics
70
What are the recommendations for amount of exercise for different levels of weight loss:
1. Maintaining and improving health: 150 mins (2.5 hours) per week
2. Prevention of weight gain: 150-200 mins (2.5-3.3 hours) per week
3. Promote clinically significant weight loss: 225-420 mins (3.75-7 hours) per week
4. Prevention of weight gain after weight loss: 200-300 mins (3.3-5 hours) per week
71
What are the benefits of exercise on metabolic health?
1. Improved lipid profile (lower TAGs, higher HDL)
2. Reduced fasting glucose and insulin (even without weight loss)
3. Reduced hepatic fat accumulation
4. Reduced BP
5. Improved cardiac function
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What is NEAT?
NEAT = non-exercise adapative thermogenesis
- Energy utilised during day to day physical activities that do not include volitional exercise e.g. walking, talking, fidgeting, postural allocation
- People with increased NEAT are less likely to gain weight
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What is adaptive thermogenesis?
- Adaptive thermogenesis is the dissipation of energy through specialised cellular heath production
- Occurs primarily in brown adipose tissue (which is retained into adulthood and regulated by the brain)
- Thermogenesis occurs in the BAT via uncoupling: process by which protons are uncoupled from ATP synthesis so energy so rather than ATP production, cellular energy is dissipated through the production of heat
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Describe the different types of adipose tissue in the body, their functions and how they are regulated:
1. White adipose tissue
- Primarily comprised of triglyceride stores (one large lipid droplet)
- Functions as an endocrine hormone and produces leptin and cortisol
2. Brown adipose tissue:
- Contains numeous mitochondria and small lipid droplets
- Closely related to muscle cells (from Myf5 + progenitor also)
- Primary function is thermogenesis (shown to secrete only small amounts of leptin)
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How do appetite stimulators regulate thermogenesis and energy expenditure?
- Hypothamalmic appetite regulating peptides also regulate the sympathetic nervous system:
1. aMSH activates sympathetic neurons to drive energy expenditure- leads to lipolysis and immobilisation of fuel in WAT and activation of uncoupling proteins and thermogenesis in BAT
2. NPY inhibits energy expenditure and decreases thermogenesis in BAT
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How do levels of BAT change throughout the lifespan?
- During early life in the neonatal period there is abundant BAT (around the neck region and visceral organs)- we cannot shiver when we are born
- As muscles develop the ability to shiver, BAT rapidly declines
- At the time of puberty when muscle mass increases, there is a reinstatement of BAT development
- BAT is reinstated in adulthood
- BAT is reduced with obesity
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Are skeletal muscles capable of thermogenesis?
- Yes, skeletal muscle cells can also expend energy through uncoupling to cause thermogenesis
- Skeletal muscle expresses uncoupling proteins 2 and 3 (UCP3 can also uncouple oxidative phosphorylation)
- Skeletal muscle can undergo adaptive thermogenesis via mitochondrial uncoupling as well as futile calcium cycling
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How does futile calcium cycling contribute to heat production?
1. Calcium is expelled out of the SR via activation of ryanodine receptor 1 (RyR1)
2. The increase in cytosolic calcium causes the cell to attempt to pump the Ca+ back into the SR using SERCA1/2a (SR calcium dependent ATPaes) to maintain Ca2+ homeostasis in the cell
3. SERCA depends on the hydrolysis of ATP to drive Ca2+ back into the SR which is a thermogenic process
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What are beige adipocytes?
- Beige adipocytes are an intermediary phenotype between WAT and BAT
- They are recruitable in WAT deposit
- When beige adipocytes are recruited, there is an increase in UCP1
- In humans the subcutaneous fat in the neck area is mainly beige
- Factors that cause beige cell recruitment include:
1. Environmental factors
2. B3 adrenoreceptor agonists
3. Cyclooxygenases
4. Exercise (rodents)
5. Cold (rodents)
6. Diet (rodents)
- The recruitment of beige adipocytes from WAT is a plastic process that can occur in both directions
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How is adaptive thermogenesis controlled by the sympathetic nervous system?
- Adaptive thermogenesis is controlled by the SNS
- Cold or food stimulus is percieved by the brain and relayed by the SNS
1. SNS is primary means of activating beige adipocytes or brown adipocytes
2. Activation of the SNS causes the release of NA at brown adipocytes which binds to B-adrenergic receptors and leads to an increase in cAMP which causes lipolysis within the BAT
3. Increased lipolysis leads to an immobilisation of FFA and these FFA drive the activation of UCP1
4. The activation of UCP1 leads to thermogenesis
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How is energy expenditure regulated by weight loss?
- There is a reflex adjustment of energy expenditure to counteract weight loss
- This means that if an individual loses weight, their energy expenditure will decrease- i.e. significantly reduced BMR (after all forms of weight loss)
- This decrease in energy expenditure can be managed with leptin, however this is only short term as leptin resistance occurs in the ARC
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What hormonal adaptations take place following weight loss?
- There is an increase in ghrelin levels (promotes hunger)
- There is a decrease in amylin, PYY and CKK (gut peptides that reduce food intake)
- This results in increased hunger levels following weight loss and also a deficit in thermogenesis and BMR
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Describe the old obesity drugs briefly:
1. Metabolic uncouplers- caused hyperthermia
2. Amphetamines- addictive and caused psychosis
3. Sibutramine- caused CVS complications
4. Axokine- lack of efficacy and autoantibodies
5. NPY R antagonists- lack of efficacy
6. Leptin- lack of efficacy and leptin resistance
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Describe the new generation of obesity drugs:
1. Orlistat:
- Lipase inhibitor
- Prevents the absorption of fat from the GIT
- Only approved anti obesity drug in Australia
- Causes side effects such as cramping, gas, diarrhea and anal leakage
2. Contrave, lorcaserin, liraglutide:
- Act to enhace the melanocortin pathway in the brain: activating POMC neurons or promoting production of aMSH
- These drugs mimic the serotonergic pathway in the brain (serotonin activates POMC cells)
e. g. Lorcaserin targets 5-HT 2CR (seratonin 2C receptor) on the POMC neurons and triggers the release of aMSH
- Concerns are that activation of POMC neurons may active the SNS and cause CVS side effects
3. Qsymia:
- Wide spectrum pharmacology that acts on the brain (not restricted to melanocortin pathway)
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How does laporscopic adjustable gastric band surgery (LAGB) work?
- An LABG is an adjustable band placed on the upper part of the stomach
- The tightness of the band is regulated by injection of saline into a port just under the skin
- The band restricts how much you can eat and lead to activation of sensory nerve terminals and is associated with enhanced satiety
- If the band placement is correct and people stick to diet e.g. do not eat icecream, LAGB causes good weight loss
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How does a laprocscopic sleeve gastrectomy work?
- LSG involves the removal of 80% of the stomach
- The stomach can hold less and therefore there is increased satiety
- It disrupts the production of gut peptides by causing decreased ghrelin and increased GLP-1 and therefore increases satiety
- Slightly more effective than LAGB, but needs to be repeated after a period of time
