Role of the kidney in human leptin metabolism

Meyer, Christian; Robson, Dave; Rackovsky, Noya; Nadkarni, Veena; Gerich, John E.

doi:10.1152/ajpendo.1997.273.5.e903

Cited by 66 publications

(69 citation statements)

References 14 publications

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“…Meyer et al reported an inverse relationship between renal fraction leptin extraction and circulating leptin level, and have suggested that renal uptake is a saturable process modelled by Michaelis ± Menton kinetics. 33 It is dif®cult to reconcile these ®ndings with our results which demonstrate that plasma clearance is virtually the same in monkeys as the value reported in humans, when plasma leptin levels in the monkeys were 1 ± 2 orders of magnitude higher.…”

Section: Discussionmentioning

confidence: 38%

Pharmacokinetics of human leptin in mice and rhesus monkeys

2000

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OBJECTIVE: The pharmacokinetic characteristics of human leptin were examined in rhesus monkeys and in C57BLa6J mice fed a normal chow or a high-fat diet. DESIGN: For the monkey study, in nine rhesus monkeys (body weight 12.4 AE 2.4 kg; mean AE s.d.), recombinant methuman leptin was injected intravenously or subcutaneously (1 mgakg). For the mouse study, after 6 months of feeding C57BLa6J mice a high-fat diet (body weight 32.9 AE 3.6 g; n 8) or a control diet (24.5 AE 1.2 g; n 6), recombinant methuman leptin was administered intraperitoneally (10 m mgag). Blood samples were collected for leptin measurement at speci®c time points after leptin administration. MEASUREMENTS: Plasma leptin concentrations were determined by radioimmunoassay and pharmacokinetic analysis was performed. RESULTS: Disposition of human leptin in rhesus monkeys was biphasic following intravenous administration, with a terminal phase half-life of 96.4 AE 16.5 min and clearance of 1.8 AE 0.2 mlaminakg. Subcutaneously administered leptin was absorbed slowly, perhaps by a zero-order process as leptin levels appeared to plateau and remained elevated throughout the 8 h sampling period. In C57BLa6J mice, the absorption and elimination of human leptin were both ®rst-order following intraperitoneal administration. Pharmacokinetic parameters did not differ between normal-weight mice fed a chow diet and obese mice fed a high-fat diet. The elimination half-life was 47.0 AE 26.4 min in mice fed a highfat diet and 49.5 AE 12.0 min in mice fed a control diet. CONCLUSION: The kinetics of leptin in rhesus monkeys were biphasic and clearance was similar to values previously reported in humans. The estimated half-life was 96.4 min in rhesus monkeys and 49.5 min in normal weight mice. The was no difference in leptin kinetics between high-fat fed and control mice, suggesting that the increased baseline leptin levels in the obese mice are due to increased leptin production and secretion.

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Section: Discussionmentioning

confidence: 38%

Pharmacokinetics of human leptin in mice and rhesus monkeys

2000

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“…37 Finally, since the calculated apparent K m of $ 10 ngaml for renal leptin uptake is close to physiological plasma leptin levels, small alterations of plasma leptin concentrations may result in major changes of leptin elimination. 38 Thus, increased renal leptin elimination by glomerular ®ltration andaor tubular metabolism might contribute to the observed decrease of plasma leptin concentrations in our diabetic patients who did not suffer from renal insuf®ciency.…”

Section: Discussionmentioning

confidence: 73%

Relative hypoleptinemia in patients with type 1 and type 2 diabetes mellitus

et al. 2000

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OBJECTIVE: To determine the relation between plasma leptin concentrations and metabolic control in human diabetes mellitus. DESIGN AND SUBJECTS: Cross sectional study consisting of 156 patients with diabetes mellitus type 1 (n 42), type 2 (n 114), and non-diabetic subjects (n 74). RESULTS: Plasma leptin concentrations were lower (P`0.05) in type 1 (8.3 AE 1.7 ngaml) and type 2 diabetic (14.9 AE 1.8 ngaml) than in non-diabetic humans (18.3 AE 1.9 ngaml). Only female type 1 and type 2 diabetic subjects also had decreased leptinaBMI ratios (P`0.05 vs non-diabetic females). The log rank test identi®ed age-adjusted correlation of plasma leptin concentration with sex (P`0.0004) and body mass index (P`0.0218), but not with glycosylated haemoglobin A 1c (P b 0.5) in all groups. Plasma leptin was correlated with age (P`0.0058) and serum triglycerides (P`0.0199) in type 1 diabetic patients, and with serum cholesterol (P`0.0059) and LDL (P`0.0013) in type 2 diabetic patients. CONCLUSIONS: Defective leptin production andaor secretion might be present independently of metabolic control in female patients with type 1 or type 2 diabetes mellitus.

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“…Estimates and 95% confidence intervals for additive genetic (h 2 , heritability) and common (c 2 ) and specific (e 2 ) environmental influences on the various phenotypes were obtained by univariate modelling of variance-covariance matrices in female monozygotic (MZ) and dizygotic (DZ) twin pairs 14 using Mx software. 11 Results are presented for the best-fitting and most parsimonious models based on the residual w 2 . In addition, heritabilities were tested against zero using a Wilcoxon two-group test of the effect of zygosity on absolute within-pair phenotypic differences.…”

Section: Methodsmentioning

confidence: 99%

“…This result implies that as fat mass increases leptin secretion increase disproportionately. 8,11,16 However, when gender was included in the model, the resulting estimate of the exponent relating ln(leptin) and ln(fat mass) was no longer different from 1 (1.10 AE 0.06, Table 2, model Ic). This represents the average relationship in males and females, and suggests that the gender effect, whatever its mechanisms, acts to vary leptin secretion either side of close proportionality with total fat mass.…”

Section: Determinants Of Circulating Leptinmentioning

confidence: 98%

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

Jenkins

Samaras

et al. 2001

Int J Obes

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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.

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Role of the kidney in human leptin metabolism

Cited by 66 publications

References 14 publications

Pharmacokinetics of human leptin in mice and rhesus monkeys

Pharmacokinetics of human leptin in mice and rhesus monkeys

Relative hypoleptinemia in patients with type 1 and type 2 diabetes mellitus

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

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