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Leptin

A Potential Biomarker for Childhood Obesity ?

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Table 1. Prevalence of Obese Children (Ages 6 to 11) at the Body Mass Index (BMI) >30

1999 to 2000 15.3%

1988 to 1994 11%

1976 to 1980 7%

Table 2. Prevalence of Obese Adolescents(Ages 12 to 19) at theBody Mass Index (BMI) >30

1999 to 2000 15.5%

1988 to 1994 11%

1976 to 1980 5%

Prevalence of Childhood Obesity

Centers for Disease Control (CDC)

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Cause ?

Consequence ?

Intervention predictor/monitor ?

Prevention indicator ?

Leptin and Obesity

Novel biomarker ?

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According to an expert working group convened by National Institutes of Health, a biomarker is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathological processes, or pharmacological responses to a therapeutic intervention” (Clin Pharmacol Ther. 69, 89-95, 2001).

What is a biomarker ?

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Use of a biomarker

A tool for diagnosing and staging disease

An indicator of disease prognosis

A tool for predicting and monitoring clinical response to an intervention

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16kDa protein hormone

White adipose tissueHypothalamusPituitarySkeletal muscle and boneArterial endotheliumIntestinesFetusTestesPlacenta

Structure of Leptin

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Action of Leptin

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Leptin Receptor Isoforms

OB-Rf

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Intracellular signaling by LRb

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Leptin Deficiency leads to Obesity

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The New England Journal of Medicine. 1999;341(12):879-884.

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n =51

J Clin Endocrinol Metab, April 2002, 87(4):1708–1716

Correlation between plasma leptin levels and BMI in adults

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J. Clin. Invest. 1996, 98(6):1277–1282

Correlation between plasma leptin levels and % body fat in adults

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Correlation between serum leptin levels and % fat in children

Endocrine Journal 1999, 46 (5), 703-709

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Correlation between serum soluble leptin receptor (sObR) levels and BMI in adults

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Correlation between serum sObR levels and BMI in children and adolescents

J Clin Endocrinol Metab, October 2002, 87(10):4587–4594

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Free Leptin Index

Leptin/sObR

J Clin Endocrinol Metab, April 2003, 88(4):1730–173

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J. Clin. Invest. 1996, 98(6):1277–1282

n=46

Correlation between plasma leptin levels and % body fat in adults

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bound

free bound

free

J. Clin. Invest. 1996, 98(6):1277–1282

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Leptin Resistance ?

Defects in leptin access into the brain

Defects in ObR

Defects in ObR signaling

Defects in pathways/neurons that mediate downstream leptin action

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Leptin and sObR: reason or consequence?

sObR ObR Leptin

Leptin sObR

-

-

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Leptin, sObR levels respond to intervention

Weight-losing Surgery

Fasting/refeeding

Physical training

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Plasma leptin levels after physical training in children

Am J Clin Nutr 1999;69:388–94.

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Leptin levels and exercise intervention in children and/or adolescents

Clinical Biochemistry 39 (2006) 1047–1056

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J. Clin. Invest. 1996, 98(6):1277–1282

Free/Bound leptin levels during Fasting/Refeeding

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Leptin, sObR levels and weight-loss in children

International Journal of Obesity (2005) 29, 1230–1235.

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Plasma concentrations of leptin (open bars) and sLR (hatched bars) in ng/ml in lean and morbidly obese subjects(MO). For the morbidly obese group preoperative (gastric restrictive surgery) as well as 3, 6, and 12 months postoperative (3m, 6m and 12m) values are shown. Data are depicted as mean SEM.

Plasma sObR and leptin levels after weight-losing surgery in adults

J Clin Endocrinol Metab, April 2002, 87(4):1708–1716

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Plasma leptin, sObR, bound leptin levels after weight-losing surgery

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Baseline levels predict effects of intervention

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Acta Pediatr 91: 132-135. 2002

Baseline leptin levels predict the ability to lose body fat

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Baseline leptin = 0.55 + 1.21(baseline fat mass)

Change in leptin = 22.02 – 0.40(pretraining leptin)+ 3.74(change in total mass)

Am J Clin Nutr 1999;69:388–94.

Baseline leptin levels correlate with leptin

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leptin levels predict probability of weight relapse

Diabetes Nutr Metab 2003;16(5-6):306-311.

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Diagnosis

Dual energy X-ray absorptiometry (DXA)

Bioelectric impedance

Skin-fold thickness

Leptin/sObR?

BMI

Adipose tissue massMetabolic risk factorsStatus of energy balance

Predict ability to lose weight?

% Boby Fat

Predict ability to gain/re-gain weight?