physiology - feeding and satiety Flashcards
energy homeostasis
physiological process whereby energy intake is matched to energy expenditure over time
>promotes body fuel stability - energy is primarily stored as fat
how does obesity occur
accessible, calorie dense food plus sedentary lifestyle
ie small constant mismatch between energy intake and energy expenditure
what are the causes and consequences of metabolic stress
we have abundant energy supplies + little energy demand >> leading to obesity >>metabolic syndrome >>dyslipidemia >>insulin resistance >>type II diabetes >>CVD
normal and abnormal BMIs
25 = thin or normal acceptable 25-29.9 = overweight 30-40 = obese >40 = morbidly obese
how to calculate BMI
weight over square height
factors contributing to obesity
obesity is a heterogeneous group of conditions with multiple causes
>genetics: through susceptibility genes, these increase risk of developing disease
>environment: ‘westernisation’ of diet
SARS-CoV-2 metabolic disease connection
> obesity linked to most of the high risk factors for covid-19
western diet leads to activation of the innate immune system and inhibition of the adaptive immune system
adipose tissue contains the components for SARS-CoV2 entry and exit
what does obese AT act as ? 2
an immune reservoir and a reservoir for the SARS virus
>higher viral load for longer
>poor recovery from disease
>prolonged viral shed from obese individuals
>efficacy of antivirals;s and vaccines reduced
consequences of obesity
- stroke
- resp. disease
- heart disease
- gallbladder disease
- osteoarthritis
- dementia
- covid 19
- NAFLD
- diabetes
- cancer
why do we need fat?
energy storage
prevention of starvation
energy buffer during prolonged illness
>starvation and infection has been a threat to human survival
>Adipose tissue accumulation would represent a survival adaptation
why is it difficult to lose weight once gained ?
it is a disease of the brain ..
increased body fat alters brain function as long term obesity induces brain re-programming
ie your brain view the extra weight as normal and dieting as a threat to body survival
what ways does the CNS influence energy balance and body weight ?
through
- behaviour (feeding and physical activity)
- ANS activity (regulates energy expenditure)
- neuroendocrine system (secretion of hormones0
**integration of these determines final output ie feeding behaviour
where does this integration happen?
the brain !
the neural centre responsible is the hypothalamus
what three basic concept underly the control system of energy intake and body weight
- satiety signalling
- adiposity negative feedback signalling
- food reward
satiation
sensation of fullness generated during a meal
>satiation signals increase during meal to limit meal size
satiety
period of time between termination of one meal and the initiation of the next
adiposity
the state of being obese
satiation signals - what are they
5 of them
>CCK - cholecystokinin >PYY3-36 - peptide YY >GLP-1 - glucagon like peptide >OXM - oxyntomodulin >obestatin
CCK
secreted from enteroendocrine cells in duodenum and jejunum
>released in proportion to lipids and proteins in meals
>signals via sensory nerves to hindbrain and stimulates hindbrain directly (nucleus of solitary tract - NTS)
Peptide YY
secreted from endocrine mucosal L cells of GI tract
>levels increase rapidly post-prandially
>inhibits gastric motility, slows emptying and reduces food intake
glucagon like peptide
product of pro-glucagon gene
>also released from L cells in response to food ingestion
>inhibits gastric emptying and reduces food intake
oxyntomodulin
from pro-glucagon gene and released from oxyntic cells and L-cells of small intestine after meal
>acts to suppress appetite - mechanisms and site unclear
obestatin
peptide produced from gene that encodes ghrelin and released from cells lining stomach/small intestine
>sugested to reduce food intake - may act to antagonise the actions of ghrelin
>actions unclear at present
what is ghrelin?
a hunger signal
> is an octanoylated peptide produced and secreted by oxyntic cells in stomach
>ghrelin levels increase before meals and decrease after meals
>levels are raised by fasting and hypoglycaemia
>peripheral ghrelin stimulates food intake, decreases energy expenditure and decreases fat utilisation
>ghrelin receptor-expressing neurons in hypothalamus help control fat metabolism increases lipogenesis and decrease lipid oxidation - prepare body to store energy
hypothalamus and obesity
> overall energy balance is controlled by feedback loops which act to maintain constancy of total body energy stores
>signals are produced in response to body nutritional status
> these are sensed in the hypothalamus
> act to modulate food intake and energy expenditure
what are the central appetite controllers
> glutamate, gaba and opioids
>monoamines
monoamines
they act to suppress food intake - many drugs developed to anti on these systems - most withdrawn due to side effects
glutamates Gaba and opioids
increase food intake when injected into hypothalamic centres - effects are modest
what are the two hormones that act on hypothalamic neurones
LEPTIN and INSULIN
>adiposity signals
>they are produced in peripheral tissues
>report fat status to brain
hormone function
inform brain to alter energy balance - eat less and increase energy burn and this malfunctions in an obese state
leptin (reduced)
reduced leptin mimics starvation causing unrestrained appetite
no leptin receptor
whole body loss of leptin signalling results in severe obesity
leptin
> circulates in proportion to body adiposity
high levels of receptors in the hypothalamus
intracerebroventricular leptin inhibits food intake and decreases body weight of rodents
biological roles of leptin
> food intake/energy expenditure/fat deposit
peripheral glucose homeostasis/insulin sensitivity
maintenance of immune system
bone formation
>and an area of other things
treating obesity !
recombinant leptin therapy works in obese humans
is leptin therapy common ?
> it is limited by severe leptin resistance present in most obese individuals
vast majority of human obesity is characterised by high leptin levels
what does diet induced obesity result in
results in leptin resistance !
perhaps due to:
1) defective lepton transport into the brain
2) altered signal transduction following leptin binding to its receptor
previous drugs for treating obesity ?
>noradrenergics >serotonergics >Fen-Phen >sibutramine >rimonabant
noradrenergics
they are appetite suppressants acting to inhibit noradrenaline uptake
-can have a CV side effects
eg
>diethylproprion
>manzindol
>phentermine
serotonergics
they are appetite suppressants acting on the 5-HT system
>fenfluramine and dexflenfluramine are no longer used due to induced heart disease
eg.
fenfluramine
dexflenfluramine
fluoxetine
Fen-Phen
is a combination of fenfluramine and phentermine
>is very effective but potentially causes fatal pulmonary hypertension and heart valve problems
sibutramine
Selectively inhibits re-uptake of noradrenaline, 5-HT and dopamine
Decreases food intake and may also increase thermogenesis.
Effective - though limited - modest weight loss (10lbs in 1 year)
Major concerns over side-effects (cardiovascular events and strokes)
Withdrawn (2010), but can be purchased – weight loss products on-line
eg
meridia
reductil
rimonabant
Antagonist of CB1 receptors – high levels in hypothalamus
Counteracts obesity; potential effectiveness to assist smokers to quit
and reduce addiction to certain drugs (ethanol, cocaine and opiates)
and to improve short-term memory
Approved for use in EU in 2006 for obesity (FDA did not approve in 2007)
Reports of severe depression and anxiety in some patients (suicide risk)
As endocannabinoids neuroprotective – worries about neurodegeneration
2008/9: Rimonabant sales suspended/drug withdrawn
eg
acomplia
over the counter drug
orlistat
>Inhibits pancreatic lipase decreasing triglyceride absorption
reduces efficiency of fat absorption (by ~30%) in small intestine
Side-effects include cramping, bloating, flatulence, abdominal
pain and diarrhoea
Need to take vitamin supplements (loss of fat soluble vitamins – e.g. A,D,E)
Not particularly effective over long-term (3 kg in 12 months)
Tendency to get ‘rebound’ in weight
upcoming anti-obesity drugs
liraglutide
bariatric surgery
is a gastric by-pass surgery - produces substantial weight loss
>surgery induce high level of complete resolution of Type II diabetes
>bypass restricts calorie intake and induces malabsorption of nutrients but resolution of TIID is not simply due to decreased energy intake
>changes in the gut microbia, altered circulating bile acids and short chain FAs
adaptive thermogenesis
adult humans possess BAT, BAT dissipates energy as heat, inducible ‘browning” of WAT
>thermogenic adipocytes - increase energy expenditure uncoupling of oxidative metabolism from ATP production
>key function of uncoupling protein 1 (UCP1) fatty acid activated protein short circuits proton gradient in mitochondria - accelerating fuel oxidation - produces heat
