LT3 Body Nutrient Status Flashcards
What causes obesity?
Imbalance of foot intake and energy expenditure
Suggestesd that defective neuronal network regulation via ANS = in turn induces global changes in nutrient and energy flux
What information is sent to the brain in obesity?
Energy stores
Food intake - amount and type
Immune status - microbiome
What in the periphery has to be controlled?
Substrate utilizaiton and storage
Describe the flow of information
Bi-directional
2nd order neurones can also signal back to 1st order
What type of inputs from from periphery to CNS?
Both neuronal and endocrine
Where do satiety signals come from and what do they control?
‘meal size’
Information from upper GIT via vagus and sympathetic afferents converge on NTS and hypothalamus
What does NTS stand for?
Nucleus of the solitary tract
What are the long term and short term signals about energy stores?
Satiety signalling = short term
Adiposity negative feedback signalling = long term
Define satiation
Senesation of fullness generated during a meal
Define satiety
Period of time between end of one meal and start of the next
Define adiposity
State of being obese
What does short-term satiety signalling regulate?
Meal initiation, termination and inter-meal frequency
What signals are generated by the GIT?
Satiation signals
CCK
PYY
GLP-1
OXM
Obestatin
All increase signalling durign meal to supress food intake and appetite
What happens to satiation signals during meal?
Satiation signal increases during meal to limit meal size
What is the role of CCK?
CCK cells are concentrated in the proximal small intestine.
CCK hormone
is secreted into the blood upon the ingestion of food.
The physiological actions
of CCK include stimulation of pancreatic secretion and gallbladder contraction,
inhibits gastric emptying, and induction of satiety.
Where does CCK signal to in the brain?
Signals to hindbrain NTS
What is the role of PYY?
Inhibits gastic motility & reduces food intake
Where is PYY secreted from?
L-cells in the gut
What is the role of GLP-1?
Inhibits gastric emtyping and reduces food intake
Where is GLP-1 released from?
L-cells of the gut
What two satiety signals are released from L-cells in the gut?
PYY and GLP-1
Why are PYY and GLP-1 considered hypo?
Because they have a significant effect on lowering blood sugar levels by stimulating insulin secretion and suppressing glucagon release, essentially promoting a hypoglycemic state when their levels are elevated, particularly after a meal when they are naturally released in the gut.
What is the role of oxyntomodulin (OXM)?
Suppresses appetite
What is the role of obestatin?
Anorexigenic = suppresses food intake
What does NTS do?***
Key integrative centre?
What neural route does long-term satiety signalling go through?
Adipose and pancreas signal thorugh ARC
Signal eventually delivered to NTS
What neural route does short-term satiety signalling go through?
Stomach and GIT signals both to ARC and to NTS (both via SNS afferent and vagus)
Liver signals via vagus nerve to NTS
Where is leptin predominantly made and released?
White adpiose cells
Explain the difference between ob/ob and db/db mice?
ob/ob mice = leptin deficient
db/db mice = LEPR b isoform deficient
What type of hormone is leptin?
Pleiotropic hormone = a hormone that influences multiple traits or phenotypes.
This means that a single hormone can have multiple functions and act at different levels in the body.
What symptoms do ob/ob and db/db mice have?
Causes morbid obesity and T2D leading to:
Hyperphagia = a feeling of extreme, insatiable hunger
Decreased energy expenditure
Insulin resistance
Hyperglycaemia
Metabolic dysfunction
What happens when leptin is given to ob/ob mice?
Rapidly restore glycaemic control (independent of food intake)
CNS leptin reduces gluconeogensis & glycogenolysis
Suppresses lipogenesis in white adipose tissue
What systems is leptin required for?
Normal function of immune and reproductive system
Important for regulation of blood pressure
What role does leptin play in puberty?
Regulates onset of puberty
Thin women enter puberty later than heavier counterparts
Extremely thin women stop ovulating
What role does leptin play in angiogenesis?
Leptin enhances angiogenesis = formation of blood vessels
What other hormones may leptin regulate?
May act to regulate the synthesis, release and actions of other hormones
Insulin
Glucocorticoids
Growth hormone
What effect does leptin have in tumours?
Enhances proliferation = poss thorugh enhancing angiogenesis
How is bone growth in ob/ob mice?
Reduced bone growth
This is corrected by leptin
What 5 areas does leptin act on?
Brain
Bone and Cartillage
Vascular function
Reproduction
Immune system
Why are there isoforms of the LEPR?
Because LEPR mRNA has multiple splice variants
Where is LEPRb isoform found abundantly?
Hypothalamus = ARC, LHA, VMH
Which LEPR isoform allows leptin to cross the BBB?
Possible a or c
What is correlated with plasma leptin levels?
Adipose tissue mass
So high leptin = high adipose tissue mass
When does plasma leptin decrease?
During fasting because leptin signals fullness
Circulating leptin levels fluctuate with nutritional state
What does i.c.v stand for?
Intracerebroventricular injection
Route of administration for drugs via injection into the cerebral ventricles so that it reaches the cerebrospinal fluid (CSF)
How do we know leptin primarily targets the CNS?
Injection of a single dose of leptin i.c.v reduces food intake at doses that have no effect given peripherally
What levels of endogenous leptin do obese people have and why?
Obesity due to high fat diet = high levels of endogenous leptin
Because there is resistance to actions of leptin
(often associated iwth high levels of circulating insulin and peripheral insulin resistance)
What precedes obesity in ob/ob and db/db mice?
Hyperinsulinaemia = the body has too much insulin in the blood relative to glucose
How would low leptin dose affect ob/ob mice?
Does not lower body weight
BUT
Reduces blood glucose and insulin levels in ob/ob mice
What is lipodystrophy?
Individuals have fewer or no fat cells
Store lipid elsewhere (muscle or liver)
Have high levels of lipid in blood
Fat redistribution syndrome = defective nutrient partitioning
What does lipodystrophy tell use about leptin metabolic effects?
Leptin metabolic effect are independent of body weight reduction
How do you get lipodystrophy?
Congenital or acquired (autoimmunity)
Symptoms of lipodystrophy?
Insulin resistant
Hyperglycaemic
Those with severe fat deficiency = hyperphagic
What is lipodystrophy associated with?
Diabetes
LIver steatosis
Common in women = failure to ovulate
Where are LEPRb localized?
Mainly in ARC neurones
When ARC destroyed and i.c.v leptin added = no longer reduced food intake because receptors were destroyed
How does fasting affect mRNA of different neuropeptides?
Increases NPY/AgRP mRNA = signalling hunger
Decreases POMC/CART mRNA = signalling satiety
What effects on the brain does leptin deficiency have?
Reudces brain size and hinders CNS development
Leptin given to NEONATES (not adults) reverses these neuroanatomical defects
What brain pathway is disrupted in ob/ob mice?
Projection pathway between ARC and PVN
ob/ob mice have altered numbers of SYNAPTIC contacts to NYP & POMC neurones copmared to wild type, what are they?
Increased EPSCs to NYP/AgRP = promotes hunger
Increased IPSCs to POMC/CART = inhibits satiety
How does leptin affect synaptic plasticity?
Lack of leptin alters number of excitatory and inhibitory synapses to these neruones
Leptin given to ob/ob mice restored number and type of synaptic connections to wild type
How does insulin act in the CNS vs the PNS?
While insulin primarily functions in the periphery to stimulate glucose uptake in tissues like muscle and liver, in the brain, its primary role is to regulate central nervous system functions like appetite, cognition, and mood, largely independent of directly influencing glucose uptake, due to the unique characteristics of the blood-brain barrier and specific brain insulin receptors; essentially, insulin has a more “neurotransmitter-like” action in the brain compared to its metabolic role in peripheral tissues.
What things are similar about insulin to leptin?
Insulin also circulates at levels proportional to body adiposity
Insulin receptors are expressed in hypothalamus (ARC)
Deletion of brain insulin receptor results in obesity
Insulin injected i.c.v inhibits foodintake and reduces body weight in rodents
Insulin i.c.v revereses fasted/diabeic-induced increase in NPY/AgRP mRNA and decrease in POMP mRNA in ARC
How does insulin access CNS?
Insulin receptor-mediated transport system in brain microvessels = allowing insulin rapid access to CNA
How does insulin act in peripheral tissues?
Insulin is anabolic and glucoregulatory
Causes hypoglycaemia, increases food intake and energy storage
Which neurones have high insulin receptor expression?
POMP and AgRP ARC neurones
What happens when insulin receptors deleted from POMC and AgRP neurones?
Mainly impacts on glucose metabolism rather than food intake and body weight
What do AgRP neurones regulate?**
They regulate insulin suppression of heptaic glucose suppression
Where are components of insulin signalling expressed?
Also in ACR neurone
What occurs when insulin is delivered to hypothalamus?
Modulate hypothalamic neuronal activity = diminish obesity state
Improves whole body insulin sensitivity
Promotes lipogenesis and peripheral fat accumulation (white adipose)
Increases adaptive thermogenesis (“brown” adipose)
How does brain insulin resistance affect the obese?
Brain insulin levels reduced in genetically obese rats
Insulin-resistant humans have lower CSF:plasma insulin ratio vs insulin sensitive subjects
Hypothalamus shows impairment of proximal insulin signalling components
How does brain insulin reduce heptaic glucose production?
Insulin acts in ARC to help reduce HGP by inhibition of gluconeogensis
What happens when brain insulin receptors are knocked out?
Decrease in ability of peripheral insulin to suppress hepatic glucose production
This apprears to be mediated through ARC AgRP neurones
What is the pathway of brain insulin reducing hepatic glucose production?
Insulin binds receptors on ARC AgRP neurones
Brain inhibits vagal efferents to liver
a7-nAChR causes IL-6 expression in Kupffer cell
IL-6 binds its receptor and activates STAT3
STAT3 dimerizes and represses transcription of gluconeogenic enzymes
In a fasting state what happens to increase food intake?
Decrease in leptin/insulin
Excitatory synapse at NPY/AgRP = promotes hunger signal
Inhibitory synapse at POMC/CART = decrease in a-MSh released
Inhibits MC3/4 receptor
In a fed state what happens to decrease food intake?
Increase in leptin/insulin
Inhibitory synapse at NPY/AgRP = inhibits hunger signal less NYP and AgRP released
Excitatory synapse at POMC/CART neurone = increase in a-MSH release which binds MC3/4-receptor
a-MSH binding its receptor = suppresses food intake
