Lack of heritability of circulating leptin concentration in humans after adjustment for body size and adiposity using a physiological approach

Abstract

OBJECTIVE:To construct a simple physiological model of leptin kinetics, based on measures of body size and composition, which is suitable for investigating the influence of genetic and other influences on circulating leptin levels in humans. METHODS: Consideration of the kinetics of the secretion and clearance of leptin led to a predicted linear relationship between ln(leptin), ln(fat mass), and a function of non-fat body compartments. Results obtained from this model were compared with those from two published empirical models based on adjustment for fat mass alone or for body mass index. Overnight fasted leptin levels, body composition data (dual-energy X-ray absorptiometry) and questionnaire responses were obtained from 527 twin pairs (127 monozygotic, 400 dizygotic; 37 male (age 18 -68 y, BMI 18 -32 kg=m 2 ), 489 female (age 18 -71, BMI 17 -44) drawn from the St Thomas' UK Adult Twin Registry. RESULTS: In a partial correlation analysis ln(fat mass) and ln(height) (r ¼ 0.80, P < 0.0001) and r ¼ 70.22, P < 0.0001 respectively) were independent predictors of ln(leptin) in females but ln(lean mass) was not (r ¼ 70.01). A regression model incorporating ln(fat mass), ln(height) and a second order polynomial in age provided an adequate fit of the ln(leptin) data in females (r 2 ¼ 71%). ln(Leptin) values adjusted for body size and composition using the model were not significantly heritable (P ¼ 0.11), were significantly related to gender (r 2 ¼ 2.3%) and to ln(insulin) (r 2 ¼ 5.7%), but not to menopausal status (r 2 ¼ 0.7%), hormone replacement therapy (r 2 ¼ 0.4%), past or current smoking (r 2 ¼ 1.1%), or percentage trunk fat (r 2 ¼ 0.5%). Both empirical models found significant heritability (h 2 ¼ 36 -42%), overestimated the effect of gender in the data (r 2 ¼ 14 -16%), and produced significant relationships between adjusted ln(leptin) and percentage trunk fat (r 2 ¼ 4 -12%). CONCLUSIONS: We conclude that our physiologically based model provides an adequate description of the relationship between leptin and body composition and provides a more reliable framework than current empirical approaches for the investigation of other influences on circulating leptin levels. Heritable variations in the control of leptin secretion are unlikely to contribute significantly to variations in leptin levels at the population level.

Association of leptin levels with obesity and blood pressure: possible common genetic variation

“…This finding, as well as the heritability estimate for leptin (0.4670.11) was in good agreement with the corresponding estimates obtained in various other samples. 12,34,35,37,38 However, once we adjusted SBP in offspring for circulating leptin levels in parents, both parent-offspring correlation and h 2 estimates became not significantly different from zero. Thus, our findings propose that genetic variation in BMI, SKFs, and even body CRCs, as well as of SBP is due to genetic variation of leptin.…”

“…12,13,34,35 Some of these studies estimated that BMI genetic variation is virtually indistinguishable from the genetic effects on leptin (eg 13 ), while others suggest the existence of both common and variable-specific genetic effects. 12,34,35 Moreover, it has been reported that one of the genetic polymorphisms strongly influencing genetic variation of BMI is reliably linked to a chromosomal area 7q33, very near to the location for the leptin gene. 36 Our present results confirm the conclusions with respect to genetic correlation between leptin and BMI.…”

High plasma leptin predicts an increase in subcutaneous adiposity in children and adults

“…Jenkins et al (Jenkins et al, 2001;Jenkins and Campbell, 2003) suggested that different associations among studies may be explained by differences in methods of adjustment for the variability in body composition. They argued that imperfect adjustments for baseline body fat are responsible for spurious positive association between baseline leptin and weight gain.…”

Future management of human obesity: understanding the meaning of genetic susceptibility

“…Using either BMI or percent body fat as covariates can lead to erroneous conclusions in a genetic context. 31 One possible approach is the use of multivariate phenotypic constructs obtained from techniques such …”

“…The expected power benefits from multivariate phenotypes are most apparent when there are strong correlations between the individual phenotypes, as is the case with many phenotypes obtained in genomic studies of obesity, but this is not the only requirement for derivation of useful phenotypes. The aim must be to construct biologically informative phenotypes which, in principle, could be achieved either by applying prior knowledge to the development of explicit physiological models composed of measurable variables 31 or by careful consideration of the biological and statistical properties of the available raw phenotypes. 18 It is also important to consider the origins of the correlations between phenotypic markers, so as to specify the correct functional forms of the relationships, and especially to avoid correlated errors when choosing phenotypes for inclusion.…”