SHORT COMMUNICATION The Gln223Arg polymorphism of the leptin receptor in Pima Indians: influence on energy expenditure, physical activity and lipid metabolism N Stefan 1 *, B Vozarova 1 , A Del Parigi 1 , V Ossowski 1 , DB Thompson 1 , RL Hanson 2 , E Ravussin 3 and PA Tataranni 1 1 Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA; 2 Diabetes and Arthritis Epidemiology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA; and 3 Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA Leptin regulates body weight by its receptor-mediated anorectic, thermogenic and antisteatotic effects. Recently, lower leptin binding to the soluble form of the leptin receptor (LEPR) was shown in carriers of the Arg223-encoding allele of the Gln223Arg polymorphism of the LEPR. To investigate whether this variant influences energy metabolism and adiposity in Pima Indians, we genotyped non-diabetic Pima Indians in whom we had measured body composition and 24 h energy expenditure (24 h EE), physical activity level (PAL) and 24 h respiratory quotient (24 h RQ) in a respiratory chamber (n ¼ 268) and who had undergone percutaneous fat biopsies from the periumbilical region (n ¼ 184). Genotype was not associated with percent body fat (P > 0.39), but was associated with 24 h EE, PAL and mean subcutaneous abdominal adipocyte size (SAAS all P < 0.05). Homozygotes for the Arg223-encoding allele had lower 24 h EE (P ¼ 0.04) and PAL (P ¼ 0.007), but larger SAAS (P ¼ 0.01) than Gln homozygotes. These findings are consistent with a role of the Gln223Arg polymorphism in reducing peripheral and central leptin binding to the LEPR in humans. However, these effects do not seem to have a major impact on adiposity in this population. International Journal of Obesity (2002) 26, 1629 – 1632. doi:10.1038=sj.ijo.0802161 Keywords: leptin receptor; energy expenditure; physical activity level; fat cell size Introduction Leptin, the product of the ob gene, is primarily secreted by the adipose tissue and it regulates body weight by its receptor mediated anorectic, thermogenic and antisteatotic effects. The leptin receptor (LEPR) is a single-transmem- brane-domain receptor of the cytokine-receptor family with widespread tissue distribution and several alternatively spliced isoforms. 1,2 In the Pima Indians of Arizona, seven polymorphic sites were identified in the LEPR gene. 3 Among these polymorphisms, we found that there was no effect of the Gln223Arg polymorphism on adiposity in a small group of individuals. The Gln223Arg polymorphism of the LEPR, however, was recently found to be associated with a lower binding capacity of leptin to the soluble form of the receptor in plasma which was interpreted as indicating abnormal receptor function. 4 Based on this new information, we tested whether the Gln223Arg poly- morphism of the LEPR was associated with adiposity, energy expenditure, physical activity level and metabolism of the adipose tissue in a large group of non-diabetic Pima Indians. Subjects and methods Pima Indians (Table 1) participating in ongoing studies on the pathogenesis of obesity and type 2 diabetes were studied. In 268 non-diabetic subjects (group 1) who were genotyped for the Gln223Arg polymorphism of the leptin receptor, we had measurements of 24 h energy expenditure (24 h EE) and *Correspondence: N Stefan, Clinical Diabetes and Nutrition Section, National Institutes of Health, 4212 N 16th Street, Rm 5-41, Phoenix, AZ 85016, USA. E-mail: nstefan@mail.nih.gov Received 18 June 2002; accepted 19 June 2002 International Journal of Obesity (2002) 26, 1629–1632 ß 2002 Nature Publishing Group All rights reserved 0307–0565/02 $25.00 www.nature.com/ijo International Journal of Obesity (2002) 26, 1629–1632 ß 2002 Nature Publishing Group All rights reserved 0307–0565/02 $25.00 www.nature.com/ijo