Pause Decline In Onset Age Leptin Imbalances, Aging, and ... › ppt › braverman2.pdf ·...

Eric Braverman, M.D.

Director, PATH Medical andFaculty at Weill Cornell Medical Center

Leptin Imbalances, Aging, and Obesity

The Secret of Obesity Science

Pause Decline In Onset Age

Electropause Electrical activity of brain waves 45

Biopause Neurotransmitters

Dopamine: 30↓Acetylcholine: 40↓

GAB A: 50↓Serotonin: 60↓

Leptin ↑

Pineal Pause Melatonin 20

Pituitary Pause Hormone feedback loops 30

Sensory PauseTouch, hearing, vision, taste and

smell sensitivity40

Psychopause Personality, health and mood 30

ThyropauseCalcitonin and thyroid hormone

levels50

Parathyropause Parathyroid hormone 50 2

Pause Decline In Onset Age

Thymopause Gland size and immune system 40

Cardio/Vasculopause Blood flow 40

PulmonopauseLung elasticity and function with

increase in blood pressure50

Adrenopause DHEA 55

Nephropause Erthyropoietin level 40

Somatopause Growth hormone 30

Gastropause Nutrient Absorption 40

Pancreopause Blood sugar level 40

3

Pause Decline In Onset AgeInsulopause Glucose tolerance 40

Andropause Testosterone in men 45

MenopauseEstrogen, progesterone, and

testosterone in women40

Osteopause Bone density 30

Dermopause Collagen, Vitamin D synthesis 35

Onchopause Finger and toe nails 40

Uropause Bladder control 45

Genopause DNA 40

4

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The Brain Pulses out Hormones!

• The four main neurotransmitter systems: Cholinergic,Catecholaminergic, Serotonergic, GABAergic, Each system affects different hormones in different ways.

• In some instances, “neurotransmitters” behave more like hormones (e.g. epinephrine and norepinephrine, and dopamine when it acts as a releasing hormone from the pituitary gland)

Neurotransmitter regulation of anterior pituitary hormones Tuomisto J, Mannisto P Pharmacol Rev. 1985 Sep;37(3):249-332

Loss of Neurotransmitters and Hormones due to Aging Leads to Widespread Breakdown

Delerium/Confusion-

Dopamine ↓

Dementia-Acetylcholine ↓

Depression-Serotonin ↓

Anxiety/Panic-GABA deficiency ↓

Hypo/Hyperglycemia

Hypothyroidism

Hypopituitarism

Vitamin B Def.

Hypercalcemia

Hypothyroidism

Vitamin B12 Def.

Diabetes Mellitus

Hypopituitarism

Decrease in Leptin

Hyperthyroid

Adrenal Insuff.

Hypopituitarism

Diabetes Mellitus

Hypercalcemia

Decrease in Leptin

Hyperthyroidism

Hypopituitarism

Increase in Leptin

6

7

Hormonal Changes with Aging

Decrease No Change IncreaseInsulin growth factor

Vitamin 25(OH) D

Testosterone(m)

Estradiol (f)

DHEA & its sulfate

Triiodothyronine

1,25(OH)2 Vit D

Inhibin

Arginine Vasopressin

Pregenenolone

Leptin?

Epinephrine

Thyroxine

Glucagon

Glucagon like Peptide 1

Thyrotropin

Calcitonin

ACTH

Prolactin(f)

Leptin?

Insulin

Vasopressin

CholecystokininAtrial naturetic peptide

Norepinephrine

Epinephrine(>80yo)

FSH

LH(f)

Parathormone

Cortisol

Leptin

*Morrison MF. Hormones, gender and the aging brain: The endocrine basis of geriatric psychiatry.(2000) Cambridge University Press. Cambridge.

These changes create the pauses of aging!

Aging is associated with a gradual loss of physiological functions and a decline in plasma concentrations of several steroid hormones

Hormonal Decline Predicts Deficiencies That Can Be Repaired Otherwise Memory And Attention Deficits Will Occur

No hormones, no brain juice to grow or maintain resilience

Age 30 HGH, IGF-1,3 deficiency

Age 40 Testosterone, Estrogen deficiency

Age 50 DHEA, Thyroid deficiency

Age 60 Progesterone, Parathyroid deficiency

Age 70 Calcitonin, Erythropoietin deficiency

8

Hormones That May Contribute to Cognitive Decline:

• Androstenedione

• Calcitonin

• Dehydroepiandrosterone (DHEA)

• DHEA-Sulfate (DHEA-S)

• Erythropoietin

• Estriol

• Estrone

• Human growth hormone (HGH)

• Hydroxycortisol/aldosterone

• Insulin-like growth factor (IGF)

• Incretin (at least 50% bioidentical)

• Insulin

• Melatonin

• Parathyroid Hormone

• Pregnenolone

• Progesterone

• Testosterone

• Thyroid: T3, T4

• Vitamins D2, D3

• Oxytocin

• DDAVP

9

Leptin

• Protein produced primarily in hypothalamus, brain stem, and adipose tissue which acts as metabolic signal to the brain.– Reaches brain, crosses blood-brain barrier, and accumulates in neuronal cell bodies

expressing leptin receptors

• An integral component of energy homeostasis and body weight regulation– Reduces body weight by inhibiting feeding behavior and increasing fuel expenditure.

• Effects are mediated in part by direct action of leptin on hypothalamic neurons

• As a biomarker indicative of the amount of fat in the body, can be used to manage obesity as HgAlc for diabetes and cholesterol for heart disease.

Leptin Insensitivity

• With aging, there is greater adiposity despite high serum leptin levels– Due in part to a reduction in number of leptin receptors in the brain– Extremely low leptin levels may be associated long term with oligomenorrhea,

anorexia, too much thinness, and dementiaPaz-Filho G, Wong ML, Licinio J. “Leptin levels and Alzheimer disease”. JAMA. 2010 Apr 21;303(15):1478; author reply 1478-9.Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, Roubenoff R, Auerbach S, DeCarli C, Wolf PA, Seshadri S. “Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging” JAMA. 2009 Dec 16;302(23):2565-72.

110

Leptin and Neurotransmitters

• Close interactions of leptin with D2 receptors and serotonergic system– Both lower leptin levels

• During the aging process, there is a decline in the dopaminergic and serotonergic systems that are both activated by leptins.

• Method of managing obesity – A closer look at the influence of leptin in the brain’s regulation of food uptake

via dopamine neurons rather than the hypothalamus provides new mechanisms for behavioral control

DiLeone RJ. “The Influence of leptin on the dopamine system and implications for ingestive behavior”. International Journal of Obesity. 2009. 33:S25-29.Blum K, Chen ALH, Chen TJH, Rhoades P, Prihoda TJ, Downs BW, Waite RL, Williams L. “LG839: Anti-Obesity Effects and Polymorphic Gene Correlates of Reward Deficiency Syndrome” Advanced Therapeutics. 2008. 25(9):894-913.

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Role of Dopaminergic Pathways in Obesity and Related Behaviors

Dopamine D2 Receptors and Gene• Dopamine stimulators normalize overeating, body fat and blood glucose levels by increasing serum DHEA.

• There is evidence that BMI and even personality disorders (temperament) are directly correlated with the ability of dopamine to bind to its respective brain receptors

• Certain dopamine gene mutations associate with BMI

• The A1 form of the dopamine D2 receptor gene is associated with an increase of fat storage and a high BMI

• In humans using PET scan, low dopamine D2 receptors have been found with obese individuals not lean controls.

• Glucose causes a release of dopamine at brain sites

• Dopamine itself increases the release of glucose from blood cells (hepatocytes)

Chen TJH, Blum K, Kaats G, Braverman ER, Pullin D, Downs BW, Martinez-Pons M, Blum SH, Mengucci J, Bagchi D, Bagchi M, Robarge A, Meskin B, Arcuri V, Varshavsky M, Notaro A, Comings DE, White L. “Reviewing the role of putative candidate genes in “Neurobesigenics”, a clinical subtype of Reward Deficiency Sundrome (RDS)” Gene Ther Mol Biol. 2007. (11):61-74. Chen TJH, Blum K, Kaats G, Braverman E, Pullin D, Downs BW, Wood R, Comings DE. “Correlation of the Taq1 Dopamine D2 Receptor Gene and Percent Body Fat in Obese and Screened Control Subjects: A Preliminary Report” GTMB (in press). 12

Dopamine Receptors and Nutritional Repair

DRD2 Receptors and Psychoactive Drugs• Anti-psychotic drugs can increase feeding behavior and weight gain byblocking dopamine D2 receptors.• Drugs that stimulate either dopamine D1 and/or D2 receptors reduce overeating.

Other Dopamine Genes• Other genes such as the dopamine D4 receptor was also associated with obesity and a high BMI.• Dopamine D1 and D2 receptors linked to glucose metabolism and feeding behavior.• Certain dopamine gene forms associate with low energy expenditure

Blum, K., Chen AL., Chen TJH., Bowirrat A., Waite RL., Prihoda TJ., Blum SH., Downs BW., Kerner M., Savarimut S., Rhoades P., Reinking J., Braverman ER., DiNubile N., Stice E., Oscar-Berman M., Gold M., “An In-Patient Randomized, Double-Blind, Placebo Controlled Investigation of the Anti-Anxiety Effects of the Nutraceutical Synaptamine ComplexTM: Putative Targeting of Dopamine D2 Receptor Function in Reward Deficiency Syndrome (RDS)” J Nutrition. Chen TJH, Blum K, Kaats G, Braverman E, Pullin D, Downs BW, Wood R, Comings DE. “Correlation of the Taq1 Dopamine D2 Receptor Gene and Percent Body Fat in Obese and Screened Control Subjects: A Preliminary Report” GTMB (in press).

Nutritional repair of dopamine receptors is possible:D-phenylalanine, L-phenylalanine, L-tryptophan, L-glutamine, Pyridoxal 5’-

phosphate

13

Mean Baseline Demographic Data for Subjects for Non-Obese and Obese Subjects

70%

60%

50%

40%

30%

20%

10%

0%Super

ControlsRegular Controls

Obese Subjects

% Carrying DRD2 Taq I A1 Allele

Chen TJH, Blum K, Kaats G, Braverman E, Pullin D, Downs BW, Wood R, Comings DE. “Correlation of the Taq1 Dopamine D2 Receptor Gene and Percent Body Fat in Obese and Screened Control Subjects: A Preliminary Report” GTMB (in press). 14

Neurotransmitters and Reward Circuitry

Blum, K., Chen AL., Chen TJH., Bowirrat A., Waite RL., Prihoda TJ., Blum SH., Downs BW., Kerner M., Savarimut S., Rhoades P., Reinking J., Braverman ER., DiNubile N., Stice E., Oscar-Berman M., Gold M., “An In-Patient Randomized, Double-Blind, Placebo Controlled Investigation of the Anti-Anxiety Effects of the Nutraceutical Synaptamine ComplexTM: Putative Targeting of Dopamine D2 Receptor Function in Reward Deficiency Syndrome (RDS)” J Nutrition.

Stimulation of Serotonergic System

15


Blum, K., Chen AL., Chen TJH., Bowirrat A., Waite RL., Prihoda TJ., Blum SH., Downs BW., Kerner M., Savarimut S., Rhoades P., Reinking J., Braverman ER., DiNubile N., Stice E., Oscar-Berman M., Gold M., “An In-Patient Randomized, Double-Blind, Placebo Controlled Investigation of the Anti-Anxiety Effects of the Nutraceutical Synaptamine ComplexTM: Putative Targeting of Dopamine D2 Receptor Function in Reward Deficiency Syndrome (RDS)” J Nutrition.

Brain Reward Cascade

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Blum, K., Chen AL., Chen TJH., Bowirrat A., Waite RL., Prihoda TJ., Blum SH., Downs BW., Kerner M., Savarimut S., Rhoades P., Reinking J., Braverman ER., DiNubile N., Stice E., Oscar-Berman M., Gold M., “An In-Patient Randomized, Double-Blind, Placebo Controlled Investigation of the Anti-Anxiety Effects of the Nutraceutical Synaptamine ComplexTM: Putative Targeting of Dopamine D2 Receptor Function in Reward Deficiency Syndrome (RDS)” J

Brain

Reward

Cascade

Stimulation of Serotonergic System

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Electrical Therapy Helps You Regain Balance

• Enhanced cognition

• Reduced anxiety

• Reduced depression

• Reduced insomnia

• Reduced withdrawal

symptoms

• Improved P300

• Improved brain wave disturbances

• Enhanced neurotransmitter function

• Relapse prevention

• Prevention of substance abuse in high risk individuals

PATH Wellness Manual. 2nd Ed. (176)

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• Energy deficiency is associated with hypoleptinemia, whereas excess energy leads to hyperleptinemia.

• Lower leptin levels correlated with:

• Testosterone

• Estrogen

• Thyroid Hormone

• IGF-1

Effects of Circulating Leptin on Neuroendocrine Axes and Energy Homeostasis

Bluher S, Mantzoros CS. “Leptins in humans: lessons from translational research”. American Journal of Clinical Nutrition. 2009; 89:991S-7S.19

Leptin and Cognition

Morrison CD. “Leptin signaling in brain: A link between nutrition and cognition?” Biochem Biophys Acta. 2009 May: 1792(5): 401-408

• Leptin impinges on many brain areas in addition to hypothalamus– Hippocampus, cortex, other areas associated with cognition.

• Alters:– Food intake– Motivation– Learning– Memory– Cognitive function– Neuroprotection– Reproduction– Growth– Metabolism– Energy expenditure….and more

Diversity of function means dysregulation of leptin secretion and signaling can have far reaching effects 20

Sick Body, Sick Brain

• Cognitive decline has been associated with almost every medical illness, including diabetes, sickle cell disease, thyroid disorders, metabolic syndrome and cancer, to name a few.

• In particular, the components of metabolic syndrome each contribute to memory loss: obesity, hypertension, hyperglycemia

Links between the pathology of Alzheimer’s disease and vascular dementia Quartermain D et al Neurochem Res. 2004 Jun;29(6):1257-66Cognitive Defects Occur with Sickle Cell Disease Family Practice News February 15, 2008Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP Nat Neurosci. 2008 Mar;11(3):309-317 Cognitive and neuropsychiatric aspects of subclinical hypothyroidism: significance in the elderly Davis JD, Stern RA, Flashman LA Curr Psychiatry Rep. 2003 Oct;5(5):384-9Metabolic syndrome and cognitive disorders: is the sum greater than its parts Yaffe K Alzheimer Dis Assoc Disord. 2007 Apr-Jun;21(2):167-71Self-Reported Cognitive Impairment in Patients with Cancer Kohli S, Griggs J, Roscoe J, Jean-Pierre P, Bole C, Mustian K, Hill R, Smith K, Gross H, Morrow G J Onc Pract. March 2007; 3(2):54-9

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Obesity

• Speeds up the aging process and reduces lifespan by 15 years

• One of five brain problems costing the country at least a hundred billion dollars or more per problem —obesity, addiction, neuropsychiatric problems, violence, and cognitive impairments.

• Current diagnostic tool is BMI – an imprecise measure of body fat

“Drug Abuse is Costly.” National Institute on Drug Abuse. www.nida.nih.gov. “Overweight and Obesity—Economic Consequences.” Centers for Disease Control. CDC.gov.“Gun Violence Costs Nation $100 Billion a Year.” Seattle Post-Intelligencer. Seattlepi.nwsource.com“The Costs of Mental Illness.” Mental Health: A Report of the Surgeon General. www.surgeongeneral.gov“The Economic Burden of Neurological Disease.” www.silverbook.org

American Bariatric Society’s Obesity

Classification

Males Females

BMI 30+

Body Fat % 25%+ 30%+

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Normal Weight Obesity

• Normal Weight Obesity (NWO): low BMI and high body fat percentage– Associated with higher risk of dyslipidemia (increased cholesterol), diabetes,

hypertension in men, cardiovascular disease for women, depression and lower physical capacity

– Normal BMI does not necessarily imply protection from consequences of ↑ body fat.– 1/3 of the sample population fell into the NWO category

• What about waist circumference?– In a recent study, increased waist circumference was not related to higher cardiovascular

mortality as was body fat in subjects with NWO

• We undertook a study to relate NWO to memory loss, cognitive processing speed, brain voltage/power, leptin resistance, and other medicalcomorbidities

We must find means to measure and manage the obesity epidemic

Romero-Corral A, Somers VK, Sierra-Johnson J, Korenfeld Y, Boarin S, Korinek J, Jensen MD, Parati G, Lopez-Jimenez F. “Normal weight obesity: a risk factor for cardiometabolic dysregulation and cardiovascular mortality”. European Heart Journal. 2009 Nov. doi:10.1093/eurheartj/ehp487

23 Braverman ER, Kerner M, Huang S, Savarimuthu S, Damle U, Yeldandi S, Quon J, Blum K, Shah NR. "DEXA more accurately predicts obesity compared to BMI utilizing American Bariatric Society criteria in 1,234 adults in primary care outpatient facility" American Association Clinical Endocrinologists Conference poster #609. Boston, MA. April 23-24, 2010.

A side by side comparison of obese and non-obese classification of 1,234 patients by BMI and body fat percentage shows the 452 obese patients who were “missed” by BMI.

Obesity Misclassification

38% of patients were misclassified by BMI:

452 were found to be obese by DEXA but non-obese by BMI and 12 were obese by BMI and non-

obese by DEXA.

Non‐obese Obese Total

Non‐obese 533 12 545

Obese 452 237 689

Total 985 249 1234

Body Fat %

(DEXA)

Body Mass Index (BMI)

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Obesity defined by BMI vs. DEXA

Braverman ER, Kerner M, Huang S, Savarimuthu S, Damle U, Yeldandi S, Quon J, Blum K, Shah NR. "DEXA more accurately predicts obesity compared to BMI utilizing American Bariatric Society criteria in 1,234 adults in primary care outpatient facility" American Association Clinical Endocrinologists Conference poster #609. Boston, MA. April 23-24, 2010.

This 5% of subjects that BMI calls obese are just big, muscular people.

Of the people who are lacking in fitness based on direct body fat measurement, 66% think they have a decent body weight.

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• 50% of women were classified as non-obese by BMI but obese by Body Fat Percent. For men, it’s not nearly as bad (25%) but still a significant amount

of misclassification.

Gender and BMI vs. DEXA


Red dots in the red shaded area indicates misclassified women with body fat >30% (obese) and BMI <30 (non-obese)

Blue dots in the blue and red shaded areas indicates men with body fat >25% (obese) and BMI <30 (non-obese)

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Inaccuracy of BMI


• Nationally, BMI has found 23% of the population to be obese, similar to the findings in our sample population, while DEXA found 56% to be obese

• BMI misclassifies muscular people as obese due to their large size

• BMI was also inaccurate in measuring fat in individuals who are thin flabby, or fall into the NWO category

Suggests that the obesity epidemic is much worse than we think

• As a predictor of obesity, BMI was found to be an inaccurate measurement tool while a direct measure of adipose tissue (DEXA scan) was very precise.

• National policy, preventative efforts, and interventions are being crafted using this imperfect measure.

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Adding Parameters to BMI

• Adding gender and plasma leptin to the BMI equation increased the sensitivity of the formula to 76% from 57%

• Simple tests can help us predict risk factors for obesity and dementia


Receiver Operating Characteristic (ROC)

curve demonstrates how much sensitivity is added

by leptin.

As the curve approaches the top left corner, or the

area under the curve increases, the

predictability of the curve’s function

improves.

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Metabolic and Neural Events Leading to Leptin Insufficiency

Kalra SP. “Central leptin insufficiency syndrome: an interactive etiology for obesity, metabolic and neural diseases and for designing new therapeutic interventions”. Peptides. 2008 January ; 29(1): 127–138. 29

Mechanisms of Leptin Resistance

Martin SS, Qasim A, Reilly MP. “Leptin Resistance: A Possible Interface of Inflammation and Metabolism in Obesity-Related Cardiovascular Disease”. J Am Coll Cardiol. 2008; 52:1201-1210.

Ob: leptin gene

Ob-R: leptin receptor

PTP1B: protein tyrosine phosphatase 1B

SLIP: serum leptin-interacting protein

SLR: soluble leptin receptor

SOCS3: suppressor-of-cytokine-signaling-3

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Negative Effects of Leptin Insensitivity on the Heart

Sweeney, G. “Cardiovascular effects of leptin” Nat. Rev. Cardiol. (2009) doi:10.1038/nrcardio.2009.224

As the body becomes more leptin resistant, there is an increase in heart disease

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Leptin Resistance and Levels in the Obese

Sweeney, G. “Cardiovascular effects of leptin” Nat. Rev. Cardiol. (2009) doi:10.1038/nrcardio.2009.224

As we become more leptin resistant, we gain weight.

Higher leptin levels are correlated with obesity, while middle to low levels in the blood associate with

better fitness.

32

Leptin Resistance and Hyperleptinemia in Obesity-Related Cardiovascular Disease


A leptin-resistant/hyperleptinemic state is a putative link between obesity anddiverse vascular and myocardial injury via direct effects or intermediary disorders.

The site of effect (central vs. peripheral) is depicted.33

Leptin Resistance and Cardiovascular Disease


Resistant Nonresistant

TissueHypothalamus (metabolic centers)skeletal muscle, pancreas, liver

Immune cells, clotting factors, platelets, vessel wall, myocardium, sympathetic nervous system

Leptin concentration High High

Pathophysiology Insensitivity to leptin (relative leptin deficiency) causes disesase

Retained sensitivity to leptin in the setting of hyperleptinemia causes disesase

Disease manifestations Obesity, insulin resistance, diabetes Hypertension, atherothrombosis, myocardial disease

Response to exogenous leptin Disease improvement Disease worsening

Potential of response to targeted treatment of leptin resistance/hyperleptinemia

Disease improvement Disease improvement

Theoretical Model of Selective Leptin Resistance and Hyperleptinemia in Cardiovascular Disease Pathophysiology

• Certain actions of leptin persist despite resistance to others

• Possibly due to post-receptor leptin signaling encountering greater feedback in resistant tissues, compared with nonresistant tissues

• Or differential leptin tissue access and circulating leptin inhibitors34

Metabolic Imbalance and Aging

Slawik M, Vidal-Puig AJ. “Lipotoxicity, overnutrition and energy metabolism in aging” Ageing Research Reviews. 2006. 5:144-164.

Preventing overnutrition and its deleterious effects should make the aging experience a more bearable process

•Aging decreases the functional reserve of important metabolic organs.

•When aged organs are challenged with excess fuel from overnutrition associated with impaired adipose tissue expandability, oxidative capacity and dysregulated energy homeostasis, result is increased exposure and accumulation of lipids in non-adipose tissues and leptin resistance.

•These conditions increase susceptibility of aged organs to nutritionally related lipotoxic effects.

•States of metabolic imbalance such as overnutrition, obesity and insulin resistance by itself challenge these homeostatic mechanisms synergising with age-related lipotoxic susceptibility.

35

Description of Aging

“Your brain ages when you burn up, you dry up,

you swell up, you turn to stone,

you get choked to death, you rust,

and then everyone calls you old and nuts.”- Eric Braverman, M.D.

•Aging-associated alterations in body composition (increased fat mass, loss in muscle size and strength, and loss of bone) are at least in part related to specific endocrine changes•Individuals with elevated leptin levels develop osteoporosis, hyperlipidemia, and obesity.

Isidori AM, Strollo F, Morè M, Caprio M, Aversa A, Moretti C, Frajese G, Riondino G, Fabbri A. “Leptin and aging: correlation with endocrine changes in male and female healthy adult populations of different body weights” Journal of Clinical Endocrinology and Metabolism. 2000 May;85(5):1954-62.Yamaguchi M. “Regucalcin and metabolic disorders: Osteoporosis and hyperlipidemia are induced in regucalcin transgenic rats” Mol Cell Biochem. 2010 March.

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Conclusion

• America has an obesity epidemic which has increased the speed of aging in our population.

• Other epidemics are being managed with biomarkers (heart disease with cholesterol, diabetes with HgA1c)

• Leptin, as a biomarker indicative of the amount or absence of fat, gives us the ability to wage a multi-disciplinary war on obesity

• By understanding how the brain controls eating, we can lay the foundation for the systematic dissection, understanding, and treatment of obesity and related disorders, and thereby ease the aging process.

DiLeone RJ. “The Influence of leptin on the dopamine system and implications for ingestive behavior”. International Journal of Obesity. 2009. 33:S25-29.37

Factors regulating circulating leptin concentrations and body fat

Bluher S, Mantzoros CS. “Leptins in humans: lessons from translational research”. American Journal of Clinical Nutrition. 2009; 89:991S-7S.

Factors promoting leptin secretionOverfeedingGlucoseAmino acidsInsulinGlucocorticoidsEstrogens

Factors inhibiting leptin secretionFastingFree fatty acids and other lipid metabolitesAndrogensThyroid hormonesCatecholaminesInflammatory cytokines

38

Potential Agents that will Increase Leptin Sensitivity and Lower Leptin Levels - Nutritional

Agent

Resveratrol

herbal supplement Integra‐Lean (irvingia)

amino acids Carnitine (easily found as a powder)

amino acids Acetyl‐l‐carnitine

hormones Melatonin

Lipids/fatty acids Conjugated linoleic acid

Lipids/fatty acids Omega‐3‐fatty acids

vitamins Vitamin D

Lipids/fatty acids 1 mM eicosapentaenoic acid

diet Increased consumption of fish

diet N‐3 polyunsaturated fatty acids

diet Increase dietary fiber

diet Increased consumption of vegetables

diet A 12‐wk high glycemic index diet

diet Lower caloric intake

diet Removing dietary fructose39

Potential Agents that will Increase Leptin Sensitivity and Lower Leptin Levels - Drugs

Agent

Symlin (amylin analog)

Metreleptin (leptin analog)

Detantol (bunazosin hydrochloride)

Metopirone (metyrapone)

Retin‐A (all‐trans retinoic acid)

Omacor (Omega‐3 polyunsaturated fatty acids)

Cardiac (Ang II type I receptor blocker) Diovan (valsartan)

Cardiac (Ang II type I receptor blocker) Atacand (Candesartan)

Cardiac (Beta Blocker) Visken (pindolol)

Cardiac (ACE inhibitor) Altace (ramipril)

Cardiac (ACE inhibitor) Combination of ramipril and candesartan

Cardiac (Ca Channel) Norvasc (amlodipine)

Cardiac (Ca Channel) Landel (efonidipine)

Cardiac (Statin) Lipitor (atorvastatin)

40

Potential Agents that will Increase Leptin Sensitivity and Lower Leptin Levels - Drugs

Agent

AntiDiabetic Byetta (exenatide)

AntiDiabetic Thiazolidinediones

AntiDiabetic Avandia (rosiglitazone)

AntiDiabetic Glucophage (metformin)

Neurological Parlodel (bromocriptine)

Neuropsychiatric Acomplia (marijuana)

Neuropsychiatric Nicotine

Neuropsychiatric Probably many other cholinergic agents

Neuropsychiatric Dopaminergic agents

Genetic D2 leptin stabilizer

Endocrine Victoza (liraglutide)

41

Potential Agents that will Increase Leptin Sensitivity and Lower Leptin Levels

Koh KK, Park SM, Quon MJ. "Leptin and CVD". Circulation. 2008 June 24; 117(25): 3238-3249. Oben JE, Ngondi JL, Blum K. "Inhibition of Irvingia gabonensis seed extract (OB131) on adipogenesis as mediated via down regulation of the PPARgamma and leptin genes and up-regulation of the adiponectin gene". Lipids Health Dis. 2008 Nov 13;7:44. Genc BO, Dogan EA, Dogan U, Genc E. "Anthropometric indexes, insulin resistance, and serum leptin and lipid levels in women with cryptogenic epilepsy receiving topiramate treatment". Journal of Clinical Neuroscience. 2010 Jun 30. Theisen FM, Beyenburg S, Gebhardt S, Kluge M, Blum WF, Remschmidt H, Elger CE, Hebebrand J. "A prospective study of body weight and serum leptin levels in patients treated with topiramate" Clinical Neuropharmacology. 2008 Jul-Aug;31(4):226-30. M. Atmaca, M. Kuloglu, E. Tezcan, A. Semercioz, B. Ustundag, A. Ayar. "Serum Leptin Levels in Patients with Premature Ejaculation". 2002. (48):5; 345-350.

Agent

Lifestyle At least 7 hours of sleep each night

Smoking

Decreasing stress

Increasing physical acitivity

Hormones High testosterone

Inreased DHEA

Lower estrogen

42

Potential Agents that will Increase Leptin Insensitivity and Raise Leptin Levels

Koh KK, Park SM, Quon MJ. "Leptin and CVD". Circulation. 2008 June 24; 117(25): 3238-3249.

Agents

Nutritional Lipids Elevated triglyceride levels

Diet Hypercaloric diets rich in SFA or n‐3 PUFA

Drug Cardiac Tenormin (atenolol) or Toprol (metoprolol)

AntiDiabetic Diabeta (glibenclamide)

Anesthetic Cocaine

Antipsychotic Seroquel (quetiapine)

Antipsychotic Risperdal (risperidone)

Anticonvulsant Neurontin (gabapentin)

Anticonvulsant Depakote (valproate)

Hormone Hydrocortisone

Hormone Decadron (dexamethasone)

Lifestyle Increased stress

Decreased sleep

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