Body Nutient Status - informing the brain about energy stores

Question 1

Where do satiety signals travel?

Answer 1

Sympathetic afferents and information from the upper GI tract Via the vagus nerve converge in the NTS (nucleus of the solitary tract) and the hypothalamus.

Other signals generated by peripheral organs are humoral and convery information about energy stores. Mostly derived from the pancreas abnd adipose - Long term energy balance.

Question 2

Meal initiation, termination and inter-meal frequency are regulated by long or short term processes?

Answer 2

Short term

Question 3

Which 3 factiors regulate food intake?

Answer 3

• Satiety signalling
• Adiposity negative feedback signalling
• Food reward

Question 4

Lack of leptin or leptin receptor causes what?

Answer 4

• Massive hyperphagia
• Decreased energy expenditure
• Insulin resistance
• Hyoperglycaemia
• Metabolic dysfunction

Leptin has been found to rapidly control glycaemia control of ob/ob mice

Question 5

Functions of leptin

Answer 5

Leptin is a pleiotropic hormone meaning it has multiple effects ie has multiple phenotypic expressions

CNS leptin: increases gluconeogensis and decreases glycogenolysis. Suppresses lipogenesis in WAT.

Required for normal function of immune an reproductive systems

Regulation of blood pressure (central - via sympathetic output)

Extremely important in regulating onset of puberty

Extremely thin women stop ovulating

Thin women enter puberty later than heavier counterparts

Enchances angiogenesis

Regulates synthesis, release and actions of other hormoines such as insulin, glucocorticoids and growth hormone

Question 6

Levels of leptin are dependent on diet and mass

Answer 6

Plamsa leptin levels highly correlated with adipose tissue mass

Fluctuates with nutritional state - fasting decreases plama leptin

Administration of leptin causes reduction on food intake - only works through icv (intracerebroventricular) and not peripherally suggesting CNS main leptin target.

Question 7

Where is leptin primarily produced?

Answer 7

WAT - White Adipose Tissue

Secereted into circulation after production

Question 8

Why is endogenous leptin paradoxiacally high ion obese patients is it reduces food intake?

Answer 8

Resistance to the actions of leptin. Vast majority of human obesity is associated woth high levels of circulating insulin.

Question 9

Leptin and glucose homestasis.

Answer 9

Hyperinsulinaemia precedes obesity in db/db or ob/ob mice

Administering a low leptin dose does not alter the weight of the moce but does reduce blood glucose and insulin levels. Conversely, giving leptin antagonists raise blood glucose and insulin before a change in body weight.

This proves that lpetin has metabolic effects indepedent of body weight reduction

Therapeutic example: humans with lipodystrophy

Question 10

What is lipodystophy and how is it related to leptin?

Answer 10

Individuals have few or no fats cells and store lipid elsewhere (muscle, liver) and have hyperlipidaemia - a fat redistribution syndrome

Patientd often severely insulin resistant and hyperglycaemic.

Lack of leptin due to low WAT

Question 11

Benefits of leptin therapy (myalept) in lipodystrophy

Answer 11

• Improved insulin sensitivity
• Reduced fat in liver and muscle cells
• decreased ciculating fat cells
• fasting blood glucose decreased
• recovered ovulation in a proportion of women

Many patients are able to discontinue insulin/hpuglycaemic drugs

Question 12

Summarise the CNS targets of leptin

Answer 12

LEP-Rb (leptin receptors) are strongly localised to ARC neurones - NPY/AgRP & POMC/CART. If you destroy ARC, i.c.v. leptin no longer reduces food intake.

Restoration of LEP-Rb in ARC in LEP-Rb null animals will reduce their obesity, hyperpohagia and hyperglycaemia.

Increases in NPY/AgRP mRNA and decreases in POMC/CART mRNS are seen in fasting mice, ob/ob mice and db/db mic. Direct administration of leptin reverses these changes.

Question 13

Summarise the role of leptin in synaptic plasticity

(great summary in notes of lecture 3 slide 18)

Answer 13

Leptin defeciency reduces brain size and hinders CNS development. ob/ob mice have disrupted projection pathways between ARC and PVN. If you give leptin to neonates these neuroanatomical defects can be reveresed.

Leptin increases the amounts of neurites (axons + dendrites) in ARC explants. ob/ob mice have altered numbers of synaptic contacts to NPY & POMC neurones compared to wild type:

• Increased EPSCs to NPY/AgRP neurones
• Increased IPSCs to POMC/CART neurones
  
  • Excitatory/Inhibitory Postsynaptic Currents​

Leptin given to ob/ob mice restored the number and type of synaptic connections to wild type.

Question 15

Summarise insulins role as an adiposity signal

Answer 15

Insulin also circulates at levels proportional to body adiposity.

Insulin receptors are expressed in the hypothalamus, most notably in ARC. Deletion of brain insulin receptor results in obesity.

Insulin administration inhibits food intake and reduces body weight in mice.

Insulin reverses fasted/diabetes induces increase in NPY/AgRP mRNA and decreased POMC mRNA in ARC.

Question 16

Describe how insulin alters energy homestasis

Answer 16

Central leptin actions are thopught to require intact insulin signalling.

CNS insulin required for the regulation of glucose homestasis - primarily via hepatic glucose production

InsR expression os high on POMC and AgRP ARC neurons. Deletion mainly impacts glucose metabolism rather than food intake/body weight. Studies indicate that AgRP neurones regulate insulin suppresion of HGP (hepatic glucose production)

Question 17

What effects does insulin delivery to the hypothalamus have?

Answer 17

• Improves whole body insulin sensitivity
• Promotes lip0genesis and peripheral fat accumulation (WAT)
• Increases adaptive thermogenesis (BAT)

Question 18

How does central insulin contribute to HGP?

Answer 18

Insulin acts in ARC to inhibit gluconeogenesis.

Reduced central InsR signalling diminishes ability of peripheral insulin to suppress HGP. This action is mediated through ARC AgRP neurons and involves vagal efferents to the liver and transduction of alpha7 nicotinic receptors and IL-6. Ultimates gluconeogenic gene expression is altered.

Basically there are two pathways involved, the central pathway modulates the peripheral pathway - see pic

Question 19

Describe leptin and insulin simmilarities in regulating ARC neurons

Answer 19

Leptin and insulin receptors are coexpressed on ARC neurons. Both hormoes increase POMC mRNA and decrease NPY/AgRP mRNA, therefore increasing aMSH and reducing NPY neuropetide release in the hypothalamus respectively.

MC3/MC4 receptor antagnoist attenuate reduction in food intake elicited by i.c.v leptin and insulin.

Consensus view is that both leptin and insulin produce similar effects on ARC neuron electrical properties, however electrophysilogical analysis reveals that NPY/AgRP and POMC/CART neurons are differently affected by these hormones, suggesting the existence og multiple discrete pathways.

Question 20

Outline the two-neuron model of ARC circuitry.

Answer 20

NPY/AgRP anf POMC both project to 2nd order neurones in the PVA/LHA. Leptin depolarises POMC neurons and mediates reduced GABA release from NPY neuron terminals onto POMC neurones, therefore inducing both direct and indirect excitation to POMC neurons.

See Pic - Note that NPY neurones take precidence over POMC neurons - Survival adaptation to eat more