The effects of leptin administration in non-obese human subjects.

OBJECTIVE: Body fatness is partly under hypothalamic control with effector limbs that include the endocrine system and the autonomic nervous system (ANS). In previous studies of both obese and never-obese subjects, we have shown that weight increase leads to increased sympathetic and decreased parasympathetic activity, whereas weight decrease leads to decreased sympathetic and increased parasympathetic activity. We now report on the effect of leptin, independent of weight change, on the ANS. RESEARCH METHODS AND PROCEDURES: Normal weight males (ages 20-40 years) were fed a solid food diet, measured carefully to maintain body weight, for 3 weeks, as inpatients at the Rockefeller University General Clinical Research Center. In a single-blind, 22-day, placebo/drug/placebo design, six subjects received leptin 0.3 mg/kilogram subcutaneously for 6 days. ANS measures of amount of parasympathetic control and sympathetic control of heart period (interbeat interval) were made by sequential pharmacological blockade with intravenous atropine and esmolol. Norepinephrine, dopamine, and epinephrine levels in 24-hour urine collections were also measured as well as resting metabolic rate. RESULTS: Sufficient food intake maintained constant body weight in all subjects. There was no evidence that leptin administration led to changes in energy metabolism sufficient to require additional food intake or to alter resting metabolic rate. Likewise, leptin administration did not alter autonomic activity. Parasympathetic control and sympathetic control, as well as the urinary catecholamines, were not significantly affected by leptin administration. Glucose and insulin levels were increased by food intake as expected, but leptin had no affect on these levels before or after food intake. DISCUSSION: ANS responses to changes in energy metabolism found when food intake and body weight are altered were not found in these never-obese subjects given leptin for 6 days. Although exogenous leptin administration has profound effects on food intake and energy metabolism in animals genetically deprived of leptin, we found it to have no demonstrable effect on energy metabolism in never-obese humans. The effects of longer periods of administration to obese individuals and to those who have lost weight demand additional investigation.

The effects of drugs used to treat obesity on the autonomic nervous system.

OBJECTIVE: Body fatness is partly under hypothalamic control with effector limbs, which include the endocrine system and the autonomic nervous system (ANS). In previous studies we have shown, in both obese and never-obese subjects, that weight increase leads to increased sympathetic and decreased parasympathetic activity, whereas weight decrease leads to decreased sympathetic and increased parasympathetic activity. We now report on the involvement of such ANS mechanisms in the action of anti-obesity drugs, independent of change in weight. RESEARCH METHODS AND PROCEDURES: Normal weight males (ages 22 to 38 years) were fed a solid food diet, carefully measured to maintain body weight, for at least 2 weeks, as inpatients at the Rockefeller University General Clinical Research Center. In a single-blind, placebo/drug/placebo design, eight subjects received dexfenfluramine, seven phentermine (PHE), and seven sibutramine (SIB). ANS measures of parasympathetic and sympathetic activity included: determination of amount of parasympathetic control (PC) and sympathetic control (SC) of heart period (interbeat interval), using sequential pharmacological blockade by intravenous administration of atropine and esmolol. These autonomic controls of heart period are used to estimate the overall level of parasympathetic and sympathetic activities. Norepinephrine, dopamine, and epinephrine levels in 24-hour urine collections were measured and also resting metabolic rate (RMR). RESULTS: Sufficient food intake maintained constant body weight in all groups. PHE and SIB produced significant increases in SC but no change in PC or in RMR. In contrast, dexfenfluramine produced marked decreases in SC, PC, and RMR. For all three drugs, the effects on urine catecholamines directly paralleled changes in cardiac measures of SC. DISCUSSION: ANS responses to PHE and SIB were anticipated. The large, and unanticipated, response to dexfenfluramine suggests further study to determine whether there could be any relation of these ANS changes to the adverse cardiovascular effects of treatment with dexfenfluramine.

Contributions of short-wavelength cones to goldfish ganglion cells.

There are conflicting reports about the existence and nature of a short-wavelength cone (S-cone) contribution to ganglion cells in the goldfish retina. The present study sought to resolve these discrepancies by examining the S-cone contribution while recording from single ganglion cells in the excised, isolated goldfish retina. The effect of variations in the retinal preparation (gas content and type of background lighting during recording) on the S-cone input was also examined. Cells were classified into one of three types based on the responses at light onset and offset, when responses were driven only by the long-wavelength cone system (L-cones) of the receptive field's center (L+/-(on-excitation/off-inhibition), L-/+, and L+/+). With rare exceptions, the threshold spectral sensitivities of the centers and surrounds of cells that possessed opposite on and off responses (L+/- and L-/+) exhibited S-cone contributions, either prior to and/or during chromatic adaptation of the middle- and long-wavelength cones; the S-cone response was antagonistic to the L-cone input. The L+/+ center cells also contained a S-cone input, but it was synergistic to the L-cone input at suprathreshold intensities. These findings were robust across all of the retinal preparations employed. The discrepancies in the previous work were probably due to the incomplete classification of cells because of the use of threshold responses only.