Lecture 9 Flashcards
what are the health conditions that stem from obesity?
- diabetes type II metabolic syndrome
- cardiovascular disease
- liver disease (non alcoholic fatty liver disease)
- PCOS
- Arthritis
- depression
- cancer
obesity and overweight account for how many premature deaths?
300,000
obesity would surpass what as the leading cause of death worldwide in the next decade?
tobacco
t or f: obesity is not what kills you, diabetes is
true, diabetes leads to retinopathy, neuropathy, nephropathy, coronary and cerebrobscular disease
what is the relationship of obesity to CVD?
obesity is an independent risk factor to CVD, meaning that without any other factors obesity makes cvd more likely
what are some traits about liver disease and obesity?
- most common of all liver disorders
- most frequent cause of abnormal liver enzymes
- affects 3-20% of gen population
- its present in 75% of people with obesity and diabetes type 2
- present in 3% of children and more than 50% of obese children
what is liver steatosis?
fatty liver
what are the stages of NAFLD (non alcoholic fatty liver disease)?
- normal liver
- steatosis
- NASH (non alcoholic steatohepatitis)
- cirrhosis
what is the description of steatosis besides fatty liver?
retention of lipids within hepatocytes
what is the description of NASH (non alcoholic steatohepatitis)?
necroinflammation and fibrosis (progressive scarring)
what is the description for cirrhosis?
end stage liver disease and can lead to HCC
what is impaired to NAFLD?
coronary flow reserve
what are the symptoms of sleep apnea?
- daytime sleepiness
- fatigue
- nightmares
- snoring
- intermittent hypoxia
how is sleep apnea described as?
pauses in breath while sleeping that can last from a few seconds to minutes, may occur 5-30 times or more an hour
what is a suggestive sign of sleep apnea?
intermittent snoring
what is the most obvious consequence of sleep apnea?
lack of oxygen to the brain
what are silent strokes?
MRI defined silent brain infarcts
what are silent strokes associated with?
subtle deficits in physical and cognitive function that commonly go unnoticed, examples are memory loss, difficulties with walking and mood problems
what does the presence of silent stroke increase the risk of?
more than doubles the risk of subsequent stroke and dementia
what is the relationship to silent strokes and sleep apnea?
- more than 1/2 of people who had silent stroke had sleep apnea
- having 25+ episodes of sleep apnea a night is linked with silent stroke
what is depression described as?
a mood disorder in which feelings of sadness, loss, anger, or frustration interfere with everyday life for weeks or longer
what is the relationship between bmi and depression?
high bmi means higher prevelance of depression
what is the relationship between depression, obesity and stress?
people suffering from depression or obesity report higher stress levels than rest of population
what are the stress management strategies for obese adults?
watching tv for more than 2 hours a day, listening to music, and eating
what does inflammatory stimuli cause/
sickness and depression like behavior
what leads to chronic immune activation?
- inflammatory stimui
- macrophages theory of depression
what is chronic immune activation common in?
depression and obesity
what are insulin resistance, inflammation, and metabolic shifts associated with obesity helping?
cancer cells
what is the family evidence of genetic influence on obesity?
- familial aggregation
- twin studies
- genetic obesity syndrome
how does familial aggregation prove as evidence for genetic obesity?
familial clustering of obesity in families
how does twin studies serve as proof for genetic obesity?
greater concordance among MZ twins compared to DZ twins
how does genetic obesity syndromes serve as proof for genetic obesity?
there are monogenic forms of human obesity, both dominant and recessive
what did the adoption study of human obesity conclude?
genetic influences have important role in determining human fatness in adults, whereas the family environment alone has no apparent effect
what are anorexigenic signals?
- suppress food intake
- increase energy expenditure
- POMC (pro-opiomelanocortin)
- CART (cocaine and amphetamine regulated transcript)
what are the orexigenic signals?
- stimulate food intake
- decrease energy expenditure
- NPY (neuropeptide Y)
- AGRP (agouti related protein)
how does the body balance energy?
using leptin, its used in long term control, helps regulate weight. low leptin in decreased body fat, increased leptin in increased body fat
what is lipostatic theory?
suggested a circulating factor that acts on the brain to inhibit food intake and adiposity then in 1994 leptin was cloned
what is the cycle for leptin?
high fat–>high leptin–>binds to receptor in brain–>stimulates metabolism and reduces appetite–>lower fat–>low leptin–>unbinds from receptor in brain–>reduces metabolism and stimulates appetite–> back to high fat and repeat
what is leptin’s effect on anorexigenic and orexigenic signaling?
increases anorexigenic signaling in the brain and decreases orexigenic in the brain
what does leptin do to POMC?
increases POMC expression, then alpha-MSH is released, that activates MC4 receptors and that leads to decreased appetite
what does leptin do to AgRP?
decreases AgRP expression, leads to decrease of MC4 receptor inhibition which leads to decreased appetite
what effect does leptin have on CART and NPY expression?
increases CART expression and decreases NPY expression leading to decreased appetite
what happens when leptin binds to its receptors?
activates JAK/STAT pathway and that turns some genes on or off
what are the leptin receptors?
LepR and for obesity factor Ob-R
what is the relationship between leptin and body fat?
since leptin regulates adiposity, leptin and body fat positively correlate in human
what are things regulated by leptin?
- immune function, leptin stimulates immunity
- bone density- leptin makes bones thinner
- reproduction- leptin initiates puberty
human heterozytoes for the G133 mutation in the leptin gene have low what?
serum leptin levels and increased body fat percentage relative to controls
how is the short term treatment for leptin gene mutations helpful?
helps leptin mutant kids reach puberty
what does exogenous leptin replacement therapy do for males?
- increases FSH
- increases testicular and seminal vesicle weights
- increases sperm count
what does exogenous leptin replacement do for females?
- increases LH
- increases ovarian and uterine weight
why doesnt leptin therapy work on regular obesity?
because they already have alot of leptin and have leptin resistance
what are the mechanistic basis of leptin resistance in obese individuals?
- receptor problems
- reduced transport of the leptin through blood brain barrier
- feedback inhibition of leptin receptor by SOCS3
- increased in PTP1B phosphatase shuts off signals downstream of LepR
what exactly are the receptor problems for leptin resistance?
mutations in LepR which are rare or decrease in receptors for leptin in the brain
what does high levels of fat in the blood do to the blood brain barrier?
disrupts transport through BBB
what is SOCS3?
stimulated by leptin so binds to leptin receptor and shuts it off
what does PTP1B do?
removes phosphatase from JAK2 and leptin receptor and shuts it off
how do obese individuals vary?
- ability of exogenously administered leptin to gain access to CNS
- degree or type of leptin resistance
how does diet induce leptin sensitivity?
exogenous leptin may be relatively more effective in subjects in whom endogenous leptin production has first been reduced by dieting
what is special about pramlintide?
- amylin derivative
- augments leptin actin in some individuals
- approved as addition to insulin therapy in diabetics
what are the symptoms of Bardet/Biedle syndrome?
- early blindness
- kidney cysts
- polydactily
- obesity
- hypogonadism
- developmental delays/mental retardation
what is bardet/biedle syndrome mainly associated with?
primary cilia dysfunction
what do bardet/biedl complexes contain?
variety of coatlike proteins that can bind and transport various receptor molecules into the cilium
what do primary cilia do?
they protrude from the surface of mammalian cells and localize components of key signal transduction pathways
what kind of cells are cilia common in?
- fibroblasts
- kidney cells (IMCD)
- POMC expressing neurons
what does the large complex of proteins implicated in BBS promote?
-cilia formation and movement of membrane proteins from the cell into the cilium
what is the relationship between BBS and leptin receptor?
- leptin receptor is located in cilia on POMC neurons
- BBS proteins deliver leptin recepter up the cilia
- problem is BBS patients are deficient in leptin signaling
which is more common, leptin mutations or melanocortin pathway mutations?
melanocortin pathway mutations
what do mutations in MC4R receptor do?
renders it insensitive to alpha MSH and beta MSH anorexigenic hormones
besides symptoms/phenotypes what are some traits of MCR4 mutations
- most common known monogenic cause of human obesity
- greater than 4% morbidly obese children have mutation in one MC4R allele due to haploinsufficiency
what are the phenotypes of MC4R mutations
- hyperphagia
- tendency towards being tall
- hyperinsulinemia
- increased bone mineral density
t or f: MC4R deficiency also stimulates increase in height
true
what risk is high for MC4R receptor mutants?
risk of obesity is high in infancy
for MC4R mutated individuals, some genetic/environmental modifiers prevent obesity like what?
- incomplete penetrance
- expression is variable
- exposed to powerful agonsts
some non-genetically obese patients have what that work against MC4R receptor?
autoantibodies
what does MC4R bind to?
POMC
ablation of what gene in humans also causes obesity
POMC
what are some of the phenotypes associated with mutations in human POMC with recessive pattern of inheritance
- red hair
- hyperphagia
- obesity
what POMC derived peptides is associated with melanocytes?
-MC1R and leads to red hair and pale skin
what POMC derived peptides is associated with adrenal gland?
MC2R and that leads to ACTH deficiency
what POMC derived peptides is associated with the brain?
-MC3R and MC4R and leads to hyperphagia and obesity
what POMC derived peptides is associated with skin?
MC5R
what does α-melanocyte-stimulating hormone (α-MSH) lead to?
- anorexigenic signal
- its cleaved from precursor molecule POMC, binds to melanocortin receptors
what does agouti related protein do in humans
leads to orexigenic signal, homologous to agouti protein in mouse antagonist of the melanocortin receptor
how is action of agouti protein reversible?
by extraneous addition of POMC encoded peptide alpha MSH
defects of melanocortin receptors MC3R produces obesity in mice but does what in humans
unknown
what are some conclusions from studies of monogenic obesity?
- defect is in the satiety centers in the brain
- affects appetite control centers in the brain
- obesity is not due to slow metabolism
what is the influence of the environment and genetics on obesity?
most cases of obesity are environmental but some people are more predisposed to obesity than others
what is the genetic definition of polymorphism?
-a sequence of variant that has an allele frequency of greater than 1% in the population, below that its just a mutation
what are the common types of SNP’s
- coding SNPs (synonymous and non synonymous)
- noncoding snps
- noncoding silent snps
what are the methodological problems in discerning gene environment interactions?
- power
- replication
- biological
what exactly is the methodological problem with power?
-we need to test genetics in a lot of people to increase sample size
what exactly is the methodological problem with replication
test for association in independent ethnic groups
what exactly is the problem for biological validation?
- functional assessment of putative disease causing variants
- evidence for pathophysiological role of the implicated gene
what is FTO?
- fat mass and obesity associated transcript
- but function not really related to obesity, nucleic acid demethylation
what is significant about where FTO gene is expressed?
-expressed in same area of the brain as leptin and POMC act (arcuate nucleus)
what kind of diet increased expression of FTO gene in animals?
high fat
what happens when FTO is expressed by 2.5 fold in the arcuate nucleus?
a 14% reduction in average daily food intake
what happens when fto expression is knocked down by 40%?
increases food intake by 16%
what happens on average when a person has both fto and MC4R variants?
they are about 8.5 lbs heavier than average
what is FTO very close to?
RPGRIP1L, it localizes in the primary cilia and centrosomes of ciliated cells
subtle differences in what kind of factors cause people to respond differently to the same environmental exposure?
genetic ,explains why some individuals have a fairly low risk of developing a disease as a result of an environmental insult, while others are much more vulnerable
what are the concepts of the thrifty genotype hypothesis?
- genotypes were selected because of the need to survive inevitable famine
- carriers of thrifty genes are efficient in the intake and utilization of food
- sedentary lifestyle and constant food availability have disrupted gene environment interaction resulting in modern obesity
how do thrifty genes operate?
-cyclically to process fuel sources in a manner that would maximize survival during food shortages
