Obesity Epidemic? Detail of chromosome 15 From the obesity map

Obesity Epidemic? Detail of chromosome 15 From the obesity map database Bacchus, Peter Paul Reubens, 1638

Recent Increases in Obesity 1985: 15% obese 2000: 30% obese Is obesity a disease? -not all obese people have poor health What’s causing this unusual Increase in obesity? -Our genes? -Environment? fast foods sedentary lifestyle -Dieting, especially low fat diets -Food choices that blind our natural ability to monitor our food intake

Obesity: Environment It’s those damn corporations QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture. again shall be king

Obesity: Environment Sedentary Lifestyle

Obesity: Ridiculousness QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

Obesity: Environment Diets too high in fat? QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture. Diets too high in carbohydrates? Too much meat and dairy? QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture. Too much sugar Refined flour Soft drinks Diet drinks make you hungry! Let’s poke carbohydrates in the eyeball QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture. QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture. QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture. QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture. Dave Barry

Avoiding Obesity: It’s all about selfdiscipline, will power, determination Good Mouse Bad Mouse

QuickTime TIFF (Uncompressed) and a de are needed to see th compressor is picture.

Recent Increases in Obesity 1985: 15% obese 2000: 30% obese

Sexually Dimorphic Mammalian Species

Humans are Dimorphic Males Taller, heavier Broader shoulder Smaller hips, buttocks Smaller breasts More facial hair Deeper voice Larger phallus Less stamina due to lower subcutaneous fat More heart disease due to tendency to gain abdominal body fat

Sexual Dimorphism in Body Fat Distribution in Humans Abdominal vs. Subcutaneous Fat Results in Apple vs. Pear Shape

Diabetes and Heart Risks if. . Triglycerides 150 mg/dL “Good Cholesterol” High-Density Lipoprotein Cholesterol Men Women NCEP Expert Panel. JAMA. 2001;285:24862497. 40 mg/dL 50 mg/dL

Plasma Triglycerides and HDL-C in Lean Men and Women and in Obese Subjects 3.5 2.8 2.1 1.4 0.7 0.0 3.5 2.8 2.1 1.4 0.7 0.0 1.50 1 Lean Men Low High Visceral AT Area Obese Men 1.2 1 Lean Women Low High Visceral AT Area Obese Women 1.25 HDL Cholesterol (mmol/L) Triglycerides (mmol/L) with High or Low Visceral Adipose Tissue (AT) 1 1.00 0.75 0.00 Lean Men Low High Visceral AT Area Obese Men 1.50 1.25 1.2 1.00 0.75 0.00 Despres JP, Krauss RM. Handbook of Obesity. 1998;651-675. Lean Women Low High Visceral AT Area Obese Women

Traits Associated with WTH in Women Trait Puberty onset Testosterone Triglycerides Insulin resistance high Risk for Type II diabetes high For gallbladder disease high Risk for cancer (ovar.,breast, uterine) Hypertension, stroke heart disease, mortality WTH High late high high low WHT Low early low low 1,4 mod-low 1,5 mod-low 6 Ref. 1 2 1,3 high mod-low 7,8 high mod-low 3,5,9

Adaptive significance of Sexual Dimorphism in Body Fat Distribution related to female lactation (fat is stored in the hips, thighs, buttocks for use in making milk during lactation)

An enzyme active in weight gain is high in thighs prior to lactation. High LPL gaining fat Low LPL losing fat 30 Gaining in thighs Femoral Abdominal Losing in thighs 20 10 Lipoprotein Lipase Activity 0 Menstruating Rebuffe’-Scrive et al., 1974 Pregnant Lactating

Nonabdominal fat critical for reproduction And it’s not unhealthy! It might even be “protective” against diabetes and heart disease

Regardless of female body weight (whether the females are very fat, very lean or in between) A large body of data supports the notion that males of North or South American or Europe strongly prefer a LOW W.T.H. ratio

Health Risks and Obesity Abdominal (apple) Subcutaneous (pear) Insulin resistance Hyperinsulinemia Hypercholesterolemia Low HDL cholesterol Diabetes mellitus Coronary artery disease Hypertension Stroke No known health risks Science sides with Sir MixAlot

What kind of epidemic has so many healthy people? Marilyn Monroe BMI overweight to obese obese Bad Cholesterol lean low high WHT

QuickTime TIFF (Uncompressed) and a de are needed to see th compressor is picture.

Leptin

Significance of Leptin It appears that body weight is regulated By a “lipostat” Leptin commonly thought to be the lipostatic signal It is still hoped by many that our knowledge of leptin will lead to a cure for obesity

The Seductive Lipostatic Hypothesis Food Intake Mystery Signal Body FAT

It’s OK to sleep with a hypothesis. You should never marry one.

History Early evidence (1970s) for a lipostat came from mutant mice that were obese Ob/ob mouse Db/db mouse Mutation in a single gene on an autosome Obese (more than 30% heavier than wild type) Hyperphagic (ate significantly more than wild type Diabetic (hyperglycemic) Infertile (does not undergo puberty, does not mate or have estrous cycles or spermatogenesis, decreases gonadal steroids)

Parabiosis An obese mouse (ob/ob) is sharing its circulation with a lean wild type mouse

How would you explain these results? ob/ob - / mouse: ob/ob lost weight db/db- / :db/db obese, / stopped eating and lost weight ob/ob -db/db: ob/ob stopped eating and lost weight, whereas the db/db unaffected An additional experiment showed that when one of a pair of / parabiotic mice was overfed, its "twin" lost weight.

Conclusion?

Conclusion of Parabiosis Experiment The ob/ob has a mutation in the gene that codes for a circulating factor that stops the rat from eating. The db/db has a mutation in the gene that codes for the receptor for this factor

Conclusions of Parabiosis Experiment Ob/ob lacks a factor that stops eating The db/db lacks the receptor for that factor

Leptin (Ob protein) Cloned by J. Friedman’s lab in 1994 (Zhang et al., 1995) Adipocyte protein secreted in proportion to body fat content in response to influx of fuels into adipocytes ( Plasma concentrations high in fat, fed animals low in lean or fasted animals Peripheral and central treatment decreases food intake (FI) and body weight (BW) in many different species Ob/ob (leptin decreases food intake and bw) Db/db (leptin treatment has no effect) Wild type mouse (leptin decrease FI and BW) Rats Hamsters Monkeys

So Is leptin the cure for obesity? Percentage of people who are obese because they have a mutation in the gene for leptin miniscule (only a few people in the world have this mutation) Clinical trials a failure gave daily leptin injections to obese patients. Only a third of the patients lost weight. Some patients dropped out of the study finding the injections irritating Some reported decrdased appetite at first, and increased appetite after continued use (they developed leptin resistance). The people gained back the weight they had lost when the leptin injections ceased.

Why is Leptin Not The Miracle Cure for Obestiy? In addtion to leptin, there are many hormones and neuropeptides that influence appetite and obesity Giving leptin alone does not curtail obesity Obese people have higher leptin than normal weight people

Some Factors Involved in Energy Balance Organizational System Metabolic Stimuli Hormones glucose oxidation ffa oxidation ketone body formation, oxidation influx of fuels into adipocytes, muscles, liver, etc. lipolysis insulin glucagon leptin glucocorticoids (cortisol, corticosterone) ghrelin growth hormone cholecystokinin (gut peptide) Neuropeptides NPY AgRP Orexin CART a-MSH

RED INHIBITORY GREEN STIMULATORY Leptin Insulin Ghrelin NPY/AGRP POMC ( MSH) Increases appetite Decreases appetite

ARC LEPTIN INSULIN PVN QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

Leptin Re-wires the NPY and POMC Circuitry Wildtype mice tend to have more excitatory synapses in the leptin-to-POMC circuit, and more inhibitory synapses in the leptin-to-NPY circuit QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture. Ob/ob mice tend to have more excitatory synapses in the leptin-to-NPY circuit and more inhibitory synapses in the leptin-to-POMC circuit

Increase Food Intake Orexin (lateral hypothalamus) NPY (arcuate and PVN) AgRP (arcuate and PVN) MCH (lateral hypothalamus)

Decrease Food Intake POMC ( MSH) (arcuate and PVN) CART (arcuate nucleus) CRH (PVN)

Current Research Any particular obese individual might have mutations or variations at these obesity-related loci You cannot assume any one obese person is just lazy Many genes, peptides and neurocircuits involved Redundancy in the system A drug that influences one of these peptides can be overridden by the others As soon as you stop taking the “antiobesity” drug, you gain all the weight back Single gene approach unlikely to solve the obesity problem.

A Pause That Refreshes

Dieting Doesn’t Work Dieting is a signal to the brain to become better at storing fat

Energy Balance Intake Storage Motivational (appetite) Consumption Glycogen in muscle and liver Lipid in adipose tissue and other tissues Amino acids in muscle and bone (used with glycerol to make new glucose) Expenditure Resting Thermogenesis Reproduction Immune function Other cellular processes (mitosis, miosis, digestion, metabolism, cell repair)

Energy BalanceNo Free Rides QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture. Intake Storage Glycogen in muscle and liver Lipids in adipose tissue and other tissues - Protein (Amino acids )in muscle and bone (used with glycerol to make new glucose) Expenditure Resting (Basal Metabolic Rate) Thermogenesis Reproduction, Immune function

Restricting Food Intake Decreases Energy Expenditure 1200 1000 Ate Ad libitum 75% Restricted 50% Restricted 800 600 400 Energy Expenditure 200 0 1st Qtr Eating Regimen

Rebound results from increased appetite coupled with decreased expenditure

Dieting Makes you Fat eventually

I’m sorry, Louis Fat doesn’t make you fat!

Diet low in simple carbs are more satisfying You feel less hungry You eat less

Good Fats QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture. Linoleic Acid has two double bonds, can be hydrogenated and is a Polyunsaturated fat. Its formula is CH3(CH2)4CH CH2CH CH(CH2)7COOH QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture. QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture. Bad Fats Water insoluble subatances. They have a relatively large nonpolar hydrocarbon part and a small oxygen containing polar part. Stearic acid has a 17 atom hydrocarbon chain and a carboxylic acid group. Its chemical formula is CH3(CH2)16COOH and it is a saturated fat. QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

Given two meals with the same caloric value, the low carb diet results in -Significantly more weight loss -Happier people -The weight will be gained back if you go back to eating carbs

Don’t Diet Make permanent changes -no soft drinks -Minimize bread and pasta -eat carbs like vegetables and fruits and berries

Diet Drinks Make You Hungry Growing up on diet drinks -precludes your ability to match taste with caloric intake -makes you significantly fatter

Diet Drinks decrease the ability to gauge the caloric value of food Davidson and Swithers, International Journal of Obesity, 28, 933, 2004. Rats were trained with a flavored premeal and then later tested for their food intake Consistent Group received flavors that consitently predicted the calorie content Inconsistent Group received flavors that did not have any relation to their caloric value Rats were given sweet flavored premeal that matched their caloric value (consistent)or did not match (inconsistent) 20 Flavored Premeal 10 Chow meal 0 Consistent Inconsistent Caloric Intake

Good luck this weekend -Don’t diet -Don’t drink soft drinks, especially diet -Eat a balance diet of real foods including polyunsaturated fat -To Sir Mixalot with love 87!

More References Taubes, Gary, What if it’s all been a big fat lie? New York Times, Sept. 15, 2002. Pollen, Michael, Unhappy Meals, York Times, January 28, 2007. New