The Relationship of Tissue Localization, Distribution and Turnover to Feeding After Intraperitoneal125I-Leptin Administration toob/obanddb/dbMice

Heek, Margaret van; Mullins, Donald E.; Wirth, Michael D.; Graziano, Marco; Fawzi, Ahmad; Compton, Douglas S; France, Charles P.; Hoos, Lizbeth; Casale, R; Sybertz, Edmund J.; Strader, Catherine D.; Davis, Hilda M.

doi:10.1055/s-2007-979872

Cited by 46 publications

(17 citation statements)

References 5 publications

(9 reference statements)

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“…Areas under the bi-exponential equation curve provide values consistent with Other reports of leptin pharmacokinetics and tissue distribution in rodents have used very high doses of recombinant leptin administered with the tracer. 8, 15 Cumin et al 8 used recombinant leptin at three supraphysiological doses (0,25, 0.5 and 1.0 mgakg), with the lowest of these, corresponding to approximately 1000 times the level of endogenous leptin. The primary aim of their study was to determine whether the major clearance process of leptin was via the kidneys.…”

Section: Discussionmentioning

confidence: 99%

Leptin: its pharmacokinetics and tissue distribution

Hill¹,

Margetic

Pegg

et al. 1998

Int J Obes

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OBJECTIVE: The pharmacokinetics and tissue distribution of leptin in rats was investigated. DESIGN: A catheter was inserted in the right jugular vein of rats on the day prior to experiment. The next day, blood was sampled and then a tracer dose of radioiodinated hormone was administered via the catheter. Thereafter, small (200 m ml) samples of blood were taken at regular intervals. Two experiments were conducted over different sampling times. TCA precipitated radioactivity was counted in samples of plasma and tissues. Pharmacokinetic parameters were calculated after ®tting a bi-exponential equation describing a two-pool model of plasma leptin distribution. Selected time-point plasma samples were fractioned using size exclusion chromatography and the leptin distribution determined. RESULTS: The two pool model described the pharmacokinetics of leptin in two forms: an initial fast decaying pool (t 3.4 min) and a slower decaying pool (t1a 2 71 min) with an overall clearance rate of 6.16 mlaminakg. Size exclusion chromatography showed a persistent peak (all time-points tested) of 125 I-leptin corresponding to the plasma albumin peak. The size of the free 125 I-leptin peak became diminished or absent in later time-point plasma samples. Tissue distribution of leptin at 60 min and 180 min time-points showed that the small intestine contained the highest concentration of leptin, almost four times the level found in kidneys, liver, stomach and lungs. 125 I-leptin was least abundant in skin, muscle, heart, caecum and brain. CONCLUSION: The pharmacokinetics of leptin are affected by three important factors: 1) its ability to bind to a plasma carrier molecule which increases its half-life; 2) its association with abundant peripheral tissue binding sites which creates an additional pool of leptin and 3) the rate of synthesis of leptin which may be less important than originally believed as the prolonged half-life and the additional pool of tissue binding sites are important factors in determining its plasma concentration.

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Section: Discussionmentioning

confidence: 99%

Leptin: its pharmacokinetics and tissue distribution

Hill¹,

Margetic

Pegg

et al. 1998

Int J Obes

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“…A study in humans reported a half-life of circulating leptin of 25 min. 18 Two studies in mice suggested the considerably longer half-lives of 1.5 and 3 h, 19,20 whereas a recently published study in Zucker rats reported a much shorter half-life of circulating leptin ( $ 6 min) with no difference between lean and obese animals. 21 Much of the disparity in the literature is attributable to a wide range of methodologies and study objectives, with half-life being determined secondarily, often based on a minimal number of time points.…”

Section: Introductionmentioning

confidence: 99%

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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“…In diet induced obese mice, the circulating leptin was significantly elevated with the increase of body weight. Studies also showed these mice are resistant to peripherally administrated leptin (Van Heek et al, 1996). Compared to normal weight people, obese people usually developed hyperleptinemia and leptin resistant, which might due to a defect in transporting of leptin through the blood barrier (Banks et al, 1996;Caro et al, 1996).…”

Section: Leptinmentioning

confidence: 99%

Potential Mechanisms of Cancer Prevention by Weight Control

Jiang

Wang

2016

Research on the Physics of Cancer

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Weight control via dietary caloric restriction and/or physical activity has been demonstrated in animal models for cancer prevention. However, the underlying mechanisms are not fully understood. Body weight loss due to negative energy balance significantly reduces some metabolic growth factors and endocrinal hormones such as IGF-1, leptin, adiponectin, and glucocorticoids, etc., that may be associated with anti-cancer mechanisms. In this review, we summarized the recent studies related to weight control and growth factors. The potential molecular targets focused on those growth factors-and hormones-dependent cellular signaling pathways are further discussed. It appears that multiple factors and multiple signaling cascades, especially for Ras-MAPKproliferation and PI3K-Akt-anti-apoptosis, could be involved in response to weight change by dietary calorie restriction and/or exercise training. Considering prevalence of obesity or overweight that becomes apparent over the world, understanding the underlying mechanisms among weight control, endocrine change and cancer risk is critically important. Future studies using "-omics" technologies will be warrant for a broader and deeper mechanistic information regarding cancer prevention by weight control.

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The Relationship of Tissue Localization, Distribution and Turnover to Feeding After Intraperitoneal¹²⁵I-Leptin Administration toob/obanddb/dbMice

Cited by 46 publications

References 5 publications

Leptin: its pharmacokinetics and tissue distribution

Leptin: its pharmacokinetics and tissue distribution

Pharmacokinetics of human leptin in mice and rhesus monkeys

Potential Mechanisms of Cancer Prevention by Weight Control

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