Grand Rounds (week 2): Obesity and Epigenetics
Times article on same subject matter as lecture:
http://www.time.com/time/health/article/0,8599,2020815,00.html
Daniel L Marks MD, PhD
Pediatric Endocrinology, Doernbecher Children's Hospital, OHSU
U Oregon alum
SLC residency
Obesity emphasis
talk is hour and 15 minutes, plenty of time for questions
"the most malnourished patients in my clinic are all obese"
in his practice NASH v common in children
**good diet just during pregnancy, even with obese mom-->all fetal risk goes away
Neonatal Nutrition, Epigenetics, and Childhood Obesity
BMI is accelerating in an upward direction
1/3 of children are overweight or obese
This has happened since late 70's
parallel increase is not necessarily causal
corn syrup consumption began increasing in 1974 and peaked once in 1984
then rose more gradually, flattened at 1998 and seems to be decreasing as of 2005
nobody knows its effect on unborn child
ETIO of obesity
genetics
supersized diet
dog walking from car
developmental biology largely ignores "nongenetic" causes of individual variation
phenotype changes based on environment
effect is transgenerational
epigenetics has to do with chemical modification of DNA regions
turning on and off?
maternal obesity increasing
how does this affect baby?
premature more common
full term babies are getting bigger
Barker hypothesis 1989
Hertfordshire England: people born there stayed there
nurse midwives of area took meticulous records for a long time
assoc of birthwt with HTN, IR
born small (under 5.5lbs)-->incr risk of many dz, stroke, htn, dm2, obesity most strong assoc
small placenta had same effect
large babies in those days didn't survive (no C-section option)
exposure to famine during preg or being SGA-->lifetime frisk of dm and obesity, independent of background
Dutch Hunger Winter 1944-45
400-800 calories/day
Holland was invaded by Germany 9/14/44 and occupied
Dutch held rail strikes, Germans ordered ban on food transport, severe early winter, food stocks ran out
5 months of extreme starvation, pregnant women not excused
then allies showed up with food in June 1945
record of effect of starvation on preg, lactation, etc
*famine in mid-late gestation-->impaired glucose tolerance, more dm2
*famine in early gestation-->atherogenic lipid profile, obesity, incr CHD, all metabolic dz much increase
effect of maternal obesity? HFCS?
we have an idea that a certain amount of weight should be gained in preg
normal BMI women
gestational weight gain variation-->?
*faster mom gains weight-->higher risk of childhood obesity
if mom already obese and gains weight fast, steepest curve-->obesity
0.3kg/wk seems to be optimal rate of wt gain
*if mom is obese before preg there is no safe weight gain
PIMA studies (tribes)
Mean BMI in Pima sibs exposed and not to Diabetic intrauterine environment
over 50% of kids under 12 have DM2, over 90% incidence of obesity in kids among Pima
mom diabetic during preg-->much more obesity as teen (almost 2x more)
prospectively followed offspring of dm mothers born 77-83 to age 14-17
mothers reported to have "tight" diabetes control
more obesity in all groups if mom dm2 during preg
another study
confirmed Barker finding that underwt babies also got obese
but being large for gestational age is bigger risk for obesity (LGA)
LGA babies: what are they like?
skin fold thickness different everywhere
length and head circ not related
TOBEC body impedance analysis shows
that fat mass is the only thing that is large about you
lean mass is not different between infants born large or small
nutrient restriction/starvation-->IR, placental and fetal inflammation
obesity/overnutrition-->IR, placental and fetal inflammation
chronic inflam during development changes longterm risk
diet study on macaques
national primate research center
in social indoor/outdoor housing
western 35% fat (incl lard) diet with HFCS, vs semiveg diet of insects, veg, 15% fat, high fiber
~85% of increased calories in western diet was from fat
single primate pregnancy
mom on western diet-->lipid structure change, N6 fatty acids incr, low N3 fatty acids, ratio: 17.3
-->bigger shift in fetal circ than maternal
-->fetal liver disease, severe fat deposition and oxidation, whether mom obese or not
-->persistent postpartum liver dz-->fetal cell death
-->apoptosis-->bridging fibrosis-->cirrhosis
**reverse diet just during pregnancy, even with obese mom-->all fetal risk goes away
mom's are willing to do things for their children
explain to them the pathology that they can cause by eating western diet
-->eat well for 8 months-->healthy child
ADIPOSITY REBOUND
see CDC chart of child weights/age
babies usu have a skinny point early in life then start gaining fat again
fat babies the point is earlier, age 2-3
skinny people have rebound point at age 7 or so
can change which curve you follow
skinny kid-->provider freakout-->feed 'em-->change rebound-->increase liftime weight
"catch up" growth not desirable
"skinny babies are OK" outside context of disease (failure to thrive, CF, etc)
don't know for sure about what happens when you intervene and delay adiposity rebound, study not done
worst scenario is skinny kid with rapid weight gain-->heart dz
positive predictive value is as high as cigarette smoking for heart dz and smoke risk
*7x risk of obesity dt rapid infant weight gain
DUTCH HUNGER WINTER revisit
n=300,000
famine in first 2 trimesters-->80% more overweight
famine in first 5 months of life-->40% less overweight
BRAIN GROWTH
much of human brain growth occurs ex-utero esp in premies
brain growth spurt: 7th prenatal month--2 years of age, more than 1/2 of eventual brain wt is added
much programming happens then
leptin, ghrelin, insulin, PYY act on feeding centers in brian, appetite, metabolic rate, fat storage
can we change brain programming by adding a hydrocarbon? yes, fetal alcohol syndrome
primate brain development, POMC, appetite regulation part of brain changed by western diet
*baby einstein disney videos sold-->delays cognitive development if it replaces exposure to humans
BRAIN ENERGY CONSUMPTION
is energy inefficient
at rest brain burns more energy than all muscloskeletal system together
infant 90% of energy budget goes to brain
calorimeter, etc, get metabolic rate of infant
12 year olds in calorimeter room reading a book, 1700kCals, about the same as sleeping
watching TV takes fewer kCals: profoundly catatonic activity
more effect on those who are overweight
Klesges et al, Pediatrics, 1993
primates also love to watch television
does it matter if tv replaces nurturing? no.
watching tv shuts down most of brain incl limbic structures (I doubt this from my own experience)
optic cortex doesn't shut off
BREASTFEEDING
metabolic state of lactating mother MATTERS
meta-analysis of obesity odds vs breastfood: breastfood decr risk of obesity
any breastfood at all helps, longer time period (1yr)-->2/3 less risk
Pima: 2 months or more of breast-->much lower risk of obesity, dm2
(1998 study on 40 year olds: milk from 1958)
what about 2009 breast milk? more fructose, fat, GFs, cytokines, leptin, adiponectin
? diet affect quality of breast milk? doesn't change output
changes fat amount and type
*trans fat, sat fat, fish oil, all goes right through
*fat amount in obese mom's milk higher independent of diet
*growth factors and cytokines in breast directly proportional to what's in mom
growth factors: EGF, NGF, insulin, IGF-1, IGF-2, relaxin, TGF-a
"diabetic breast milk" vs some babies given banked nondiabetic milk
strong dose response relationship: more milk from diabetic-->more obese
**11% of US kids first solid food is french fry
WHAT TASTES GOOD TO YOU
Infant flavor preference altered by maternal diet
during lactation gave moms alarm clock that range bid
control: water, intervention: carrot juice
babies first solid food: cereal with water or carrot
babies want what mom had, ate more, liked it better
flavor preference is modeled during lactation
WHY KIDS EAT WHAT THEY EAT
NATURE VS NURTURE in childhood nutrition
behavior mostly learned from modeling by parents
stick to gather termites vs SUV to gather McDonalds
reward increases food pref
"stashing" incr food preference: locked up in cabinet
new food must be introduced at least 10x to be accepted
decrease food pref: bribery, masking (broc with chs sauce, ketchup is #1)
children learn by example
children need the opportunity to eat and the ability to refuse
*for parents with kids that won't try new foods
SCIENCE PROVING 10X INTRODUCTION EFFICACY
best way to introduce new foods to children's diet is to eat them yourself
scientificamericanfrontiers.com
goldfish, fig newtons, were snack foods at school lunch
captive students and teachers all ate together, had snack every day always same then
added raw tofu to snack plate, no comment about it, just suddenly there
adults ate without question
no performing about how good it was
after 10 introductions the kids were eating it too
no questions, no complaining
"dad comes home and commits metabolic obscenities in front of the TV"
bladder and stomach synapse to same neurons
empty or full is all they know
pee training is immediate
kid says they're hungry and have to wait
give food and they're not hungry: parents try to override
**let kid eat or not eat when they want
"science says that starvation is actually really good for us"
QUESTIONS
PLASTICS AS OBESOGENS
flouridated polycyclic hydrocarbons
released in sunlight
estrogenic, est is mildly obesogenic
confuses sterol receptors and make you think you are starving for sterols ie cholesterol
http://www.time.com/time/health/article/0,8599,2020815,00.html
Daniel L Marks MD, PhD
Pediatric Endocrinology, Doernbecher Children's Hospital, OHSU
U Oregon alum
SLC residency
Obesity emphasis
talk is hour and 15 minutes, plenty of time for questions
"the most malnourished patients in my clinic are all obese"
in his practice NASH v common in children
**good diet just during pregnancy, even with obese mom-->all fetal risk goes away
Neonatal Nutrition, Epigenetics, and Childhood Obesity
BMI is accelerating in an upward direction
1/3 of children are overweight or obese
This has happened since late 70's
parallel increase is not necessarily causal
corn syrup consumption began increasing in 1974 and peaked once in 1984
then rose more gradually, flattened at 1998 and seems to be decreasing as of 2005
nobody knows its effect on unborn child
ETIO of obesity
genetics
supersized diet
dog walking from car
developmental biology largely ignores "nongenetic" causes of individual variation
phenotype changes based on environment
effect is transgenerational
epigenetics has to do with chemical modification of DNA regions
turning on and off?
maternal obesity increasing
how does this affect baby?
premature more common
full term babies are getting bigger
Barker hypothesis 1989
Hertfordshire England: people born there stayed there
nurse midwives of area took meticulous records for a long time
assoc of birthwt with HTN, IR
born small (under 5.5lbs)-->incr risk of many dz, stroke, htn, dm2, obesity most strong assoc
small placenta had same effect
large babies in those days didn't survive (no C-section option)
exposure to famine during preg or being SGA-->lifetime frisk of dm and obesity, independent of background
Dutch Hunger Winter 1944-45
400-800 calories/day
Holland was invaded by Germany 9/14/44 and occupied
Dutch held rail strikes, Germans ordered ban on food transport, severe early winter, food stocks ran out
5 months of extreme starvation, pregnant women not excused
then allies showed up with food in June 1945
record of effect of starvation on preg, lactation, etc
*famine in mid-late gestation-->impaired glucose tolerance, more dm2
*famine in early gestation-->atherogenic lipid profile, obesity, incr CHD, all metabolic dz much increase
effect of maternal obesity? HFCS?
we have an idea that a certain amount of weight should be gained in preg
normal BMI women
gestational weight gain variation-->?
*faster mom gains weight-->higher risk of childhood obesity
if mom already obese and gains weight fast, steepest curve-->obesity
0.3kg/wk seems to be optimal rate of wt gain
*if mom is obese before preg there is no safe weight gain
PIMA studies (tribes)
Mean BMI in Pima sibs exposed and not to Diabetic intrauterine environment
over 50% of kids under 12 have DM2, over 90% incidence of obesity in kids among Pima
mom diabetic during preg-->much more obesity as teen (almost 2x more)
prospectively followed offspring of dm mothers born 77-83 to age 14-17
mothers reported to have "tight" diabetes control
more obesity in all groups if mom dm2 during preg
another study
confirmed Barker finding that underwt babies also got obese
but being large for gestational age is bigger risk for obesity (LGA)
LGA babies: what are they like?
skin fold thickness different everywhere
length and head circ not related
TOBEC body impedance analysis shows
that fat mass is the only thing that is large about you
lean mass is not different between infants born large or small
nutrient restriction/starvation-->IR, placental and fetal inflammation
obesity/overnutrition-->IR, placental and fetal inflammation
chronic inflam during development changes longterm risk
diet study on macaques
national primate research center
in social indoor/outdoor housing
western 35% fat (incl lard) diet with HFCS, vs semiveg diet of insects, veg, 15% fat, high fiber
~85% of increased calories in western diet was from fat
single primate pregnancy
mom on western diet-->lipid structure change, N6 fatty acids incr, low N3 fatty acids, ratio: 17.3
-->bigger shift in fetal circ than maternal
-->fetal liver disease, severe fat deposition and oxidation, whether mom obese or not
-->persistent postpartum liver dz-->fetal cell death
-->apoptosis-->bridging fibrosis-->cirrhosis
**reverse diet just during pregnancy, even with obese mom-->all fetal risk goes away
mom's are willing to do things for their children
explain to them the pathology that they can cause by eating western diet
-->eat well for 8 months-->healthy child
ADIPOSITY REBOUND
see CDC chart of child weights/age
babies usu have a skinny point early in life then start gaining fat again
fat babies the point is earlier, age 2-3
skinny people have rebound point at age 7 or so
can change which curve you follow
skinny kid-->provider freakout-->feed 'em-->change rebound-->increase liftime weight
"catch up" growth not desirable
"skinny babies are OK" outside context of disease (failure to thrive, CF, etc)
don't know for sure about what happens when you intervene and delay adiposity rebound, study not done
worst scenario is skinny kid with rapid weight gain-->heart dz
positive predictive value is as high as cigarette smoking for heart dz and smoke risk
*7x risk of obesity dt rapid infant weight gain
DUTCH HUNGER WINTER revisit
n=300,000
famine in first 2 trimesters-->80% more overweight
famine in first 5 months of life-->40% less overweight
BRAIN GROWTH
much of human brain growth occurs ex-utero esp in premies
brain growth spurt: 7th prenatal month--2 years of age, more than 1/2 of eventual brain wt is added
much programming happens then
leptin, ghrelin, insulin, PYY act on feeding centers in brian, appetite, metabolic rate, fat storage
can we change brain programming by adding a hydrocarbon? yes, fetal alcohol syndrome
primate brain development, POMC, appetite regulation part of brain changed by western diet
*baby einstein disney videos sold-->delays cognitive development if it replaces exposure to humans
BRAIN ENERGY CONSUMPTION
is energy inefficient
at rest brain burns more energy than all muscloskeletal system together
infant 90% of energy budget goes to brain
calorimeter, etc, get metabolic rate of infant
12 year olds in calorimeter room reading a book, 1700kCals, about the same as sleeping
watching TV takes fewer kCals: profoundly catatonic activity
more effect on those who are overweight
Klesges et al, Pediatrics, 1993
primates also love to watch television
does it matter if tv replaces nurturing? no.
watching tv shuts down most of brain incl limbic structures (I doubt this from my own experience)
optic cortex doesn't shut off
BREASTFEEDING
metabolic state of lactating mother MATTERS
meta-analysis of obesity odds vs breastfood: breastfood decr risk of obesity
any breastfood at all helps, longer time period (1yr)-->2/3 less risk
Pima: 2 months or more of breast-->much lower risk of obesity, dm2
(1998 study on 40 year olds: milk from 1958)
what about 2009 breast milk? more fructose, fat, GFs, cytokines, leptin, adiponectin
? diet affect quality of breast milk? doesn't change output
changes fat amount and type
*trans fat, sat fat, fish oil, all goes right through
*fat amount in obese mom's milk higher independent of diet
*growth factors and cytokines in breast directly proportional to what's in mom
growth factors: EGF, NGF, insulin, IGF-1, IGF-2, relaxin, TGF-a
"diabetic breast milk" vs some babies given banked nondiabetic milk
strong dose response relationship: more milk from diabetic-->more obese
**11% of US kids first solid food is french fry
WHAT TASTES GOOD TO YOU
Infant flavor preference altered by maternal diet
during lactation gave moms alarm clock that range bid
control: water, intervention: carrot juice
babies first solid food: cereal with water or carrot
babies want what mom had, ate more, liked it better
flavor preference is modeled during lactation
WHY KIDS EAT WHAT THEY EAT
NATURE VS NURTURE in childhood nutrition
behavior mostly learned from modeling by parents
stick to gather termites vs SUV to gather McDonalds
reward increases food pref
"stashing" incr food preference: locked up in cabinet
new food must be introduced at least 10x to be accepted
decrease food pref: bribery, masking (broc with chs sauce, ketchup is #1)
children learn by example
children need the opportunity to eat and the ability to refuse
*for parents with kids that won't try new foods
SCIENCE PROVING 10X INTRODUCTION EFFICACY
best way to introduce new foods to children's diet is to eat them yourself
scientificamericanfrontiers.com
goldfish, fig newtons, were snack foods at school lunch
captive students and teachers all ate together, had snack every day always same then
added raw tofu to snack plate, no comment about it, just suddenly there
adults ate without question
no performing about how good it was
after 10 introductions the kids were eating it too
no questions, no complaining
"dad comes home and commits metabolic obscenities in front of the TV"
bladder and stomach synapse to same neurons
empty or full is all they know
pee training is immediate
kid says they're hungry and have to wait
give food and they're not hungry: parents try to override
**let kid eat or not eat when they want
"science says that starvation is actually really good for us"
QUESTIONS
PLASTICS AS OBESOGENS
flouridated polycyclic hydrocarbons
released in sunlight
estrogenic, est is mildly obesogenic
confuses sterol receptors and make you think you are starving for sterols ie cholesterol