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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 1 402-407
Copyright © 2003 by The Endocrine Society

Original Article

Intact Sympathetic Nervous System Is Required for Leptin Effects on Resting Metabolic Rate in People with Spinal Cord Injury

Justin Y. Jeon, Robert D. Steadward, Garry D. Wheeler, Gordon Bell, Linda McCargar and Vicki Harber

The Steadward Center, Department of Physical Education and Recreation, and Faculty of Agriculture, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada T6G 2H9

Address all correspondence and requests for reprints to: Dr. Justin Y. Jeon, The Steadward Centre for Personal and Physical Achievement, W1–67 Van Vliet Complex, University of Alberta, Edmonton, Alberta, Canada T6G 2H9. E-mail: justin.jeon{at}ualberta.ca.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Compared with able-bodied (AB), people with spinal cord injury (SCI) have a 3- to 5-fold higher risk of developing type 2 diabetes mellitus, which may be associated with increased fat mass. Evidence suggests that leptin regulates body adiposity through the sympathetic nervous system, which is impaired in people with high lesion SCI. The purpose of this study was to determine the relationship among leptin levels, body composition, and resting metabolic rate (RMR) in people with high lesion SCI and body mass index-, weight-, height-, and waist circumference-matched AB subjects. Fourteen subjects (seven SCI and seven AB) participated in the study. After an overnight fast, various hormones, glucose, and RMR were measured. There was no significant difference in plasma glucose, insulin, GH, cortisol, and glucagon levels between the two groups. The SCI group had 105% higher plasma leptin levels than the AB group (P < 0.05). Plasma leptin levels correlated with body mass index (SCI: r = 0.80; P = 0.028; AB: r = 0.79; P = 0.035) and fat mass (SCI: r = 0.95; P = 0.001; AB: r = 78; P = 0.038) in both groups. The plasma leptin level correlated with the absolute RMR (SCI: r = 0.15; P = 0.75; AB: r = 0.99; P < 0.006) and the RMR per unit fat-free mass (SCI: r = -0.70; P < 0.08; AB: r = 0.845; P < 0.017) in the AB group, but not in the SCI group. The absolute RMR was significantly reduced in the SCI group compared with the AB group, but there was no difference in the relative RMR between the groups. In conclusion, the SCI group has a significantly higher plasma leptin level than the AB group. The absolute and relative RMR correlated with leptin only in the AB group.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INDIVIDUALS WITH SPINAL cord injury (SCI) undergo abrupt changes in body composition as a result of the injury (1, 2, 3). These changes include a reduction in fat-free mass (FFM) and bone mineral density and an increase in fat mass. Consequently, people with SCI have a greater risk of developing obesity-related disorders such as cardiovascular disease and type 2 diabetes mellitus (4, 5).

Leptin, the product of the obese gene, is a 16-kDa protein primarily produced by adipocytes (6). Leptin may regulate body adiposity via central nervous system pathways that modulate both food intake and energy expenditure (7, 8, 9). Although a wide variety of central and peripheral tissues express leptin receptors (10, 11), intracerebroventricular (icv) administration of leptin is more potent than iv administration, suggesting that its target of action lies within the central nervous system (8, 12, 13). In particular, the ventromedial hypothalamus (VMH) and specific nuclei of the hypothalamus are known targets for leptin action (12, 13). In VMH-lesioned animals, food intake is increased, whereas energy expenditure is decreased, accompanied by a reduction in sympathetic nerve activity (14, 15). Satoh et al. (16) demonstrated that a single direct injection of leptin into the VMH caused a significant increase in plasma epinephrine and norepinephrine concentrations. Similar results were reported by Tang-Christensen et al. (8); circulating norepinephrine was increased by 55 ± 16% 1 h after icv leptin administration. The finding that leptin led to a significant elevation of plasma catecholamine levels provides strong evidence that central leptin administration activates the sympathetic nervous system (SNS).

Moreover, it has been reported that iv or icv administration of leptin significantly increases glucose uptake by certain tissues in mice in the absence of insulin changes (12, 13). These findings suggest that leptin-mediated glucose uptake is not due to an increase in insulin secretion. More likely, leptin-mediated glucose uptake pathways are activated by sympathetic nerves innervating the tissues. An enhanced rate of glucose uptake by brown adipose tissue in response to leptin injection into the VMH was abolished by surgical sympathetic denervation of the tissue (12). In addition, leptin suppresses glucose-induced insulin secretion via SNS activation (17). Therefore, it has been suggested that a major target site for leptin is the brain and requires an intact SNS for normal leptin action (11, 12, 13, 16, 17, 18).

People with SCI suffer decentralization of the SNS after the injury (19). Complete SCI results in a loss of motor and sensory functions via afferent and efferent spinal pathways and also in an interruption of pathways from the brain to the peripheral SNS (20, 21, 22). This interruption leads to pathological changes in sympathetic innervation through the anatomic reorganization of pathways in the spinal cord (23). As a result, leptin’s influence on the regulation of energy intake and energy expenditure in people with high lesion SCI may be impaired and may increase the risk of obesity. However, the relationship between plasma leptin levels and resting metabolic rate (RMR) has not been investigated in people with high lesion SCI.

Thus, the purpose of this study was to identify basal leptin levels and determine the relationship among leptin levels, body composition, and RMR in an SCI group and an able-bodied (AB) group matched for age, weight, height, body mass index (BMI), and waist circumference (WC).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Healthy male subjects [n = 7 with complete SCI (C5–C7), SCI group; n = 7 in the AB group) agreed to participate in the study. AB subjects were matched to SCI subjects for age, weight, height, BMI, and WC. Participants were free of type 2 diabetes mellitus or coronary heart disease. An institutional ethics review board at University of Alberta approved this study. All subjects gave written informed consent to participate in the study. Subjects were asked to abstain from any strenuous physical activity during the period of study. Subject characteristics are summarized in Table 1Go.


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  		Table 1. Subject characteristics

 
Protocol

At 1800 on d 1, subjects consumed a standard meal (55% carbohydrate, 30% fat, and 15% protein) containing 12 kcal/kg body weight for lean subjects and 12 kcal/kg adjusted body weight for obese subjects (BMI, >30; adjusted body weight = ideal body weight + (actual body weight - ideal body weight) x (0.25)] (24). At 2100 on d 1, all subjects ingested a snack (140 kcal, 27 g carbohydrate, 2.7 g fat, and 1.6 g protein). At 900 on d 2, after a 12-h fast, blood samples (18 ml) were collected in heparinized tubes. Blood samples were immediately centrifuged (at 4 C) and separated, and the plasma was frozen (-80 C) until analysis was performed.

RMR

RMR was measured at 0800 h on d 2 after an 11.5-h fast. During testing all subjects were instructed to lie still and awake. Subjects rested for 30 min in a quiet room in the supine position. An adult-size canopy hood was used to collect expired air for an additional 30 min to measure RMR. The Weir equation was used to calculate RMR (25) (CPX-D, MedGraphics, Minneapolis, MN).

Body composition

Fat mass, FFM, abdominal obesity, and percent body fat were determined by a trained technician using dual energy x-ray absorptiometry (QDR 4500A, Hologic, Inc., Waltham, MA) on all subjects according to a previously published procedure (26). With the participant in the supine position, a series of transverse scans was made from head to toe at a standardized transverse scan speed of 5 cm/sec. Dual energy x-ray absorptiometry has been shown to be the most practical and accurate way to measure body composition in people with SCI (27).

Analytical procedures

All plasma samples from each subject were analyzed in duplicate in a single assay to eliminate between-assay variation. Plasma leptin (nanograms per deciliter) and glucagon (picograms per milliliter) levels were measured by RIA (human leptin RIA, Linco Research, Inc., St. Charles, MO). The intraassay coefficients of variation (CVs) were 4.7% and 7.5%, respectively. Plasma insulin (microunits per milliliter) and GH (nanograms per milliliter) levels were measured by RIA (Diagnostic Products, Los Angeles, CA). The intraassay CVs were 6.9% and 10.5%, respectively. Glucose levels were measured by the enzymatic method (Glucose Analyzer II, Beckman, Irvine, CA). Plasma epinephrine (picomoles per liter) and norepinephrine (nanomoles per liter) levels were measured by HPLC with electrochemical detection (electrochemical detector model 1045, Hewlett-Packard Co., Waldbronn, Germany) (28). The intraassay CV for these assays was 3% for epinephrine and 2.8% for norepinephrine.

Statistical analysis

Variables between the two groups were analyzed using independent t tests. Pearson’s product-moment correlation was used to measure the strength of association between the variables. Stepwise multiple linear regression was used to determine the strongest predictor for RMR (dependent variable) from leptin, FFM, and GH (independent variables). All data were expressed as the mean ± SE. Statistical significance was set at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Body composition

Subject characteristics are listed in Table 1Go. Although subjects were matched for age, weight, height, BMI, and WC, the SCI group showed a significantly higher percent body fat (34.6 ± 7% vs. 24.4 ± 6.5%; P = 0.016) and lower FFM (52.7 ± 4.1 vs. 63.4 ± 1.1; P = 0.03) than the AB group.

Leptin

The 12-h fasting leptin level in the SCI group was significantly higher than that in the AB group (15.1 ± 3.8 vs. 7.3 ± 2.0 ng/dl; P = 0.004) when BMI was controlled for. When the plasma leptin levels were expressed relative to fat mass (kilograms), the SCI group still had higher plasma leptin levels than the AB group (0.45 ± 0.14 vs. 0.31 ± 0.15 ng/dl·kg fat mass; P = 0.92). The difference, however, was not statistically significant. In both groups leptin correlated with weight, WC, BMI, and fat mass (Fig. 1Go and Table 2Go).



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  		Figure 1. Relationship between plasma leptin and fat mass in the SCI and AB groups. Leptin correlated with fat mass both in SCI (r = 0.95; P < 0.001) and AB (r = 0.78; P < 0.038) groups.

 

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  		Table 2. Association (R) between 12-h leptin and body composition and hormones

 
Catecholamine, insulin, glucose, glucagon, and GH

The SCI group had significantly lower 12-h fasting plasma epinephrine (16.3 ± 16.3 vs. 121.4 ± 23.3 pmol/liter; P = 0.003) and norepinephrine (0.6 ± 0.1 vs. 2.5 ± 0.3 nmol/liter) concentrations compared with the AB group (P < 0.001). There was no significant difference in the levels of 12-h fasting plasma insulin, glucose, glucagon, and GH between the two groups. Table 3Go summarizes the hormone levels in both groups.


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  		Table 3. Metabolic parameters

 
Leptin and RMR (Fig. 2Go)

Absolute RMR was lower in the SCI group compared with the AB group (SCI, 1451 ± 241; AB, 1848 ± 258 kcal/d; P = 0.01). However, when RMR was expressed relative to FFM, the difference was not detected between the groups (SCI, 28.3 ± 6.3; AB, 29.1 ± 3.8 kcal/d·kg FFM; P = 0.77; Table 4Go). Positive correlations were found between fasting leptin levels and absolute RMR (kilocalories per day; Fig. 2Go) and between leptin levels and relative RMR (kilocalories per kilogram of FFM per day) in the AB group, but not in the SCI group.



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  		Figure 2. Relationship between plasma leptin and RMR in the SCI and AB groupd. Leptin significantly correlated with RMR in the AB group (r = 0.90, P < 0.006), but not in SCI subjects (r = 0.44; P = 0.43).

 

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  		Table 4. RMR

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the following study we hypothesized that 1) people with high lesion SCI would have higher plasma leptin levels compared with AB controls, and 2) plasma leptin levels would not correlate with absolute RMR and relative RMR in people with high lesion SCI. Results from the current study demonstrated that people with high lesion SCI had significantly higher plasma leptin levels compared with the AB group. These findings are consistent with other studies (29, 30). Bauman et al. (29) and Huang et al. (30) reported that people with SCI have significantly higher plasma leptin levels than the AB controls. Higher leptin levels in people with SCI may be partly explained by a higher fat mass in the SCI group than in the AB group. A positive linear relation was found between plasma leptin levels and BMI, fat mass, percent body fat, weight, and WC in both the SCI and AB groups. Adiposity appears to predict plasma leptin levels in people with high lesion SCI as well as in the general population. In our study we found increased percent body fat in the SCI group compared with the AB group. When fat mass was controlled (plasma leptin per kilogram of fat mass), leptin levels remained 45% higher in the SCI group compared with the AB group. Although this difference was not statistically significant, these findings suggest that factors other than fat mass may also be responsible for the higher leptin levels in this group.

Recent evidence suggests that adrenergic activation may modulate leptin levels. {alpha}-Methyla-p-tyrosine or its more soluble methyl ester depletes tissue norepinephrine by inhibiting tyrosine hydroxylase, the initial and rate-limiting step in neuronal catecholamine synthesis (31). Intraperitoneal administration of soluble methyl ester of {alpha}-methyla-p-tyrosine (250 mg/kg) increased both plasma leptin (15-fold) and leptin mRNA levels in interscapular brown adipose tissue and epididymal fat (31). Additional evidence by Pinkney et al. (32) demonstrated that infusion of a ß-adrenergic agonist (isoprenaline) rapidly reduces circulating levels of leptin. As well, Commins et al. (33) illustrated that leptin’s effect on gene expression in brown and white adipose tissue is dependent upon norepinephrine synthesis and secretion. These results suggest the presence of a tonic inhibitory adrenergic influence on leptin secretion (31, 32, 33, 34, 35). Removal of this inhibition would probably contribute to increased plasma leptin levels. Our data support reduced SNA accompanied by significantly lower norepinephrine levels in SCI subjects. Therefore, in addition to a higher fat mass, an impaired SNS may explain the elevated leptin levels in our SCI group.

The current study demonstrated that the SCI group had a significantly lower absolute RMR (kilocalories per day) compared with the AB group; however, when expressed per kilogram of FFM, the differences in the RMR between groups disappeared. Monroe et al. (36) reported significantly lower 24-h energy expenditures, RMR, and sleeping metabolic rates in people with SCI compared with the AB controls. They reported significantly lower RMR even after FFM, fat mass, and age were controlled, suggesting that reductions in peripheral SNS activity in those individuals may lead to a reduction in the overall metabolic rate. In the current study the SCI group had a significantly lower catecholamine level compared with the AB group. The lower sympathetic nerve activity in the SCI group may be related to a reduced RMR (20, 36). It has been well documented that lower sympathetic nerve activity is associated with decreased RMR in humans (37, 38). Reduced absolute RMR in the SCI group in the current study can be explained by reduced FFM and sympathetic nerve activity.

The present study showed that plasma leptin positively correlated with absolute and relative RMR in the AB group. When a multiple stepwise forward regression analysis was performed with RMR as the dependent variable and plasma leptin, FFM and GH as the independent variables, plasma leptin was the strongest predictor of RMR, accounting for 80.9% of the RMR variation. These data strongly support previous findings (39, 40, 41, 42), which have demonstrated that a leptin level is a positive determinant of RMR in men (39), Pima children (40), women with anorexia nervosa (41), and patients with heart failure (42).

In contrast, leptin does not correlate with absolute RMR or with relative RMR in the SCI group. This result supports our hypothesis that normal SNS function is required for leptin’s influence on energy expenditure. Administration of exogenous leptin or activation of the gene that encodes for leptin in normal mice (44), rats (12, 45), and rhesus monkeys (8) has resulted in increased energy expenditure, increased glucose uptake, and decreased insulin secretion. The enhanced rate of glucose uptake and the decreased insulin secretion due to administration of leptin were effectively suppressed with surgical sympathetic denervation of the tissue (12, 17). In addition, increased glucose uptake in skeletal and heart muscles after leptin injection in rats was completely prevented by pretreatment with guanethidine and not adrenal demedulation (13). Because guanethidine does not inhibit epinephrine secretion from adrenal medulla and does not affect brain norepinephrine, this result suggested that increased glucose uptake in peripheral tissue was via the SNS. Also, Monroe et al. (46) examined the effects of iv propranolol infusion (a ß-adrenergic blocker) on RMR and demonstrated that ß- adrenergic blockade decreased RMR. This suggests the presence of a tonic SNS ß-adrenergic support in healthy adult humans. They suggested that the activity of the SNS was a determinant of energy expenditure, and that individuals with low resting SNS may be at risk for body weight gain because of the lower metabolic rate. It is, therefore, likely that leptin increases overall sympathetic nerve activity, leading to a significant increase in energy expenditure. Therefore, decentralization and impairment of the SNS may interrupt the pathway of leptin-mediated energy expenditure change. Loss of association between plasma leptin levels and RMR in the SCI group, therefore, may be due to the dysfunction of SNS in this group.

Consequently, impaired or reduced activity of the SNS may put people with high lesion SCI at a higher risk of developing obesity (1, 2, 3). Peterson et al. (47) reported a negative correlation between body fat and plasma norepinephrine levels and suggested that decreased sympathetic activity may be a cause of obesity. Overfeeding and underfeeding in lean subjects result in significant changes in plasma norepinephrine fluxes, correlating with changes in energy expenditure (48). In addition, SNS ß-adrenergic support of RMR in the healthy population accounts for approximately 71 kcal/d. In other words, those with a reduced sympathetic tone would need to compensate 26,000 kcal/yr through decreased energy intake or increased energy expenditure by non-SNS mechanisms to prevent weight gain (46).

In conclusion, the results from the present study support the hypothesis that people with high lesion SCI have higher plasma leptin levels than AB controls, and these differences are associated with increased fat mass and SNS dysfunction. To our knowledge, this is the first study to examine SNS activity, leptin levels, and RMR in people with SCI. Subjects with high lesion SCI have reduced SNS activity, which may lead to a higher risk of developing obesity and obesity-related metabolic disorders.


   Acknowledgments
 


   Footnotes
 
This work was supported by the Canadian Paraplegic Foundation, the Alberta Paraplegic Foundation (Edmonton, Canada) and the Rick Hansen Institution (Vancouver, Canada).

Abbreviations: AB, Able-bodied; BMI, body mass index; CV, coefficient of variation; FFM, fat-free mass; icv, intracerebroventricular; RMR, resting metabolic rate; SCI, spinal cord injury; SNS, sympathetic nervous system; VMH, ventromedial hypothalamus; WC, waist circumference.

Received July 14, 2002.

Accepted September 24, 2002.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals