LEPTIN INHIBITS FOOD INTAKE IN MACAQUES 713

The present study was performed to determine the effects of central administration of leptin on food intake and sympathetic nervous system activity in a nonrodent species, the rhesus monkey. Peripheral administration of leptin at doses (1 and 3 mg/kg, sc) that produced increments of circulating leptin concentrations within a physiological range did not inhibit food intake over the subsequent 3 days. In contrast, leptin (1 mg/kg, intracerebroventricularly) had no acute effect on food intake, but caused a significant and sustained suppression (40–50%) of food intake during the entire following day (P , 0.01). In addition, circulating norepinephrine levels increased by 55 6 16% (P , 0.02) 1 h after intracerebroventricular leptin administration, but did not increase after artificial cerebrospinal fluid administration. These results indicate that leptin can provide a signal to the central nervous system that decreases food intake in primates and in addition acutely activates the sympathetic nervous system. However, the results showing an acute increase in circulating leptin concentrations after peripheral administration of human leptin suggest that in primates, increases in circulating leptin within the physiological range do not acutely regulate food intake. Leptin may be more important in regulating food intake when there are sustained changes in circulating concentrations of leptin (e.g. with obesity, prolonged energy restriction, or diabetes). (J Clin Endocrinol Metab 84: 711–717, 1999) L a hormone produced by adipocytes, is believed to play an important role in the regulation of body adiposity by acting at the level of the central nervous system to modulate both food intake and energy expenditure (1, 2). The original evidence for these actions of leptin came from studies in which exogenous hormone was administered to ob/ob mice, a strain with a defect in the gene that encodes for leptin (3–5). The ob/ob mice are markedly obese and hyperphagic. Administration of exogenous leptin to ob/ob mice reduces food intake, increases energy expenditure, and results in dramatic decreases in body weight (3–5). Congenital leptin deficiency or defects in its receptor leading to extreme early onset obesity have recently been reported in humans (6, 7). Although circulating leptin concentrations are closely related to body adiposity (1, 8–10), a dynamic role for leptin in the regulation of food intake and energy expenditure has been suggested by the finding that circulating leptin concentrations decrease during fasting (9, 10) or energy restriction (11) and increase after refeeding (9, 12). In addition, circulating leptin concentrations exhibit a diurnal pattern (13–15) with a nocturnal peak that is entrained by meal timing (16). Furthermore, insulin infusions that produce physiological increments in plasma insulin increase circulating leptin concentrations in human subjects (17). Lastly, 24-h leptin concentrations are increased in subjects consuming high carbohydrate meals, which enhance insulin secretion (18), an effect that may be mediated by increased adipocyte glucose metabolism (19). Administration of exogenous leptin or activation of the gene that encodes for leptin in normal mice and rats has been shown to effectively decrease food intake, increase energy expenditure, and result in body weight loss (3, 4, 20–22). However, despite the wealth of data collected over the past 2 yr on these effects of leptin in rodents, several critical issues remain unresolved. First, very few of the studies administering leptin have measured the plasma levels created by exogenous hormone administration, and those that have indicate that most published studies have examined the effects of pharmacological doses of this hormone. Thus, we do not know whether the physiological changes in circulating leptin levels that occur with meal consumption and brief periods of fasting have a role in regulating food intake and energy expenditure. Second, there have been no reports to date of regulation of food intake and energy expenditure by leptin in nonrodent species; thus, the applicability of findings in rodents to the control of food intake and energy expenditure in nonrodent species has not been established. Several lines of evidence indicate that in rodents, leptin appears to exert its actions on food intake and energy expenditure by acting at the level of the central nervous system. Received July 16, 1998. Revision received October 13, 1998. Accepted October 30, 1998. Address all correspondence and requests for reprints to: Judy L. Cameron, Ph.D., Oregon Regional Primate Research Center, 505 N.W. 185th Avenue, Beaverton, Oregon 97006. E-mail: cameronj@ohsu.edu. * This work was supported by grants from the Juvenile Diabetes Association, Novo Nordisk A/S, the Novo Nordisk A/S Foundation, the Danish Diabetes Association, the NIH (Grants HD-26888, DK-50129, DK-35747, and RR-00169), the Danish Medical Research Council (J12– 1642), and a Research Scientist Development Award from the NIMH (MH-01182, to J.L.C.). 0021-972X/99/$03.00/0 Vol. 84, No. 2 Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1999 by The Endocrine Society