Social isolation and depressed mood are associated with elevated serum leptin levels in men but not in women

Summary

Background

Leptin, involved in energy homeostasis and a predictor of cardiovascular disease, has recently been recognized as mediator in stress reactions. We aimed to explore the association between leptin levels and two stress-related conditions, social isolation and depressed mood, both associated with increased cardiovascular mortality.

Methods

We analysed leptin levels in 1229 subjects (643 men, 586 women), derived from the population-based MONIKA/KORA study. Standardized questionnaires were used to assess depressive mood and social isolation. In a multiple linear regression adjusted for body weight, age and survey, the association between leptin, social isolation and depressed mood and its interaction was explored in men and women separately. Leptin was then dichotomized and four analyses, adjusted for age, BMI, lifestyle factors, psychosomatic complaints and metabolic variables were performed to compare the risk of elevated leptin levels in the risk groups.

Results

Increased leptin levels were associated with social isolation (p = 0.04) and the interaction between social isolation and depressed mood (p = 0.02) in men but not in women. In socially isolated and depressed men, leptin levels (mean: 6.07 ng/ml) were significantly increased compared to neither depressed nor isolated men (mean: 4.51 ng/ml, p = 0.04). In the multivariate adjusted logistic regression model, the combination of depressed state and social isolation was associated with a 4-fold increased risk (p < 0.001) for elevated leptin levels.

Conclusion

The finding of elevated leptin levels in socially isolated and depressed men raises the possibility that increased cardiovascular mortality in socially isolated men is partially mediated by hyperleptinemia.

Introduction

Leptin, an adipose tissue derived hormone that is involved in the regulation of energy homeostasis (Crowley, 2008) and multiple endocrine pathways in the body (Corsonello and Corica, 2008, Rutters et al., 2009, Velloso et al., 2009), has been implicated in contributing to an increased risk of cardiovascular disease. Elevated leptin levels are associated with an accelerated development of atherosclerosis and glucose intolerance (Dubey and Hesong, 2006, Knudson et al., 2008, Wallander et al., 2008) and predict cardiovascular events and diabetes (McNeely et al., 1999, Soderberg et al., 1999, Soderberg et al., 2007, Soderberg et al., 2009), even after adjustment for raised CRP levels (Romero-Corral et al., 2008). Individuals with raised concentrations of both leptin and CRP are at highest risk of developing cardiovascular disease (Romero-Corral et al., 2008).

Growing evidence now points to leptin as an important mediator in stress reactions (Bornstein, 1997, Wilson et al., 2005). In vitro experiments have shown the involvement of leptin in the feedback-system of the HPA axis (Newcomer et al., 1998) resulting in the inhibition of the corticotropin releasing hormone. Continuous infusion of leptin to rhesus monkeys during stress-induced activation of the HPA axis attenuates the neuroendocrine response to the stressor (Wilson et al., 2005). In humans, conditions of non-sustained stress (Otsuka et al., 2006), and posttraumatic stress disorder (Liao et al., 2004) are associated with increased levels of leptin. There is evidence that leptin levels are increased in anxiety disorders (Brennan et al., 2009, Narita et al., 2008). Studies in depression have shown mixed results with some showing increased levels (Antonijevic et al., 1998, Rubin et al., 2002) and others decreased levels of leptin (Jow et al., 2006, Kraus et al., 2001).

Social isolation is a potent chronic stress condition (Grippo et al., 2007, Kennedy et al., 1988). In clinical cardiology, social isolation clustering together with a depressed mood state is a particularly malignant bio-behavioural risk factor for cardiovascular morbidity and mortality (Frasure-Smith et al., 2000, Mookadam and Arthur, 2004, Wang et al., 2006). It is not unlikely that leptin acts as one mechanism bridging the gap between a chronic stress condition and its deleterious impact on health, particularly on cardiovascular health. Indeed, preliminary data in rats provide evidence that social isolation leads to increased leptin levels (Perello et al., 2006). However, until now, no study in humans has investigated the influence of neither social isolation nor its combined effect with depression on leptin levels.

We, therefore, aimed to investigate whether social isolation, depression and the combination of both are associated with increased leptin levels. To this end, we analysed data from a large population-based study in southern Germany, representing a middle European population.