food intake Flashcards
how is obesity defined
state of body energy stores that exceeds physiological needs
how is the degree of obesity measured and what does it correlate with
BMI; correlates with total body fat
what creates an obesogenic environment (4)
- increased food availability
- increased portion size
- increased sedentary leisure time activities
- decreased occupational physical activity
health risks associated with obesity (6)
- type 2 diabetes
- CVD
- sleep-breathing abnormalities
- gallstones
- menstrual irregularities or difficulty getting pregnant
- cancer
describe energy homeostasis
energy intake balances energy expenditure
what systems regulate food intake (2)
- homeostatic system
- hedonic system
role of homeostatic system
motivation to eat when energy goes down (biological needs)
role of hedonic system
eat because of pleasure (can override homeostasis)
which system is main cause of obesity
hedonic system
which brain area control hedonic system
VTA
which brain areas control homeostatic system (2)
- brainstem
- hypothalamus
hypothalamic regions regulating food intake (4)
- 3rd ventricle (3V)
- dorsomedial nucleus (DMN)
- ventromedial nucleus (VMN)
- ARC
how did they find that hypothalamus controls food intake
lesioning PVN, VMN and DMN caused obesity; lesioning LHA caused weight loss
what are parabiosis experiments
surgical union of 2 individuals so they share common blood circulation
result of ob/ob + normal parabiosis mice
weight gain of ob/ob mouse suppressed (indistinguishable from WT)
result of db/db + normal parabiosis mice
normal mouse slowly loses weight and dies of apparent starvation
result of db/db + ob/ob parabiosis mice
ob/ob mouse rapidly loses weight and ides of apparent starvation
conclusions from parabiosis experiments (2)
- circulating factor involved in energy balance regulation
- defects in ob/ob and db/db mice may be in signal and receptor for signal
ob/ob mice are deficient in
leptin
db/db mice are deficient in
leptin receptor
leptin is produced by
adipocytes (proportionally)
increase in leptin leads to (2)
- decreased food intake
- increased energy expenditure
decrease in leptin leads to (2)
- increased food intake
- decreased energy expenditure
effect of leptin administration on ob/ob mice
restores normal body mass
why doesn’t leptin administration affect obese people (not leptin deficient)
obesity associated with increased circulating leptin; person becomes leptin-resistant; lack of response to exogenous leptin administration
action of leptin at genomic level (5 steps)
- leptin binds to leptin receptor (LepR) causing dimerization of receptor
- JAK phosphorylates LepR
- STAT binds to phosphate
- STAT dimerizes with other STAT
- dimer binds to gene in nucleus and induces transcription
orexigenic and anorexigenic hormones
orexigenic: ghrelin
anorexigenic: leptin
orexigenic and anorexigenic neurons
orexigenic: NPY/AgRP
anorexigenic: POMC
location of NPY/AgRP and POMC neurons
ARC
NPY/AgRP and POMC neurons synapse on
MC3/4R neurons
action of ghrelin in ARC
activates NPY/AgRP neurons (increase food intake)
action of leptin in ARC
activates POMC neurons and inhibits NPY/AgRP neurons (decrease food intake)
how did they determine colocalization of NPY/AgRP neurons
IHC; NPY & AgRP overlapped; NPY & POMC or AgRP & POMC didn’t overlap
how did they create a LepR KO
- expressed Cre under a neuron specific promoter
- crossed with mouse with LepR flanked with loxP sites
- Cre cleaves LepR in Cre-dependent manner (in neurons)
LepR KO on POMC or AgRP neurons leads to
mild obesity (similar to db/db mice, but not as obese)
LepR KO on VMH neurons leads to
very mild obesity
double KO of LepR on POMC and VMH neurons leads to
higher body weight than single mutant (potentiation), but still not db/db phenotype
what leads to replication of db/db mouse (2)
- whole body LepR KO
- brain-specific LepR KO
effect of leptin action on GABAergic neurons (2)
- prevents obesity
- reduces inhibitory tone to POMC neurons (decreased appetite)
leptin’s anti-obesity effects are mediated by what type of neuron
GABAergic neurons
result of Vgat-LepR-KO mice and Vglut2-LepR-KO mice
GABA: mimics whole body LepR KO (db/db phenotype)
glut: similar to control
which ARC neuron is GABAergic
AgRP
why are AgRP neurons the only neurons (known) to contribute directly to obesity (not POMC for ex.)
AgRP neurons are GABAergic; leptin’s effects are mediated by GABAergic neurons as seen in Vgat-LepR-KO mice that have db/db phenotype (compared to vglut2-LepR-KO mice that look like control)
what leads to the hypothesis that the majority of leptin’s anti-obesity effects are uncharacterized
vgat-LepR-KO mice leads to db/db phenotye -> AgRP neurons are known to be involved in leptin’s anti-obesity effects (because they are GABAergic) -> but LepR KO in AgRP neurons only leads to mild obesity (not db/db phenotype) -> other GABAergic neurons must be involved
AgRP expression in fasted & fed mice and potential conclusion from this
increased expression in fasted mice (activity of AgRP neurons correlated with fasting behavior; activity of AgRP neurons induces feeding?)
tools used to conduct experiments (5)
- neurosurgery
- IHC
- Cre
- GCaMP
- optogenetics
explain GCaMP
- GFP bound to calmodulin and M13 in inactive conformation
- calcium binds to calmodulin and induces conformational change
- fluorescence
activity of AgRP neurons when (a) fasted; (b) being fed
(a) fasted: high activity
(b) get food: activity drops fast
activity of AgRP neurons when being fed false food
- fasted: high activity
- get false food: activity drops
- when realize not food: activity increases
-> activity is related to food specifically
when do AgRP neurons decrease activity
in the discovery or consumption of food
effect of non-nutritive value things on AgRP neurons
fail to sustain decreased AgRP neuronal activity
effect of shining blue light on AgRP neurons with ChR2
induces food intake
how did they prove that hunger has a negative valence
- conditioned mice to eat orange flavor by shining light when eat orange flavor (AgRP-ChR2 neurons)
- no shining light: mice preferred to eat pink flavor (associate orange with hunger, so want to avoid)
how did they prove that hunger has negative valence, but isn’t food specific
- photostimulation of AgRP-ChR2 neurons in place #1
- no photostimulation: mice avoid place #1 (prefer place #2) because associate with hunger
valence of AgRP activity
negative (try to avoid it)
how do we avoid AgRP activity
eating
for what physiological purpose did leptin evolve
serve as a metabolic signal of energy sufficiency (rather than excess)
ob/ob mice and fertility
ob/ob mice are infertile and obese
why do opposite body weight types have same repoduction deficit
lean: not enough adipocytes, not enough leptin = no leptin signalling
obese: too much leptin, leptin resistance = no leptin signalling
relationship bw starvation and gonadal hormone
starvation = decreased gonadal hormone and delays ovulation in females
delayed ovulation and leptin administration in fasted mice
fasted + saline = delayed ovulation
fasted + leptin = no delay (like control)
what causes fertility dysregulation in lean people
specific impairment of leptin signalling, not the body weight change
result of leptin administration to female athletes that lost their period
improvement of reproductive function after (only) few months (not due to altered exercise patterns or weight gain)
when are ghrelin levels maximal
just before eating
where is ghrelin produced from
stomach cells
ghrelin is mediated by which receptor
GH receptor
what activities does ghrelin have (2)
- appetite-stimulating activities
- GH-releasing activities
what role does ghrelin presumably have
meal initiation
how does ghrelin impact body weight
increases body weight
interindividual variability of ghrelin
- wide range of circulating ghrelin values
- maximal value always before eating
relationship bw ghrelin and diet-induced weight loss
after diet-induced weight loss, plasma ghrelin levels increase -> maybe mechanism of rebound weight gain
relationship bw bariatric surgery and ghrelin
bariatric surgery suppresses ghrelin levels (remove stomach cells -> less ghrelin release): contributes to weight-reducing effect and maintenance of reduced weight
relationship bw cancer patients and ghrelin
ghrelin increases energy intake in cancer patients with impaired appetite
location of LepR expression
VTA, which releases DA to striatum/NAc, amygdala and PFC (reward and motivation processing centers) and LHA (projects to VTA)
effect of presenting highly palatable food
release of DA into nucleus accumbens
high vs low fat diet and DA release
high fat diet induces more DA release than low fat diet
brain activation towards high vs low calorie food & obese vs non-obese patients + conclusion
- higher response to high calorie foods
- obese people show stronger response
- conclusion: some people (obese people) are more attracted to caloric food than others
relationship bw leptin and DA release in response to palatable food
leptin decreases DA release even before food presentation
direct leptin administration to VTA + conclusion
reduces food intake -> VTA regulation important component of leptin’s ability to regulate food intake
leptin and brain response to food images
- leptin-deficient state: even when fed, high brain response to food
- post-leptin treatment: when fed, no brain activation when shown food
- conclusion: enhanced neuronal activation normalized by leptin replacement therapy
relationship bw ghrelin injection and brain response to food pictures
dramatic increase in brain response in VTA to food images following ghrelin injection -> ghrelin favors consumption by enhancing hedonic response to food-related cues
receptor involved in sweet tasting
TRPM5 ion channel expressed in taste receptors cells
WT vs trmp5-KO mice
WT -> strong attraction for sucrose solutions
trmp5-KO -> no preference for sucrose solution over water (no distinction bw both)
long-term result of trmp5-KO mice
even lacking sweet receptors, mice eventually developed a preference for sucrose solutions (learned to distinguish)
does TRMP5 distinguish sweet from non-sweet or calories and why (how do they know)
calories (and sweet) -> trmp5-KO presented with water and sucralose (noncaloric sweetener) and weren’t able to distinguish bw them
barrel cortex plasticity (when eat something highly caloric?) after whisker trimming
dendritic spine turnover in pyramidal neurons -> some spines are lost, some new spines, some spines always present, some transient spines
activity-dependent morphological plasticity of astrocytic processes in SON
- unstimulated SON: astroglia separates magno neurons
- stimulated (lactation) SON: astroglia retract & increased neuronal communication (NTs)
synapse type and number in ob/ob mice: NPY neurons
more excitatory synapses in ob/ob mice than WT; less inhibitory synapses in ob/on mice than WT -> leads to increased appetite
synapse type and number in ob/ob mice: POMC neurons
less excitatory synapses in ob/ob mice than WT; more inhibitory synapses in ob/ob mice than WT -> leads to increased appetite (decrease of loss of appetite)
changes in synaptic density and properties in hypothalamus after leptin replacement: NPY neurons
- decreased excitatory synapses
- increased inhibitory synapses
- result: silencing of NPY neurons (decreased appetite)
changes in synaptic density and properties in hypothalamus after leptin replacement: POMC neurons
- increased excitatory synapses
- no change in inhibitory synapses
- result: excitation of POMC neurons (increased appetite)
differences bw ob/ob mice and WT synapses
different excitatory & inhibitory inputs onto NPY and POMC neurons
what is DiI
fluorescent lipophilic dye that labels axonal projections
leptin deficiency effect on projections from ARC to PVN
leptin deficiency disrupts normal pattern of projections from ARC to PVN: decrease in processes, less communication
relationship bw leptin and neurite outgrowth
leptin promotes neurite outgrowth directly from ARC
neurite outgrowth in ob/ob mice vs ob/ob + leptin mice
increases neurite outgrowth when leptin administration
leptin actions in hypothalamus (3)
- acts directly on neurons of ARC by binding to LepR -> changes in their production & release of neuropeptides NPY and a-melanocyte (POMC product)
- produces rapid changes in strength and number of excitatory and inhibitory synapses that input onto NPY and POMC ARC neurons
- induces neurite outgrowth of ARC neurons -> stimulating projections from ARC to PVN during critical postnatal period
projections of ARC -> PVN in obesity-resistant and obesity-prone rats
obesity-resistant rats have more processes than obesity-prone rats (more communication) -> obesity-prone rats become obese when given moderate diet compared to obesity-resistant rats (obesity-prone have defective ARC projections seen as early as 1st week and can persist into childhood)
response of ARC neurons to leptin in obesity-prone rats
fail to respond to leptin (no neurite outgrowth)
