Studies in both animals and humans indicate that the autonomic nervous system (ANS) responds to changes in systemic energy balance. In the present study, ANS response to weight change was examined by sequential blockade of cardiac autonomic innervation with parasympathetic (atropine) and sympathetic (esmolol) blockers. Change in heart period (interbeat interval) from baseline after atropine defined the amount of parasympathetic control (PC), and the subsequent change after esmolol defined the amount of sympathetic control (SC). In nonobese subjects, weight gain to 10% above initial body weight resulted in a decrease in PC and an increase in SC, and conversely, weight loss to 10% below initial weight resulted in an increase in PC and a decrease in SC. In obese subjects, weight loss resulted in the same pattern of changes in PC and SC. The major changes were in the parasympathetic arm of the ANS. These findings support the hypothesis that the ANS acts to oppose weight change.
Changes in autonomic function were studied during experimentally induced weight changes in seven subjects. A spectral analysis of heart rate variability (HRV) was used to evaluate autonomic activity during weight change. With a 10% increase in body weight above the usual or starting weight, there was a decline in parasympathetic power accompanied by a rise in mean heart rate. Heart rate declined during weight reduction, but the power of HRV did not change significantly. Because heart rate power at the frequency of respiratory rate can be affected by respiratory rate, three additional subjects were tested at a constant respiratory rate. Weight increases in this group also led to a decline in the power of HRV at a frequency attributable to the parasympathetic nervous system. Such a parasympathetic effect of weight increase may be one mechanism for the arrhythmias and other cardiac alterations that accompany obesity.
In an effort to understand the genetics of human obesity, we have studied the physiology and molecular genetics of rodent models with monogenetic forms of obesity including the leptin gene-defective ( Lepob / Lepob ) and leptin receptor gene-defective ( Leprdb / Leprdb ) mouse. In the experiments reported here, we investigated the effects of heterozygosity at Lepob and Leprdb on body composition and circulating leptin concentration in +/+, Leprdb /+, and Lepob /+ adult mice to identify possible gene dosage effects of these mutations that might elucidate their physiology. Adult mice heterozygous for the Lepob or Leprdb allele had equivalent fat mass and percentage body fat, which was increased 27–47% and 23–35%, respectively, relative to +/+ littermates. Plasma leptin concentrations adjusted for fat mass were 6.5 ng/ml in the Lepob /+, 9.6 ng/ml in the +/+, and 11.5 ng/ml in the Leprdb /+ mice. Sex had no effect on plasma leptin after controlling for fat mass. These data, and data from a small number of mice heterozygous at both Lepob and Leprdb (compound heterozygotes), suggest that leptin protein produced per mass of body fat is reduced in Lepob /+ mice and that body fat is increased in Lepob /+ mice until plasma leptin concentrations reach that of a normal +/+ mouse. The elevated plasma leptin concentration in the Leprdb /+ mice suggests that LEPR may mediate autocrine suppression of Lep expression. These results raise the possibility that human mutations that have even subtle effects on the leptin/leptin receptor system in either the homozygous or heterozygous state may have significant effects on adiposity.
MACKINTOSH, RONALD M. AND JULES HIRSCH.The effects of leptin administration in non-obese human subjects. Obes Res. 2001;9:462-469. 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 neverobese humans. The effects of longer periods of administration to obese individuals and to those who have lost weight demand additional investigation.
, respectively) was evaluated by sequential blockade of cardiac autonomic innervation with weight-adjusted doses of parasympathetic (atropine) and sympathetic (esmolol) blockers so as to produce maximal effects on heart rate. Change in heart period (interbeat interval) from baseline, induced by atropine, defined parasympathetic control (PC), and the subsequent change, after esmolol administration, defined sympathetic control (SC). The heart period, after PC and SC blockade, defined intrinsic heart period (I). In the OB group, baseline heart period and PC were lower, and SC and I were higher, than in the NO group. The results in the OB, relative to the NO subjects, are similar to those reported in a previous study of NO subjects who had undergone a 10% weight gain by overfeeding. These findings suggest that the ANS of individuals with obesity is chronically altered in a way that would tend to oppose their excessive adiposity, and that these autonomic changes are more likely to be responses to other forces that induce obesity, rather than being primary agents in the production of the disease.
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