Beyond the Classic Endocrine Glands Flashcards
Adipocytes store energy as triglycerides and release energy as free fatty acids.
two key enzymes - what are they? and where are they found?
What can be stimulated by insulin and what does this result in?
How do lipids circulate in the body?
what must happen to TAG before it is stored?
What happens when there is too much glucose?
what allows stored tag to be broken down?
what causes this to happen?
Adipocytes store energy as triglycerides and release energy as free fatty acids.
There are two key enzymes:
Lipoprotein lipase found on the outside of fat cells and hormone sensitive lipase on the inside.
LPL can be stimulated by insulin and lead to the uptake of fatty acids in the circulation for storage.
Circulating lipids can be in the form of FFA in which case they would be bound to serum proteins. But mostly they are part of lipoproteins, so chylomicrons which contain newly digested ones or VLDLs from the liver. These are sources of TAGs.
LPL is a lipase so actually hydrolyses the TAG -> FFA and glycerol and taken up, these are then re-synthesised into TAG and stored.
This similar thing can occur when there is too much glucose, more than can be put into glycogenesis, the glucose is taken up by adipocytes and synthesised into glycerol or acetyl-CoA -> TAG.
In order to release energy, the stored TAG can be broken down (undergo hydrolysis) and FFA and glycerol released into the circulation, for energy use (so this process is energy releasing).
It is hormone sensitive lipase that allows this to happen. It is called hormone sensitive because its activity can be stimulated by hormones such as adrenaline and cortisol.
In medical terms it is more the energy storage that is the problem because it is associated with the epidemic of obesity.
Fat as an endocrine organ
3 hormones released by adiposed tissue?
what does leptin do? what receptors does it act on? what pathways does it trigger?
What is the negative feedback?
why wouldn’t leptin therapy work with obese people>
Hormones released by adipose tissue include:
• Leptin
• Adiponectin
• Resistin
These are released into the circulation and act at distant targets, so by definition they are hormones.
Leptin is released by fat cells and acts on receptors on the hypothalamus where it triggers pathways that are associated with satiety (fullness). It triggers pathways that say we don’t need more fat, we can start burning energy.
- It is a type of negative feedback, as adipose stores increase they release leptin which triggers metabolic pathways that turn down lipogenesis and turn down appetite behaviour.
- The initial hope was to give leptin to obese people, but it turned out only a small minority had an actual mutation with leptin. For most obese people it was more complex and instead associated with very high leptin levels and leptin resistance. (already high in obese people)
Conversion of sex hormones
what can adipose tissue convert?
Weak androgens produced by the adrenal glands don’t have much biological function, however they can be converted in various tissues, especially in adipose tissue. Notably they can convert weak androgens to strong androgens and androgens to oestrogens.
Cytokines
what are cytokines? how do they blur lines between paracrine and hormones?
Cytokines are local signalling molecules that are paracrine. However, some of these molecules can enter into the circulation (blurring lines between paracrine and hormone)
Adiponectin and Resistin released from adipose tissue
what do they do? levels during obesity?
- Adiponectin seems to be a hormone that potentiates insulin, seems to be needed to maintain insulin sensitivity and can increase sensitivity.
- We know in obesity that adiponectin levels decrease, which can compromise insulin effectiveness.
Resistin seems to be associated with insulin resistance, in obesity Resistin levels go up.
Obesity as a cause of Cancer
What is chronic hyperinsulinemia? What will this be associated with?
what can insulin itself stimulate the release of? what do adipocytes release during obesity?
what brings in more immune cells to fat cells? what state does this put adipose tissue?
why won’t the high leptin have any effect?
what levels will decrease and what levels will increase?
Firstly, where obesity is associated with insulin resistance you’re likely to have raised insulin levels -> Chronic Hyperinsulinemia.
Insulin itself can stimulate the release of other factors including IGF-1,
• Also, the adipocytes tend to release more of the pro-inflammatory cytokines in obesity.
On the left is fat cells in a normal, lean body mass and these tend to be smaller with fewer macrophages. High adiponectin, lower leptin.
In obesity (on right), the number of immune cells (particularly macrophages) increases, this is due to chemokines secreted by fat cells which bring in more macrophages etc.
So, with more adipose tissue, and that more adipose bringing more macrophages. So, in obesity, adipose tissue is in a semi-inflammatory state, which can be associated with some of the complications of obesity.
In obese individuals, there is a large amount of leptin release, but they have leptin resistance. Adiponectin levels are decreased which can contribute to insulin resistance (inversely correlated) while Resistin is increased (positively correlated), which can also contribute to insulin resistance.
Metabolic Syndrome
4 key characteristics of metabolic syndrome
Metabolic syndrome is a disorder of energy metabolism, in particular energy storage and is associated with a number of factors:
- Obesity (especially visceral/abdominal)
- Hypertension
• Raised serum glucose (prediabetes, intermediate between above normal and diabetes)
- High serum triglycerides (but low HDL)
• Insulin resistance (you get high glucose and stimulate high insulin which doesn’t work as well)
Visceral (VS)/intra-abdominal fat versus subcutaneous (SC) fat
which is worse? which is more evenly distributed?
what do they express and are they the same?
Visceral fat is much worse, SC fat is more evenly distributed. This is more easily seen in women, with the apple vs pear shaped.
VS and SC fat express different developmental genes. The precise reasons why visceral fat isn’t really known, it may be because it drains easier into the liver.
Gut as an Endocrine organ
what hormone is released from the stomach to make you hungry?
Ghrelin is a hormone released from the stomach that promotes feeding,
Regulation of food intake
what hromones increase when we are in absorptive state? what do they lead to via hypothalamus?
when we are in a fasting state which hormone promotes hunger? where is it released from? where does it go? what effect is this called?
Hormones are secreted from the stomach and intestines, there is leptin released from adipocytes and vagal afferents travel to the nucleus tractus solitarius.
All these signal to the hypothalamus which can stimulate appetite or satiety. So, the hypothalamus will integrate and decide to move towards burning fat/conserving.
When there is food intake, absorptive phase, we have increases in insulin, leptin, PPY, CCK, GLP-1 etc.
o These stimulate neurones in the hypothalamus which lead to an anorexigenic effect -> inhibits food intake/appetite suppressor.
Alternatively, when the stomach is empty, the hormone ghrelin released from the stomach will stimulate various neural pathways in the hypothalamus leading to an orexigenic effect -> stimulating food intake.
o Ghrelin is a potent appetite stimulator.
o Reducing leptin increases appetite.
Obesity Genetics
what 2 mutations can lead to abnormal eating behaiviour?
How can you treat one of these?
why is leptin treatment rare?
what is obesisty associated with?
Mutations of the leptin (LEP) gene, in adipose tissue or the leptin receptor (LEPR) can happen. Here it can lead to abnormal eating behaviour and early onset morbid obesity.
Leptin deficiency has been successfully treated with leptin resulting in a reduction in fat mass.
But these single mutations are very rare, and it is much more complex than simple gene mutations.
o For this reason, leptin treatment is rarely effective.
Obesity is associated with leptin resistance (leptin levels already high in obesity).
Heart and Kidney as Endocrine Organs
Where is renin produced?
what hormone does the heart produce? what is this in response to and what detects this change?
how does ANP effect the RAAS system?
what are the 2 main effects of ANP?
How does it modulate the RAAS system? what effect does this have?
what three things will cause renin to be released? what detects these changes?
Where does the conversion of Ang I to ANG II take place?
what does ANG II do? and what does it stimulate? what is released here? what effect does this molecule have?
what is released by kidneys in response to hypoxia? what does this molecule stimulate? what happens if you live in high altitude?
what can be used to treat anaemia due to renal failure? who else may use this?
Final hormone made by kidney?
sources of vit D? (2)
what is the function of vit D? what will cause more release of vit D?
What are the effects of vit D? (2)
what other hormone involved in ca homeostasis?
what is the main store of ca?
Renin is an enzyme produced by the kidney which can cleave pro-hormones in the circulation. Heart cells can release atrial natriuretic peptide (ANP), a hormone.
ANP is released in response to atrial stretch. If there is raised blood volume (increasing BP) there will be greater venous return and greater stretching. This would result in release of this hormone.
ANP effects are to oppose/inhibit the RAAS system.
ANP main effects are vasodilatation (to reduce BP) and it inhibits sodium reabsorption in the kidney promoting diuresis.
It also modulates the RAAS system by inhibiting renin which means there is less Ang II and Aldosterone, which would usually increase blood volume, increase BP, vasoconstrict etc.
So, by lowering these hormones we get the reverse.
Kidney as endocrine organ (indirectly)
In response to low perfusion pressure (detected in juxtoglomerular apparatus), reduced Na+ or sympathetic stimulation the kidney produces an enzyme, renin which converts angiotensinogen to angiotensin I.
Ang I is then converted to Angiotensin II when it passes through the lungs by angiotensin converting enzyme (ACE).
Ang II then counteracts the low BP, it does this by causing vasoconstriction and stimulating the adrenal cortex to secrete aldosterone.
Aldosterone works to increase salt and water retention in the kidneys, thus increasing blood volume and blood pressure.
Another hormone released from the kidney is erythropoietin, which is released in response to low partial pressure of oxygen in the circulation (hypoxia).
- Erythropoietin stimulates the bone marrow to make more red blood cells.
- If you permanently moved to a higher altitude, you would have less PO2 in your blood which would cause discomfort, but your body would start adapting and this is one of the ways.
Recombinant EPO can be used to treat anaemia due to renal failure, in critical illness as well as a blood doping agent for endurance sports.
The final hormone with regards to the kidney is the synthesis of active vitamin D (calcitriol). Sources of vitamin D include precursors in food and through UV light on the skin.
In the kidney there is the final conversion to the active compound (calcitriol), by the specific enzyme. The function of vitamin D is in calcium homeostasis. If calcium levels in the blood drop, the activity of this enzyme increases, and we get more release of vitamin D.
The effects of vitamin D are to increase absorption of Ca2+ from the gut and helps release Ca2+ from bone. So, it is raising blood Ca2+ levels. Parathyroid hormone also is involved in the calcium homeostasis.
Bone is main store of calcium.
Bone as an Endocrine Organ
wat do osteocytes produce? which has 2 direct effects when it reaches the kidney?
what produces uncarboxylated osteocalcin (uOCN)? what are the 3 effects of this?
Osteocytes produce fibroblast growth factor 23 (FG23), when this reaches the kidney it has the direct effect of decreasing absorption of phosphate and it also decreases the synthesis of active vitamin D.
Osteoblasts produce uncarboxylated osteocalcin (uOCN), which seems to:
- Increase insulin production and secretion (in pancreatic beta cells)
- Increase adiponectin secretion (potentiates insulin, in adipocytes)
- Increases insulin sensitivity and glucose uptake in muscle.
Tumours as Endocrine Secreting Tissues
what can benign tumours do in encodrine organs? give an example
what can ectopic tumours do?
name a hormone dependent tumour and how they work? How do we therapeutically target this?
Tumours (usually benign) can develop in classical endocrine organs and increase secretion of a hormone(s) e.g. pituitary adenoma, increased corticotropes = Cushing’s disease.
- Sometimes tumours can be an ectopic source of hormone (outside normal gland of release), for example certain lung tumours may secrete ACTH and thus stimulate cortisol secretion.
- Some tumours such as breast and prostate cancer are hormone dependent. They convert circulating precursors into biologically active steroids that stimulate their own growth.
The oestrogens and active hormones are needed by the tumour to continue growing. Here oestradiol is the end active product. Because of this we can use it therapeutically to target enzymes to stop production of these hormones to stop growth.
Circadian Rhythms
What controls this? where is it released from? when is it low and when does it peak?
what other physiological functions work in correlation with this?
Is cicardian rhythmn entrained by light/dark cycle? how may it influence it?
What happens in the abence of light?
what controls the cicadian rhytm and has links to the pineal gland?
what happens to shift workers and SAD and jet lag? what do they have higher prevalence of?
Circadian rhythms (body’s biological clock) are controlled by melatonin secreted from the pineal gland. It is secreted in a rhythmical pattern, that seem to low levels in day, rise at night reach a peak and then fall by morning.
In correlation with this we have various rhythmically active physiological functions, such as body temp dropping during sleeping. Subjective alertness decreases at night.
Circadian rhythms are endogenous, they are not entrained to the light-dark cycle, they instead run in about a 24hr cycle. But it is capable of being influences via sensory input from environmental cues in order to adapt to this cycle (of light-dark).
- As in the absence of light, the pineal gland still releases melatonin in approx. 24hr cycle
It is the suprachiasmatic nucleus that controls circadian rhythms and has neural links to the pineal gland, which can secrete melatonin.
Jet lag, shift workers, SAD (seasonal affective disorder)— Rhythms out of synchrony with dark/light cycle
- Epidemiological studies show that shift workers, long distance flight crews etc. have higher prevalence of cancers, diabetes etc.
