62) Beyond the classic endocrine glands

Question 1

How can adipocytes aid energy metabolism?

Answer 1

• Fats are able to stores energy in the form of triglycerides and can later release energy by breaking triglycerides down into free fatty acids

Question 2

What is lipotoxicity?

Answer 2

• When there are too many free fatty acids in tissue which leads to many cellular and metabolic consequences

Question 3

What is the mechanism for the formation of stored fats?

Answer 3

• Triglycerides in circulation (either VLDLs or chylomicrons) will be taken up for storage through the mechanism of lipoprotein lipase (LPL)
• LPL hydrolyses the triglycerides into free fatty acids and glycerol so they can be taken up by the adipocytes
• They are then re-esterified into triglycerides for storage.
• Glucose is another source of stored as lipogenesis (in the adipocytes and liver) is able to synthesise free fatty acids from glucose
• These fatty acids can also be esterified into triglycerides for storage and occurs when glycogen stores are full
• The process of lipogenesis is stimulated by insulin

Question 4

What is the mechanism for fat mobilisation during energy metabolism?

Answer 4

• Triglycerides (in adipocytes) are broken down into free fatty acids and glycerol which can then be released into circulation
• In circulation they are bound to albumin and are taken to other tissues for energy use (Beta-oxidation in tissues and ketogenesis in the liver)
• Counter regulatory hormones (e.g. Hormone Sensitive Lipase, adrenaline, noradrenaline) stimulate the mobilisation of triglycerides from storage into the circulation

Question 5

What hormones do adipose tissue secrete?

Answer 5

• Leptin: Signals satiety (fullness sensation) in the brain (negative feedback system of fat storage)
• Adiponectin: Increases insulin sensitivity
• Resistin: Correlated with insulin resistance
• Androgens: Contains aromatase which converts androgens into oestrogen (in men and women)
• Oestrogens: Important for bone health in men and women
• Cytokines: Involved in local signalling for an immune response

Question 6

How is leptin release under negative feedback control?

Answer 6

• Leptin (released from adipose tissue) signals satiety in the brain (i.e. it tells the brain to stop eating)
• As fat stores build up increasing leptin is released which signals the brain that energy store is adequate and so there is no need to consume and store more energy
• This means there is a decreased energy store and decreased food intake

Question 7

How is leptin linked with obesity?

Answer 7

• Leptin is a peptide which is formed through the expression of genes (i.e. the transcription and translation of genes)
• A mutation regarding leptin can lead to unrestrained eating (over eating) which lead to obesity
• This mutation can either be a mutation in the leptin receptor or in the leptin gene but these mutations are very rare
• Instead obesity is associated with leptin resistance as leptin levels are already high in obesity (as in obesity fat stores are large which triggers increased leptin secretion)

Question 8

How do we treat obesity caused by a mutation in the leptin gene?

Answer 8

• Leptin treatment/ leptin replacement therapy is given

Question 9

Why was leptin not a suitable explanation for obesity?

Answer 9

• There are multiple interacting pathways that control food intake and energy utilisation
• Instead leptin is just one of many different pathways that leads to obesity

Question 10

Why is obesity bad?

Answer 10

• Obesity leads to negative metabolic consequences (such as insulin resistance) as the balance of secretions from adipose tissue gets changed
• In obesity we have decreased adiponectin secretion, increased leptin secretion (and resistance) and increased resistin
• The balance of cytokines also changes in obesity and there is a shift to more pro inflammatory cytokines
• This will attract more macrophages and so more macrophages will infiltrate adipose tissue which will signal inflammation
• Overall there is an induced state of chronic, low-level inflammation
• It can also lead to adverse cardiovascular effects, stroke and other complications

Question 11

What are the explanations for the changes in signalling pattern in obesity?

Answer 11

• As adipose tissue mass expands new adipocytes are made and already existing adipocytes expand in volume (as more triglycerides accumulate within them)
• This means there is a greater diffusion distance from the capillaries and so there can be metabolic changes associated with hypoxia leading to pro inflammatory cytokines release
• Another possibility is that there is increased metabolic stress in the mitochondria and/or endoplasmic reticulum
• This is due to the increased load of nutritional processing
• Another possibility is that visceral adipose tissue (around the middle) blood supply will drain into the portal vein
• This means that signalling molecules from visceral adipose tissue will reach the liver first
• This means that many of the metabolic changes we see may be mediated by visceral adipose tissue signalling to the liver

Question 12

Why is distribution of adipose tissue in obesity important?

Answer 12

• More visceral adipose tissue (stored in the abdomen) is more strongly correlated with the adverse effects of obesity compared to subcutaneous adipose tissue (stored in the thighs and hips)
• This is because visceral adipose tissue will drain directly into the liver via the portal circulation
• This means that looking at BMI is not enough on its own but rather we should consider the distribution of the adipose tissue

Question 13

What is metabolic syndrome?

Answer 13

• A cluster of metabolic disorders commonly associated with excess adipose tissue/ obesity
• Metabolic syndrome is diagnosed when a persons suffers from three side effects:
• Obesity
• Hypertension
• Hyperglycaemia (prediabetes by using impaired fasting glucose tolerance)
• High serum triglycerides (with low HDLs/good cholesterols)
• Insulin resistance

Question 14

What is the largest endocrine gland within the body?

Answer 14

• The gastroenteropancreatic tract is the largest endocrine gland within the body

Question 15

What is ghrelin?

Answer 15

• A hormone secreted by endocrine cells in the stomach epithelium and is a strong stimulant for feeding (a potent appetite stimulator)
• It also has an effect on growth hormone secretion in the hypothalamus
• Its secretion peaks before feeding and decreases as the stomach fills

Question 16

What are the incretin hormones?

Answer 16

• Gastric Inhibitory Peptides (GIP) and Glucagon-Like Peptide 1 (GLP-1)
• They are stimulated by the presence of nutrients (in the small intestines) and have many effects

Question 17

How do incretin hormones bring about changes in the body?

Answer 17

• After a meal the presence of nutrients in the intestines leads to the stimulation of these hormones as well as the increased absorption of glucose into circulation
• This means blood glucose concentration rises (so their secretion is coupled with increase in blood glucose) which potentiates (makes stronger) insulin release
• Thus insulin release is increased when the incretin hormones are secreted (the incretin effect)
• GLP-1 is also an appetite suppressant

Question 18

How is food intake regulated?

Answer 18

• Hormones secreted from the stomach and intestines
• Leptin secreted from adipocytes
• Vagal afferents to the nucleus of the tractus solitarius (through food in the GI tract triggering sensors)
• These hormones/signals are sent to the hypothalamus which then balances the inputs and control feeding behaviour (i.e. by promoting feeding behaviour or promoting energy spending behaviour)

Question 19

What parts of the hypothalamus affect appetite?

Answer 19

• Ventromedial hypothalamus: When stimulated food intake is suppressed (anorexigenic). This is done by stimulating POMCs on neurons. It is influenced by increased leptin, insulin, GLP-1 and CCK
• Lateral hypothalamus: When stimulated stimulates feeding behaviour (orexigenic). This is done by stimulating AGRP and Neuropeptide Y (NPY) on neurones. It is influenced by increased ghrelin and decreased leptin

Question 20

What are other non-classical endocrine organs?

Answer 20

• Heart: Releases peptide hormones such as ANP (stimulated by atrial stretch and causes Na+ secretion)
• Kidneys: Secretes Renin which is used for RAAS
• Bone
• Tumours: Could be an adenoma of a classical endocrine gland (e.g. pituitary adenoma) or could be on non endocrine organs (e.g. carcinoma of the lungs)
• Pineal gland

Question 21

How does the kidney function as an endocrine organ?

Answer 21

• The kidney secretes erythropoietin in response to low partial pressure of oxygen
• The hormone stimulates the production of erythrocytes (increased red blood cell count)
• This is under negative feedback control as when partial pressure of oxygen decreases it will increase erythropoietin secretion
• This increases red blood cell count which will increase the oxygen carrying capacity and so will increase oxygen partial pressure
• This increased partial pressure decreases the release of erythropoietin

Question 22

What is recombinant erythropoietin (EPO) used for?

Answer 22

• Used to treat anaemia due to renal failure and critical illness
• Used as a blood doping agent for endurance sports

Question 23

How can we increase the oxygen carrying capacity within our blood without drugs?

Answer 23

• By training at high altitude (where partial pressure of oxygen is low) the oxygen-haemoglobin dissociation curve shifts to the left.
• This means we induce hypoxia within our body which in turn stimulates the secretion of erythropoietin
• This increases red blood cell count which in turn increases oxygen carrying capacity
• Several weeks of high altitude training will increase EPO levels

Question 24

What are circadian rhythms?

Answer 24

• Physiological or psychological endocrinological rhythms that vary on a daily basis
• There is a biological clock that senses the time of day which is located in the suprachiasmatic nucleus

Question 25

What is the suprachiasmatic nucleus?

Answer 25

• Many rhythms are under the influence of the suprachiasmatic nucleus (e.g. melatonin secretion, temperature, reactions)
• The suprachiasmatic nucleus is synchronised to the light dark cycle (i.e. day and night cycle)
• It does not require the external day and night cycle (i.e. external night and day) as it will free run (and so has an intrinsic period)
• By alternating periods of darkness and light on a regular basis the circadian rhythm will entrain to that rhythm
• A lack of light and darkness will allow the rhythm to free run which (over a long period of time) will start to deminish

Question 26

Describe the mechanism of melatonin release

Answer 26

• Melatonin is secreted by the pineal gland and is driven by the suprachiasmatic nucleus
• The suprachiasmatic nuclei sends signals to other hypothalamic nuclei which then stimulate the superior cervical ganglion (via the sympathetic nervous system)
• From here a signal is sent to the pineal gland which triggers the release of melatonin
• The circadian variation in the activity of the suprachiasmatic nucleus is passed onto the pineal gland via a multistage route
• During the light phases of the day little to no melatonin is made whereas in the dark stages secretion rises and peaks during the night where it remains constant. As it becomes morning time secretion decreases

Question 27

How is melatonin secreted only when it is dark?

Answer 27

• There are direct projections from the retina to the suprachiasmatic nucleus (in the hypothalamus)
• Neural inputs are sent from a special class of retinal ganglion cells which are responsible for sensing light levels (and not involved in visual perception) to the suprachiasmatic nucleus (causing melatonin secretion)
• The connection between the special retinal ganglion and the suprachiasmatic nucleus are inhibitory and so when light enters the eyes it sends inhibitory signals to the suprachiasmatic nucleus which inhibits the pathway of melatonin release
• As we transition from daytime to night time the inhibition wears off and so melatonin levels increase

Question 28

Why is the variation of melatonin secretion important?

Answer 28

• It is important for synchronising sleep to the circadian rhythm

Question 29

How can sleep disorders be treated?

Answer 29

• Sleep disorders can be treated using melatonin (depending on the cause)
• When we travel into a different time zone our circadian rhythm will not immediately switch to the new light/dark cycle
• It will be out of phase initially and will take some time
• Melatonin can be used to reset this circadian rhythm and help you better adjust to the new time zone

Question 30

Why are sleep disorders bad?

Answer 30

• Patients with sleep disorders have shown a higher prevalence of cancer, physiological disorders, metabolic syndrome, diabetes and cardiovascular diseases.