1 Leptin A Potential Biomarker for Childhood Obesity ?

2 Table 1. Prevalence of Obese Children (Ages 6 to 11) at the Body Mass Index (BMI) > to % 1988 to % 1976 to 19807% Table 2. Prevalence of Obese Adolescents (Ages 12 to 19) at the Body Mass Index (BMI) > to % 1988 to % 1976 to 19805% Prevalence of Childhood Obesity Centers for Disease Control (CDC)

3 Cause ? Consequence ? Intervention predictor/monitor ? Prevention indicator ? Leptin and Obesity Novel biomarker ?

4 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 ?

5 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

6 16kDa protein hormone White adipose tissue Hypothalamus Pituitary Skeletal muscle and bone Arterial endothelium Intestines Fetus Testes Placenta Structure of Leptin

7 Action of Leptin

8 Leptin Receptor Isoforms OB-Rf

9 Intracellular signaling by LRb

10 Leptin Deficiency leads to Obesity

11 The New England Journal of Medicine. 1999;341(12):

12 n =51 J Clin Endocrinol Metab, April 2002, 87(4):1708–1716 Correlation between plasma leptin levels and BMI in adults

13 J. Clin. Invest. 1996, 98(6):1277–1282 Correlation between plasma leptin levels and % body fat in adults

14 Correlation between serum leptin levels and % fat in children Endocrine Journal 1999, 46 (5),

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

16 Correlation between serum sObR levels and BMI in children and adolescents J Clin Endocrinol Metab, October 2002, 87(10):4587 – 4594

17 Free Leptin Index Leptin/sObR J Clin Endocrinol Metab, April 2003, 88(4):1730–173

18 J. Clin. Invest. 1996, 98(6):1277–1282 n=46 Correlation between plasma leptin levels and % body fat in adults

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

20 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

21 Leptin and sObR: reason or consequence? sObR ObR Leptin sObR --

22 Leptin, sObR levels respond to intervention Weight-losing Surgery Fasting/refeeding Physical training

23 Plasma leptin levels after physical training in children Am J Clin Nutr 1999;69:388–94.

24 Leptin levels and exercise intervention in children and/or adolescents Clinical Biochemistry 39 (2006) 1047–1056

25 J. Clin. Invest. 1996, 98(6):1277–1282 Free/Bound leptin levels during Fasting/Refeeding

26 Leptin, sObR levels and weight-loss in children International Journal of Obesity (2005) 29, 1230–1235.

27 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

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

29 Baseline levels predict effects of intervention

30 Acta Pediatr 91: Baseline leptin levels predict the ability to lose body fat

31 Baseline leptin = (baseline fat mass) Change in leptin = – 0.40(pretraining leptin)+ 3.74(change in total mass) Am J Clin Nutr 1999;69:388–94. Baseline leptin levels correlate with leptin

32 leptin levels predict probability of weight relapse Diabetes Nutr Metab 2003;16(5-6):

33 Diagnosis Dual energy X-ray absorptiometry (DXA) Bioelectric impedance Skin-fold thickness Leptin/sObR? BMI Adipose tissue mass Metabolic risk factors Status of energy balance Predict ability to lose weight? % Boby Fat Predict ability to gain/re-gain weight?