biochemistry of obesity made easy
TRANSCRIPT
The Biochemistry of The Biochemistry of ObesityObesity
Made Easy Made EasyRick Voakes, MD FAAP
www.health-bytes.com
Healthy Weight KHealthy Weight Kidsids Coalition CoalitionFormed in 2003, multidisciplinary
community coalitionCATCH grant, Foundation for a Healthy
Kentucky grantwww.healthyweightkids.org
Obesity EpidemicObesity Epidemic60% of adults have BMI>25 (85th%)22% of adults have BMI>30 (95th%)In 1990, there was no state with over 15%
adults with BMI>3025% of children have BMI over 85th%Every state is increasing yearlyExcept Arkansas, where they made logical
proactive food changes in public schools.Lee, Arch Peds Ad Med, 162(7):682 July 2008
Pediatric BMIPediatric BMINEVER write it as a single numberThis has no meaning at allALWAYS write it with two numbers, like
writing a blood pressure23/19, for example, is the calculated
number OVER the 85th% BMI for that child’s age (say “23 over 19”)
Use the “age + 10” rule, age 7-15Only 2 BMI points more, goes to 95th%
Energy In = Energy Out ?Energy In = Energy Out ?
Think Again! Think Again!
Robert Lustig Article:Robert Lustig Article:
The Hypothalamic-Leptin AxisThe Hypothalamic-Leptin AxisFeedback systemAllows the fat cells to tell the brain to quit
seeking more food when too much fat is present.
Allows the brain to adjust the metabolic rate to control energy use.
Lustig, Ped Annals, 35:12 Dec 2006
The Hypothalamic-Leptin AxisThe Hypothalamic-Leptin AxisHow it works:How it works:When excess fat builds up in the fat cell,
leptin is produced and enters the bloodstream.
Leptin receptors in the hypothalamus are triggered.
This shifts the hypothalamus into “Spend Energy” mode.
Leptin changes SLOWLY (days to weeks)Lustig, Ped Annals, 35:12 Dec 2006
““Spend Energy” ModeSpend Energy” Mode
““Spend Energy” ModeSpend Energy” ModeAppetite reduction
(Don’t need to waste time looking for more food)
Increase sympathetic tone to skeletal muscle increasing ATP and mitochondrial proteins (Muscles are prepared to function optimally)
Lustig, Ped Annals, 35:12 Dec 2006
Increase TSH to increase thyroid output and increase baseline energy expenditure
Beta-adrenergic stimulus to fat cells increases lypolysis (Break out stored energy for immediate use)
““Conserve Energy” ModeConserve Energy” Mode
““Conserve Energy” ModeConserve Energy” ModeAppetite increases
(Need to seek more food for energy)
Decrease sympathetic and increase vagal tone to slow down muscle function
Increase fat absorption by fat cells
Lustig, Ped Annals, 35:12 Dec 2006
Vagus increases peristalsis and insulin production (for food processing)
Vagus nerve also slows heart rate and myocardial oxygen consumption
What if leptin feedback is blocked?What if leptin feedback is blocked?Hypothalamus is tricked into thinking that
there is no leptin being released from fat cells.
It then sends Orexin-A all over your brain, making you think you are starving.
The hypothalamus is stuck in “conserve energy” mode, increasing appetite, slowing down metabolic rate, increasing fat storage.
Your brain is constantly “starving” even though the fat cells are busting at the seams!
Orexin-A (hypocretin-1)Orexin-A (hypocretin-1)Small peptide hormone released by the
hypothalamus to act on the rest of the brain.
It signals hunger, after the hypothalmus is stimulated by ghrelin from the stomach
It also signals wakefulness, so that your brain stays awake long enough to seek food, and not to hibernate!
Another reason obese children don’t sleep well
Energy in = Energy out ???Energy in = Energy out ???Obese children are “leptin resistant”
(leptin receptors are blocked)They are stuck in “Conserve Energy”
modeTheir brains are starving, so they are
constantly seeking more foodYet very little of that energy is available
for activity, since it is routed away into the fat cells.
What blocks leptin?What blocks leptin?Brain damage to the leptin receptor area:
hypothalamic obesity syndromeInsulin excess blocks leptin receptors(Fructose is what leads to insulin excess)
Lustig, Ped Annals, 35:12 Dec 2006
Insulin excess blocks leptinInsulin excess blocks leptin
Lustig, Ped Annals, 35:12 Dec 2006
Insulin excess blocks leptinInsulin excess blocks leptinInsulin receptors in the brain share the
same substrate as leptin receptorsWhen there is excess insulin, it hogs all
the substrate, leaving none for leptin to use.
Leptin attaches to the receptor, but nothing happens.
In the hyperinsulin stateIn the hyperinsulin stateEven high levels of leptin have no effect
on the hypothalamusKnown as “leptin resistance”Occurs in a large percentage of
overweight children and adults
Causes of Hyperinsulin StateCauses of Hyperinsulin StateHigh fat dietLow fiber dietSleep deprivationHigh fructose diet!!
Fructose:Fructose:A major cause of hyperinsulinemiaA major cause of hyperinsulinemiaFructose is absorbed from the intestine
and enters the liver without insulin regulation, AND it does not suppress ghrelin (hunger hormone).
It is then converted into acetyl-CoA, which floods the Kreb cycle, forcing excess production of FFA, triglycerides and VLDL lipoproteins.
Fructose:Fructose:A major cause of hyperinsulinemiaA major cause of hyperinsulinemiaAll this excess fat production leads to fatty
liver which causes hepatic insulin resistance
Fructose also activates the enzyme jnk-1 which causes hepatic inflammation, and more insulin resistance
Faulty feedback to the liver results in massive insulin production, leptin resistance, and obesity
Review: Review:
What fructose becomes in your liverWhat fructose becomes in your liverFFA (free fatty acids, the building blocks
of all lipids)VLDL lipoproteins and triglycerides (the
nasty lipids most associated with cardio- vascular disease)
Uric acid (oxidative stress, vascular inflammation)
What changed since 1970?What changed since 1970?In 1970 few children and adults were
overweight.In 2008 obesity is epidemic!What is so different now?
Genetics?Genetics?A common argumentBut how could our DNA change in only one
generation?Unless, a massive gamma ray storm from
sun spots, like in the movie “Night of the Living Dead”?
““We want fructose”We want fructose”
© 1990 Night of the Living Dead
Super-sized everything?Super-sized everything?
©2007 Zits, by Scott and Borgman
Super Size Me (the movie, 2004)Super Size Me (the movie, 2004)Required viewing!View for free, any time, at
www.freedocumentaries.orgThey missed the major cause of the junk
food addiction: fructose in his giant-sized cokes, not the super-sized meal
Stress?Stress?Is there more stress now?Do we eat too much to deal with stress?Too much “comfort food” available?Addictive behavior does temporarily
reduce stress. But stress itself does not cause the addiction, whether it is tobacco, fructose, or other drugs.
Garfield is obviously leptin resistant, Garfield is obviously leptin resistant, and his brain is constantly hungryand his brain is constantly hungry
What What reallyreally changed since 1970? changed since 1970?Gradual decrease in dietary fiberLess sleep (Cause or effect?)Gradual decrease in physical activityGradual increase in portion sizeGradual increase in screen timeIntroduction of HFCS in the 1970’s
High Fructose Corn Syrup (HFCS)High Fructose Corn Syrup (HFCS)HFCS first introduced in the 1970’s as
42% and 55% to simulate sucrose tasteThen higher levels up to 90% to make it
much sweeter, addictiveIndustry denies using addictive levels, but
no regulation of nutrition content of foodAddiction is caused by leptin resistance,
leading to constant hunger and craving more sweet foods
Fructose is in everythingFructose is in everythingBreakfast cereal, many packaged foods,
hot dogs, ketchup, ice cream, etc“Junk food”, candy, sweetsTable sugar (sucrose) is 50% fructose“Sports drinks”, “energy drinks” (ironic!)Sodas are also a very concentrated source
USA TodayUSA Today, July 2008, IoM testifies to Congress, July 2008, IoM testifies to Congress
Fiber is also a factorFiber is also a factorFiber adds bulk to foods, so the stomach
turns off ghrelin soonerFiber slows absorption of sugar in the gutFiber binds to bile acids, reducing fat
absorption from the gut Fruits and veggies are a good source
Veggies have a relatively short shelf lifeVeggies have a relatively short shelf life
Why foods are “processed”Foods are “processed” to remove fiberThis removes the part that spoilsFructose (HFCS) is often added to retard
spoiling (poisons the bacteria!)Shelf life is greatly increasedBut nutritional value is greatly
DECREASED !
TV + Food = OverweightTV + Food = Overweight
Why? Marketing of junk food!Why? Marketing of junk food!
Marketing by the junk food industryMarketing by the junk food industryFood industry learned from previous
experience with tobacco (eg, Kraft/RJ Reynolds Corp)
It’s OK to sell stuff to kids that will kill them, and easy to do it with ads
$11 billion budget for advertising (2004)Less than 3% of TV food and beverage
advertising is for non-harmful foodsIoM: “Food industry should promote
healthy foods” (why would they do that?)
Decreased sleep is associatedDecreased sleep is associatedwith obesitywith obesityMany studies show an associationThis may be explained by other causesLeptin resistance leads to excess Orexin-A
which keeps you awake! (and hungry)Obesity is a cause of sleep apneaLess sleep often goes with more TV
Can shorter sleep time add to obesity?Can shorter sleep time add to obesity?Lumeng postulated that shorter sleep
time in 3rd grade led to obesity in the 6th grade
But this was only an associationThere was no controlled variableEasily explained by children on high
fructose intake were already not sleeping well in 3rd grade (orexin-A)
Lumeng, Pediatrics, 120(5):1020, Nov 2007
Do babies who sleep less get fat?Do babies who sleep less get fat?Taveras looked at babies 6-24 monthsThose with less sleep had higher BMI at
age 3Again this is just an association6 months is the age when fructose is
generally introduced into the diet!
Taveras, Arch Peds Adol Med, 162(4):305, Apr 2008
How can we help our patients?How can we help our patients?
Taking a diet historyTaking a diet historyBetween meal snacks? Eat in front of TV?High fat foods?High sugar foods?5-a-day rule: 5 fruits or veggies?Eliminate white foods (overly processed)
such as potato flakes, white bread, table sugar, white rice
White dairy (milk, yogurt) is OK in moderation
Encourage moms to breastfeed
Taking a “drinking” historyTaking a “drinking” historyWhat does the child drink?Ask about tea, juice, Gatorade, milk, popSuggest alternatives: diet soda, sugar-free
Koolade, Crystal Lite, sweet tea with sugar substitute only, flavored water
Low-fat milk, with meals onlyLots of WATER!No juice! No sports or energy drinks!
Let children and families know what Let children and families know what overweight does to you!overweight does to you!DiabetesHeart and vascular diseaseHigh blood pressure and strokeLiver damage (fatty liver)Worsens asthmaSleep apneaBack pain, hip and knee damageColon cancer
Non-alcoholic fatty liverNon-alcoholic fatty liverRare until recentlyCan cause death from cirrhosisFound in 9% of children autopsied in LAIncreased with BMI to 38% in obese kidsLinear correlation with their BMICause? excess fructose increasing hepatic
lipid content
Schwimmer, Pediatrics, 118(4):1388, Oct 2006
4-Pronged Attack4-Pronged AttackDr Robert LustigDr Robert Lustig
Get rid of all liquid in the house that contains sugar or HFCS
Eat your carbs with fiber (not white!)Wait 20 minutes before seconds (wait
for peptide YY to kick in, from colon)No TV in child’s room, trade TV time for
activity time, minute for minute (Activity can fight fructose craving)
Lustig, Ped Annals, 35:12 Dec 2006
Old view of foodOld view of foodAll food is energySome more concentrated than othersWhatever amount of energy we eat can
be burned off as activityThere is no such thing as “junk food”
New view of foodNew view of foodThere are definite qualitative differences
in food choicesFoods that are high in fiber and low in
fructose are beneficial to healthFoods that are low in fiber and high in
fructose are harmful to health, and are the major cause of the hyperinsulin state
What are the implications?What are the implications?We now must consider that not all foods
are equalJunk food really is “junk”, or worse
(fructose = poison)The body’s energy management is a
complex process, influenced strongly by the types of food we eat, especially by their content of fiber and/or fructose
Is obesity a disease?Is obesity a disease?Obesity is not just a matter what weight is
currently fashionable or socially acceptable
It’s not even a diseaseIt’s just a symptom of fructose poisoning
Other symptoms of fructose poisoningOther symptoms of fructose poisoningDiabetes (hyperinsulin state, insulin
resistance)Cardiovascular disease Hypertension (renovascular damage)Fatty liver HyperlipidemiaIncreased BMI from excess lipid stored in
fat cellsSound familiar?
Metabolic Syndrome = Fructose PoisoningMetabolic Syndrome = Fructose PoisoningWith higher BMI, other symptoms can
evolvePCOS (polycystic ovary syndrome)Acanthosis nigricansDiabetic complicationsElevated CRP, endothelial damage
We may consider that diabetes, We may consider that diabetes, hyperlipidemia, cardiovascular disease, and hyperlipidemia, cardiovascular disease, and fatty liver are all part of the same pathologic fatty liver are all part of the same pathologic spectrum…spectrum…….a result of damage to the leptin-….a result of damage to the leptin-hypothalamic axis by fructose and hypothalamic axis by fructose and hyperinsulin state.hyperinsulin state.
Overweight is just a symptom that alerts us Overweight is just a symptom that alerts us to the progression of that disease state.to the progression of that disease state.
In the future….