Gender differences in the relationship between leptin, insulin resistance and the autonomic nervous system
Introduction
The prevalence of obesity in industrialized nations continues to rise. Adiposity is associated with an increased risk of cardiometabolic syndrome and insulin resistance appears to be an important link between the two. Our understanding of the mechanisms controlling body weight and energy homeostasis continues to grow, but the mechanisms whereby overweight is translated into the features of the metabolic syndrome remain unclear. Leptin is a crucial hormone in the regulation of body weight. It is produced by adipose tissue and acts centrally by decreasing appetite and increasing energy expenditure [1]. There is a strong positive relationship between leptin and insulin resistance, and leptin behaves as a component of the metabolic syndrome [2]. Moreover, exogenous leptin has been shown experimentally to stimulate sympathetic nervous (SNS) system activity in animal models [3]. Increased SNS activity has been implicated in the pathogenesis of insulin resistance and increased cardiovascular risk [4]. In the present study, we used cardiac autonomic activity as a surrogate measure of SNS activity in young healthy subjects with normal glucose tolerance, measured by spectral analysis of heart rate variability. We then explored the inter-relationships between cardiac autonomic activity, insulin sensitivity/secretion and leptin concentrations.
Section snippets
Methods
The study sample comprised 68 males (mean age 20.9 SEM ± 0.03 years) and 62 females (mean age 20.9 SEM ± 0.04 years) drawn from an existing prospective cohort of young adults born in Adelaide, South Australia [5]. Subjects suffering from diabetes or other current illness were excluded. Investigation of the relationship between leptin and insulin resistance was an a priori part of the study design. The protocol was approved by the Human Ethics Committee of the Women's and Children's Hospital
Results
Table 1 compares the mean age, BMI, measures of body fat distribution, metabolic variables and measures of heart rate variability in men and women. The genders were of similar age and BMI, but women showed significantly greater skinfold thickness at each site measured. Skinfold thickness is highly correlated with adiposity (% body fat). The waist-to-hip ratio was lower in the females, reflecting a likely lower visceral fat mass. Women, however, also had higher fasting insulin, higher fasting
Discussion
Numerous studies have reported gender differences in the physiology of leptin, but it remains unclear whether the dichotomy reflects differences in total body fat, or in body fat distribution [14], [15], [16]. Previous work has also indicated an association between leptin and the SNS [17]. Our data confirm this, but find the association to be closer in women than in men.
Although there was no gender difference in BMI, women were considerably more adipose than men and their circulating leptin
Acknowledgements
The authors would like to thank Sister M. Logan, Ms M. Rourke, Ms L. Raggett for assistance with the fieldwork. This study was generously supported by the Medical Research Council, Diabetes UK, the Wessex Medical Trust and the Women's and Children's Hospital Foundation. VMM was supported by the PHRDC, National Health and Medical Research Council of Australia. IFG is supported by the Heart Disease and Diabetes Research Trust.
References (30)
- et al.
Enhanced sympathetic nervous system activity. The linchpin between insulin resistance, hyperinsulinemia, and heart rate
Am J Hypertens
(1996) Estimation of parameters for a linear difference equation with application to EEG analysis
Math Biosci
(1969)- et al.
Serum leptin concentrations in children with type 1 diabetes mellitus: relationship to body mass index insulin dose and glycemic control
Metabolism
(2002) - et al.
The role of the sympathetic nervous system in the regulation of leptin synthesis in C57BL/6 mice
FEBS Lett
(1999) - et al.
Positional cloning of the mouse obese gene and its human homologue
Nature
(1994) - et al.
Hyperleptinemia as a component of a metabolic syndrome of cardiovascular risk
Arterioscler Thromb Vasc Biol
(1998) - et al.
Receptor-mediated regional sympathetic nerve activation by leptin
J Clin Invest
(1997) - et al.
Fetal growth and the physiological control of glucose tolerance in adults: a minimal model analysis
Am J Physiol
(2000) - et al.
The autonomic control of heart rate and insulin resistance in young adults
J Clin Endocrinol Metab
(1999) - et al.
Quantitative estimation of insulin sensitivity
Am J Physiol
(1979)
Evaluation of four mathematical models of glucose and insulin dynamics with analysis of effects of age and obesity
Am J Physiol
Sensitive amplified immunoenzymometric assays (IEMA) for human insulin and intact proinsulin
Eur J Clin Chem Clin Biochem
A new analysis technique for time series data. Erschede Netherlands: NATO Advanced Study Institute on signal processing with emphasis on underwater acoustics
Statistical predictor identification
Ann Inst Stat Math
Cardiovascular neural regulation explored in the frequency domain
Circulation
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