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Interleukin 1 Increases Serum Leptin Concentrations in Humans

Medicine Branch (J.E.J., B.D.C. B.L.G.), Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1906; Indiana University School of Medicine (R.V.C.), Indianapolis, Indiana 46202; Clinical Services Program (H.C.R., G.C.P., W.C.K.), SAIC Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201; Earle Chiles Research Institute (J.W.S.), Providence Medical Center, Portland, Oregon 97213; and Data Management Services, Inc. (W.G.A.), SAIC Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201

Address all correspondence and requests for reprints to: Dr. Janik, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Building 10, Room 12N226, 9000 Rockville Pike, Bethesda, Maryland 20892-1906.

	Abstract

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Leptin, the protein product of the ob gene, regulates appetite and body weight in animals. Endotoxin and cytokines, induced by endotoxin, interleukin (IL) 1 and tumor necrosis factor, increase expression of leptin in mice and hamsters. We measured serum leptin concentrations in patients with cancer before and after administration of recombinant human IL-1. Fourteen patients received IL-1 at one of three dose levels (0.03, 0.1, or 0.3 µg/kg·day) for 5 days. Serum leptin concentrations increased in all but two patients within 24 h after the first dose. The increase in leptin was correlated directly with IL-1 dose (P = 0.0030). Despite continued administration of IL-1, serum leptin concentrations returned to pretreatment levels by day 5 of therapy. An increase in serum leptin concentrations may be one mechanism by which anorexia is induced by IL-1. However, tachyphylaxis of the leptin response suggests that other mechanisms also are involved.

	Introduction

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WASTING is a frequent complication of AIDS and advanced malignancy (1, 2, 3, 4, 5). Chronic immune stimulation, with its attendant increase in inflammatory cytokines (such as interleukin (IL)-1, tumor necrosis factor (TNF), and interferon), is postulated to be involved in the wasting syndrome.

Understanding the regulation of body weight in normal subjects has been a major focus of research in recent years, and several genes involved in body weight regulation and their interactions have been elucidated (6, 7, 8, 9, 10, 11). Leptin, the protein product of the ob gene, regulates body weight in mice. Gross obesity is the consequence of mutation of the leptin gene in the ob/ob strain of mice (12) or its receptor in the db/db strain (13). Administration of recombinant leptin to ob/ob and normal mice produces a decrease in body fat but not in the db/db mouse (14, 15, 16, 17).

Leptin concentrations in serum and leptin messenger RNA levels in fat cells are increased in hamsters by administration of IL-1, TNF, or endotoxin (18). Similar effects on serum leptin are seen in mice after administration of endotoxin, IL-1, or TNF (19). We retrospectively examined serum leptin concentrations in cancer patients, before and after administration of recombinant human IL-1, to determine whether this cytokine has a similar effect in humans.

	Materials and Methods

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All patients were treated at the Biological Response Modifiers Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, MD, between May 1990 and March 1992), as previously described (20). The protocols were approved by the Institutional Review Boards of the Clinical Oncology Program, National Cancer Institute, and the Frederick Cancer Research and Development Center. All patients voluntarily gave their written informed consent before treatment. None of the patients reported weight loss before starting therapy.

Treatment plan

Groups of four or five patients each were treated with 0.03, 0.1, or 0.3 µg/kg IL-1, produced in Escherichia coli by Dainippon Pharmaceutical Co. Ltd, Osaka, Japan. IL-1 was administered by iv infusion over 15–30 min daily for 5 days.

Leptin assay

Serum leptin concentrations were determined before treatment and on the day after the first, fourth, and fifth doses of IL-1 using an RIA obtained from Linco Research, Inc. (St. Charles, MO.). Frozen sera were thawed, and samples from individual patients were tested together.

	Results

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Samples were available from 14 patients treated with IL-1, 5 with 0.03 µg/kg, 4 with 0.1 µg/kg, and 5 with 0.3 µg/kg daily for 5 days. Table 1 shows the serum leptin concentrations at baseline and 24 h after the first treatment. There was no association between change in serum leptin concentration and baseline leptin concentration, age, sex, or body mass index. All 5 patients treated with 0.3 µg/kg IL-1 showed an increase in serum leptin concentration, and the percent increase from pretreatment to day 1 was significant (P = 0.0417, by a paired t test). Leptin concentrations increased in 3 of 4 patients treated with 0.1 µg/kg (mean increase, 18%) and 4 of 5 patients treated with 0.03 µg/kg (mean increase, 13%). The Jonckhere-Terpstra test for ordered alternatives was used to determine if a dose-related trend was present for the percent increase in leptin. The trend for percent increase in leptin, with increasing dose of IL-1, was highly significant (P = 0.0030). The need for fluid replacement caused by hypotension precluded weight change as a relevant measure in this study. All but 2 of these patients experienced a loss of appetite with IL-1 administration. The patients whose serum leptin concentration failed to increase in response to IL-1 did experience a loss of appetite.

View this table: [in this window] [in a new window]   Table 1. Serum leptin concentrations in patients treated with IL-1

View larger version (16K): [in this window] [in a new window]   Figure 1. Serum leptin concentrations in patients treated with IL-1 at 0.3 µg/kg·day. Each line represents an individual patient’s serum leptin concentration.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

The mechanism for leptin induction by IL-1 is unknown. Leptin production is increased in hamsters, mice, and humans by IL-1. IL-1 could act directly on fat cells to stimulate leptin production. Alternatively, leptin concentrations could be increased by secondary effects of IL-1. CRH production is stimulated by IL-1 in animal models (22, 23, 24). CRH, in turn, stimulates ACTH, which elevates corticosteroid production in the adrenal glands. Leptin production by human and murine fat cells is increased by glucocorticoids and insulin (25, 26), and short-term treatment with dexamethasone increases serum leptin concentrations in humans in vivo (27, 28). IL-1 significantly elevates serum cortisol levels in humans, and its pattern of induction parallels that of leptin (29). Serum cortisol levels peak 2–3 h after IL-1 administration on the first day of treatment, but peak levels are significantly lower after repeated exposure. Mean serum cortisol levels increase from 525 to 1155 nmol/L on the first day but only from 437 to 580 nmol/L on the final day of IL-1 treatment. In vitro incubation of fat cells with IL-1 will clarify whether leptin messenger RNA and protein levels increase as a direct effect.

Received March 26, 1997.

Revised May 19, 1997.

Accepted June 2, 1997.

	References

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