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International Journal of Obesity (2002) 26, 496–503 ß 2002 Nature Publishing Group All rights reserved 0307–0565/02 $25.00 www.nature.com/ijo

PAPER Obesity is associated with decreasing levels of the circulating soluble leptin receptor in humans
´ V Ogier1, O Ziegler2, L Mejean1, JP Nicolas3 and A Stricker-Krongrad1*
´ Department of Human Nutrition, Animal Sciences Laboratory, EcoleNationale Superieure d’Agronomie et des Industries Alimentaires (ENSAIA), Vandoeuvre les Nancy, France; 2Department of Diabetology, Metabolic and Nutrition Diseases, Center of ˆ Clinical Investigation INSERM-Centre Hospitalier Universitaire de Nancy, Hopital Jeanne d’Arc, Dommartin-les-Toul, France; and 3 Faculty of Medicine, Medical and Pediatric Biochemistry Laboratory, Vandoeuvre les Nancy, FranceOBJECTIVE: Leptin plays a major role in the regulation of body weight. It circulates in both free and bound form. One of the leptin receptor isoforms exists in a circulating soluble form that can bind leptin. In the present study, we measured the soluble leptin receptor (SLR) levels in lean and obese humans. We investigated the relationship between plasma SLR levels, plasma leptin levels and thedegree of obesity. We also examined whether SLR concentrations could be modulated by fat mass loss induced by a 3 month weight-reducing diet. SUBJECTS: A total of 112 obese (age 18 – 50 y; body mass index (BMI) 30 – 44 kg=m2; 23 men and 89 women), 38 overweight (age 19 – 48 y; BMI 25 – 29 kg=m2; 10 men and 28 women) and 63 lean (age 18 – 50 y; BMI 17 – 24 kg=m2; 16 men and 47 women) humans.MEASUREMENTS: A direct double monoclonal sandwich enzyme-linked immunosorbent assay (ELISA) was used for the quantitative measurement of the soluble human leptin receptor. Leptin was measured by radioimmunoassay (RIA). Body composition was assessed by biphotonic absorptiometry DEXA (dual energy X-ray absorptiometry). RESULTS: We observed that the SLR is present in human plasma (range 10 – 100 ng=ml). SLRlevels were lower in obese and overweight than lean subjects (28.7 Æ 8.8, 40.2 Æ 14.9, 51.2 Æ 12.5 ng=ml, respectively) and were inversely correlated to leptin and percentage of body fat (r ¼ 70.74 and r ¼ 70.76; respectively; P < 0.0001). The ratio of circulating leptin to SLR was strongly related to the percentage of body fat (r ¼ 0.91; P < 0.0001). Interestingly a gender difference was observed inSLR levels, which were higher in obese and overweight men than in obese and overweight women. In obese subjects after a 3 month low-calorie diet, SLR levels increased in proportion to the decrease in fat mass. In the gel filtration profile, SLR coeluted exactly with the bound leptin fractions. CONCLUSION: Obesity, in humans is associated with decreasing levels of the circulating soluble leptinreceptor (SLR). The relationship of SLR with the degree of adiposity suggests that high SLR levels may enhance leptin action in lean subjects more than in obese subjects. International Journal of Obesity (2002) 26, 496 – 503. DOI: 10.1038=sj=ijo=0801951 Keywords: leptin; leptin receptor; obesity; binding protein; cytokine receptor; low-calorie diet; metabolism

Leptin, the ob geneproduct1 is implicated in the regulation of food intake and energy balance.2 – 4 In rodents, the severe obese phenotype of the ob=ob or db=db mice is induced by a

*Correspondence: A Stricker-Krongrad, Metabolic Diseases Physiology and Pharmacology, Millennium Pharmaceuticals Inc., 75 Sidney Street, Cambridge, 02139, MA, USA. E-mail: krongrad@mpi.com Received 23 July 2001; revised 22 October2001; accepted 12 November 2001

mutation in the leptin or leptin receptor gene.1,5 However, in obese humans there are only a few cases of obesity that can be explained by mutation of the leptin gene6 – 8 or of the leptin receptor gene.9,10 Moreover, in obese humans, leptin levels are elevated,11,12 suggesting that a hallmark of obesity is not leptin deficiency but hyperleptinemia. Leptin achieves...
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