Absence of Linkage of Obesity and Energy Metabolism to Markers Flanking Homologues of Rodent Obesity Genes in Pima Indians

Norman, R. A.; Leibel, Rudolph L.; Chung, Wendy K.; Power-Kehoe, Loraine; Chua, Streamson C.; Wc, Knowler; Thompson, David V.; Bogardus, Clifton; Ravussin, Éric

doi:10.2337/diab.45.9.1229

Cited by 56 publications

(34 citation statements)

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“…The contributions of the leptin-receptor polymorphisms Lys109Arg, Gln223Arg, and Lys656Asn on obesity were analyzed (36). On the other hand, other investigators have observed no linkages between leptin-receptor polymorphisms and obesity in Pima Indians (37) and in French subjects (38). The contributions of leptin-receptor polymorphisms to obesity are thus controversial.…”

Section: Discussionmentioning

confidence: 99%

Leptin-Receptor Polymorphisms Relate to Obesity through Blunted Leptin-Mediated Sympathetic Nerve Activation in a Caucasian Male Population

et al. 2008

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Leptin plays a key role in the regulation of body weight through the sympathetic nervous system; however, the contributions of leptin-receptor polymorphisms to obesity and sympathetic nerve activity have not been fully clarified. In the present study, we examined the relationships between leptin-receptor polymorphisms, plasma leptin and whole-body norepinephrine (NE) spillover as an index of sympathetic nerve activity in a Caucasian male cohort. In 129 young healthy normotensive men with a wide range of body mass index (BMI) (19.4-39.5 kg/m 2 ), we measured leptin-receptor polymorphisms (Gln223Arg, Lys656Asn, and Lys109Arg), plasma leptin levels, whole-body NE spillover, whole-body NE clearance, BMI and blood pressure (BP) levels in the supine position after overnight fasting. Overweight-obese (BMI≥25 kg/m 2 ) subjects had significantly greater BMI, BP levels, plasma leptin and whole-body NE spillover compared to lean (BMI <25 kg/m 2 ) subjects, but the NE clearance was similar. Overweight-obese subjects had significantly higher frequencies of the Arg223 allele and the Arg223 homozygous allele of Gln223Arg and the Asn656 allele of Lys656Asn compared to lean subjects. Subjects carrying the Arg223 homozygous or the Asn656 allele had higher levels of plasma leptin, BMI, waist circumference, and waist-to-hip ratio, but significantly less whole-body NE spillover, especially when they were also overweight-obese. BP levels and whole-body NE clearance were similar between subjects with and without the Arg223 homozygous or Asn656 allele. No differences were found in the distributions of the Arg109 allele of Lys109Arg polymorphism between nonobese and overweightobese subjects. In addition, BMI, BP, plasma leptin levels, whole-body NE spillover and whole-body NE clearance were similar between those with and without the Arg109 allele. Together, these findings demonstrate that leptin-receptor polymorphisms were related to the incidence of obesity in a Caucasian male population. These polymorphisms were accompanied by high plasma leptin levels (leptin resistance) and lower whole-body plasma NE spillover (blunted sympathetic nerve activity). We therefore hypothesize that leptin-receptor play a role in the development of obesity through leptin resistance and blunted leptin-mediated sympathetic nerve activity. (Hypertens Res 2008; 31: 1093-1100)

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Section: Discussionmentioning

confidence: 99%

Leptin-Receptor Polymorphisms Relate to Obesity through Blunted Leptin-Mediated Sympathetic Nerve Activation in a Caucasian Male Population

et al. 2008

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“…46 At the genetic level, the leptin receptor and acute insulin response loci appear to be closely co-localised on chromosome 1, as demonstrated in Pima Indians. 47 It has been suggested therefore, that the leptin receptor gene could play a secondary role in regulation of the acute insulin response (AIR), with high leptin levels down-regulating the receptor gene and diminishing AIR, which may in turn have implications for insulinaemia and insulin sensitivity. However, if leptin and insulin are acting as part of a feed-back loop controlling adipose tissue mass, each could modulate the other simultaneously.…”

Section: Leptin and Insulin Sensitivity Pz Zimmet Et Almentioning

confidence: 99%

Is there a relationship between leptin and insulin sensitivity independent of obesity?A population-based study in the Indian Ocean nation of Mauritius

Collins²,

et al. 1998

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and 7 WHO Of®ce, Port Louis, Mauritius OBJECTIVE: It has been shown previously in smaller studies that fasting serum leptin and insulin concentrations are highly correlated, and insulin sensitive men have lower leptin levels than insulin resistant men matched for fat mass. We have examined the association between insulin resistance (assessed by fasting insulin) and leptin after controlling for overall and central adiposity in a population-based cohort. DESIGN: Leptin levels were compared across insulin resistance quartiles within three categories of obesity (tertiles of body mass index (BMI)). Partial correlation coef®cents and multiple linear regression models were used to assess the relationship between leptin and fasting insulin after adjusting for BMI and waist to hip ratio (WHR) or waist circumference. SUBJECTS: Subjects were normoglycemic participants of a 1987 non-communicable diseases survey conducted in the multiethnic population of Mauritius. 1227 men and 1310 women of Asian Indian, Creole and Chinese ethnicity had normal glucose tolerance and fasting serum leptin measurements. RESULTS: Mean serum leptin concentration increased across quartiles of fasting insulin in each BMI group and gender, after controlling for BMI, WHR and age. Furthermore, fasting insulin was a signi®cant determinant of serum leptin concentration, independent of BMI and WHR, in both men and women. Similar results were found if waist circumference replaced BMI and WHR in the model. CONCLUSION: These results suggest that insulin resistanceaconcentration may contribute to the relatively wide variation in leptin levels seen at similar levels of body mass or alternatively, leptin may play a role in the etiology of insulin resistance. Further studies will be important to determine whether the hyperleptinemiaainsulin resistance relationship has a role in the natural history of obesity, Type 2 diabetes mellitus and the other metabolic abnormalities associated with insulin resistance.

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“…28 Polymorphisms in the fatty acid synthase (FAS) gene were shown to be associated with substrate oxidation rates in nondiabetic Pima Indians. 29 No significant linkages were found between traits of resting metabolic rate, 24-h TEE, and 24-h RQ and the diabetes (DB), obesity (OB), tubby (TUB) and yellow agouti (ASP) 30 genes.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide scan revealed genetic loci for energy metabolism in Hispanic children and adolescents

et al. 2008

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Objective: Genome-wide scans were conducted in search for genetic locations linked to energy expenditure and substrate oxidation in children. Design: Pedigreed data of 1030 Hispanic children and adolescents were from the Viva La Familia Study which was designed to investigate genetic and environmental risk factors for the development of obesity in Hispanic families. A respiratory calorimeter was used to measure 24-h total energy expenditure (TEE), basal metabolic rate (BMR), sleep metabolic rate (SMR), 24-h respiratory quotient (24RQ), basal metabolic respiratory quotient (BMRQ) and sleep respiratory quotient (SRQ). Protein, fat and carbohydrate oxidation (PROOX, FATOX and CHOOX, respectively) were also estimated. All participants were genotyped for 384 single tandem repeat markers spaced an average of 10 cM apart. Computer program SOLAR was used to perform the genetic linkage analyses. Results: Significant linkage for TEE was detected on chromosome 1 near marker D1S2841, with a logarithm of the odds (LOD) score of 4.0. SMR, BMRQ and PROOX were associated with loci on chromosome 18, 17 and 9, respectively, with LOD scores of 4.88, 3.17 and 4.55, respectively. A genome-wide scan of SMR per kg fat-free mass (SpFFM) peaked in the same region as SMR on chromosome 18 (LOD, 5.24). Suggestive linkage was observed for CHOOX and FATOX. Several candidate genes were found in the above chromosomal regions including leptin receptor (LEPR). Conclusion: Regions on chromosomes 1, 9, 17 and 18 harbor genes affecting variation in energy expenditure and substrate oxidation in Hispanic children and adolescents.

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Absence of Linkage of Obesity and Energy Metabolism to Markers Flanking Homologues of Rodent Obesity Genes in Pima Indians

Cited by 56 publications

References 0 publications

Leptin-Receptor Polymorphisms Relate to Obesity through Blunted Leptin-Mediated Sympathetic Nerve Activation in a Caucasian Male Population

Leptin-Receptor Polymorphisms Relate to Obesity through Blunted Leptin-Mediated Sympathetic Nerve Activation in a Caucasian Male Population

Is there a relationship between leptin and insulin sensitivity independent of obesity?A population-based study in the Indian Ocean nation of Mauritius

Genome-wide scan revealed genetic loci for energy metabolism in Hispanic children and adolescents

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