Metabolic Syndrome
Describe the NORMAL function of Leptin
1) Leptin binds to the leptin receptor (OB-R). 2) This is found on membranes of cells in the nervous system (hypothalamus) and peripheral tissues such as adipose tissue, skeletal muscles, pancreatic beta cells and liver
What does waist circumference indicate?
Indicates body fat distribution and relates to risk of CVD
Why is hyperglycemia caused in insulin resistance?
Instead of insulin receptor substrate being phosphorylated on tyrosine, it is phosphorylated on serine (PI3K & Akt pathway are not activated) This causes hyperglycemia because the message does not get sent, this shifts to lipid metabolism and hyperlipidemia
What is the relationship between insulin and leptin?
Insulin triggers leptin production Leptin increases insulin sensitivity
Where is leptin produced from and what is it?
Leptin is produced mainly by adipose tissue and the circulating level of leptin correlates directly with body fat mass (increased in fed-state) - It is a 167 amino acid (16kDa) peptide hormone encoded by the obesity gene (ob) - Leptin is a satiety signal that tells the body it is well-fed and reduces appetite. - It also regulates energy metabolism more directly
How is a fasting plasma glucose test taken and what are the normal levels?
Plasma glucose test taken several hours after a meal. - If glucose is more than 110mg/dL it indicates risk of metabolic syndrome (Around 9/10mM) - Normal glucose fasting level is 3-4mM
Give examples of the risk factors associated with metabolic syndrome
1) Abdominal obesity 2) Insulin resistance — Relating to diabetes (type ii) 3) Glucose intolerance — Relating to diabetes (type ii) 4) Dyslipidemia (high TAGs, low HDL) — Means that it doesn't work, lipid metabolism or status in the body is not correct 5) Non-alcoholic fatty liver disease (NAFL) — (not induced by alcohol) 6) Hypertension — High blood pressure 7) Cancer 8) Osteoarthiritis 9) Sleep apnoea 10) Reproductive disorders
What are the symptom criteria for metabolic syndrome?
1) Abdominal obesity: Waist circumference in cm. MEN <102 WOMEN > 88 2) Blood Pressure (mm/Hg) >140/90 3) Fasting Plasma Glucose (mg/dL) >110 4) Triglycerides (mg/dL) >150 5) HDL Cholesterol (mg/dL) <40 MEN <50 WOMEN
Describe the cellular response of metabolism after a meal (Post-prandial)
1) After a meal, nutrients are absorbed from the intestines and increase the blood glucose level and the blood lipid levels (in VLDL, LDL etc) 2) The body responds to this by secretion of insulin from pancreatic Beta cells. 3) Insulin secretion indicates the fed-state 4) Insulin signals to many cells in the body to take up glucose and lipids, which can be stored as glycogen and TAGs respectively 5) Insulin binds to insulin receptors (IRs) on cell, leading to a signalling network responsible for cell nutrient uptake and anabolic metabolism
What are the current therapies for treating obesity?
1) Dieting, to reduce energy intake and increase energy expenditure 2) Surgery either liposuction or gastric surgery 3) Drug interventions, including appetite suppressants and drugs that decrease fat absorption in the intestine as well as many specific treatments for diabetes, hyperlipidaemia, hypertension etc. 4) A new idea: Brown adipose tissue has been suggested to improve metabolic condition in contrast to white adipose tissue
Describe the NORMAL physiological insulin signalling pathways
1) Gab (G protein) and IRS (Insulin receptor substrate) are signalling factors associated with the insulin receptor — switches on the MAPK pathway 2) When insulin binds the receptor they get activated 3) IRS is normally active by being phosphorylated on a tyrosine residue Gab switches on one of the MAPK pathways which leads to mitogenesis and cell proliferation, whereas IRS switches on phosphoinositol 3 phosphate kinase and then the serine/threonine kinase Akt (controls what happens in the cell, especially fatty acid metabolism) 4) This alters energy metabolism, upregulating glucose uptake.
Describe the mechanisms by which leptin resistance cause hypertension
1) Increased leptin results in an increase in sympathetic nervous system activity 2) This increases renin-angiotensin-aldosterone system 3) This increases peripheral resistance 4) Results in Hypertension & CVD
What are the 2 major factors considered in Metabolic Syndrome?
1) Insulin 2) Obesity
What are 2 examples of hormones which are satiety signals?
1) Insulin (released from the pancreas) 2)Leptin (released from adipose tissue) They reduce appetite, increase energy storage and energy utilisation In metabolic syndrome this regulation is dysfunctional
Describe the mechanisms by which insulin resistance cause hypertension
1) Insulin resistance results in endothelial dysfunction 2) This results in a decrease in Na+ excretion 3) This results in an increase in plasma volume 4) Results in hypertension & CVD
What is the relationship between leptin and adipose tissue?
1) Obese people have much higher levels of leptin (80ng/ml) than normal physiological levels (3-5ng/ml) this follows logically from them having much more white adipose tissue producing leptin The problem is that leptin doesn't seem to work. This suggests a deficiency of the leptin receptor or another mechanism of leptin resistance As adipose tissue increases in the body, there seems to be a switch in its behaviour. From cells that regulate fat mass correctly (healthy-lean) to ones that have an inflammatory phenotype (toxic/fat) Recently the concept that white adipose tissue which mainly stores fat is bad for Metabolic syndrome and brown adipose tissue which burns lipids using a mitochondrial uncoupling protein is good. Possible BAT is healthy/lean and WAT is toxic/fat
Describe how insulin & leptin resistance leads to chronic inflammation
1) Release of proinflammatory cytokines such as IL-6 and TNF-alpha from several different tissues, including neurones in the hypothalamus 2) Endothelial dysfunction (also through glucotoxicity) 3) Activation of endothelial NADPH oxidises this causes glucotoxicity However, it is important to note that not all obese people have metabolic syndrome and not all people with metabolic syndrome are obese. This is where the concept of healthy versus toxic adipocytes came from
What are the alternative terms for metabolic syndrome?
1) Syndrome X 2) Polymetabolic syndrome 3) Insulin resistance syndrome 4) Deadly quartet (4 main important factors - diabetes, hypetension, obesity) 5) Civilisation syndrome — Most common in civilised parts of the world
Describe the sites of actions of insulin and leptin in relation to their activation and secretion
1) The hypothalamus controls many basic functions of the body and behaviours by secreting peptide hormones that act on other organs e.g neuro anorectic peptides which reduce appetite 2) The hypothalamus interacts with the pituitary and thyroid glands both involved in energy metabolism. 3) Both insulin and leptin can act directly on neurones in the hypothalamus to control appetite 4) Leptin improves optional body functions that are reserved for time of plenty
What is Sibutramin (Reductil)?
A centrally acting appetite suppressant. It acts by inhibiting the reuptake of noradrenaline and serotonin which are neuro-signalling molecules involved in controlling mood and appetite amount other functions. But it has been withdrawn due to adverse reactions and increased CVD risk
What is metabolic syndrome?
A clustering of cardiometabolic risk factors
Define the term syndrome
A syndrome is defined as a group of symptoms that consistently occur together and collectively indicate or characterise a disease, psychological disorder or other abnormal condition
What does an apple shape indicate?
Apple shaped relates to a large amount of abdominal fat or visceral fat, this is fat that surrounds the organs and this has an increased risk of disease, in contrast with the fat on the hips, button, thighs which is subcutaneous.
How are excess calories mainly stored?
As Triglycerides in white adipose tissue
Why are insulin and obesity seen as the major factors in Metabolic Syndrome?
Diabetes is a result of 1) Hyperglycemia 2) Insulin resistance Obesity is a result of 1) Hypercholesterolemia 2) Hyperlipidaemia 3) Low HDL & High LDL Metabolic Syndrome results in 1) Hypertension 2) CVD 3) Increased mortality
How was leptin discovered?
Friedmann et al (1994) identification of leptin as the gene product of the ob gene which is mutated in the obese mouse model ob/ob - Both the fa/fa phenotype in rats and the db/db (diabetic) phenotype in mice have now been established as resulting from mutations in the leptin receptor gene (ObR) - Therefore mutations of either the gene for leptin or its receptor cause extreme overeating and obesity in rodents, this shows leptin has a role in weight control - The animal are fed as much as they want (ad libitum) - Both leptin deficiency and leptin receptor deficiency cause obesity, the - LepR deficiency also gives a clear diabetic phenotype
How is type II diabetes caused?
Over-nutrition leads to continual production of insulin and hyperinsulinemia which eventually desensitises the system so that it no longer responds (receptors are not longer responsive to insulin even though it is still being produced it no longer has the same effect)
Why is LDL & VLDL regarded as being bad cholesterol?
Regarded as bad cholesterol as they transport cholesterol from the liver to the tissues and their levels go up with high lipid consumption and general over-nutrition
Why are fatty acids always converted to acetyl Co-A and not back to glucose?
The conversion of pyruvate to acetyl-CoA (catalysed by pyruvate dehydrogenase) is irreversible
Why is there seen to be an underlying pathology between the risk factors associated with metabolic syndrome?
These factors more commonly occur together than can be explained by chance, which leads you to conclude that there is an underlying pathology that links them
What occurs in the swelling of adipocytes?
They produce more leptin and more TNF and IL-6 leading to inflammatory effects, triggering insulin resistance leading to diabetes, hypertension etc
What is mTOR and how is it evidence that a caloric deficiency can extend lifespan?
mTOR is a connection between 2 pathways, very important in controlling lifespan of cells and humans in general.