چاقی، لپتین و واکنش پذیری استرس در انسان

Abstract Evidence suggests that individuals who are more obese may be more responsive to stress. Stress activates the sympathetic nervous system (SNS) and the adipose-tissue cytokine leptin stimulates SNS activity in animals. We examined the relationship between adiposity, leptin and physiological responses to acute laboratory stress in 67 women. We predicted that individuals with greater adiposity and/or higher plasma leptin would be more stress-responsive. Adiposity was unrelated to cardiovascular or neuroendocrine stress reactivity. However, women with larger waists had greater stress-induced increases in plasma leptin and interleukin-1 receptor antagonist (IL-1Ra). Similarly, women with higher basal leptin displayed greater stress-induced increases in heart rate and plasma interleukin-6, and larger decreases in heart rate variability and cardiac pre-ejection period. Heightened cardiovascular and inflammatory stress responses are predictive of future cardiovascular risk. Our findings suggest that the cytokines leptin and IL-1Ra may play a role in the association between obesity, stress and cardiovascular health.

Introduction The prevalence of obesity has risen sharply in recent years, reaching epidemic proportions world-wide. According to latest figures from the World Health Organisation approximately 1.6 billion adults are currently overweight (body mass index, BMI ≥25 kg m−2), and at least 400 million are clinically obese (BMI ≥30 kg m−2). These figures are estimated to reach an alarming 2.3 billion and >700 million by 2015 (WHO Global InfoBase, 2006). Obesity is a major risk factor for several chronic conditions including hypertension, cardiovascular disease (CVD), type 2 diabetes, and certain types of cancer and as such poses a major challenge to public health care (Lavie et al., 2009). Understanding the biological mechanisms linking obesity and health is therefore of fundamental importance. Psychological stress is associated with an increased risk of hypertension and CVD and evidence emerging in the past decade suggests that individuals who are more obese may be more responsive to stress. Two of the principle pathways activated by stress are the hypothalamic–pituitary–adrenal axis, leading to elevations in circulating glucocorticoids and the sympathetic nervous system (SNS), resulting in increases in blood pressure, heart rate and circulating catecholamines (Black, 2006). Studies have shown that women with a larger waist circumference or waist–hip ratio have heightened cortisol responses to acute laboratory stress, as well as impaired dexamethasone suppression of cortisol (Epel et al., 2000 and Pasquali et al., 2002). Similarly, central obesity has been associated with elevated or prolonged cardiovascular responses to acute stress in some but not all studies (Steptoe and Wardle, 2005, Goldbacher et al., 2005, Carroll et al., 2008, Davis et al., 1999, Waldstein et al., 1999 and Barnes et al., 1998), and a recent report found larger cortisol and cardiovascular responses to public speaking stress in obese versus non-obese women (Benson et al., 2009). The biological mechanisms linking obesity and stress reactivity are poorly understood. Adipose tissue is now recognised as a major endocrine organ that secretes signalling molecules playing a central role in inflammation, weight regulation and metabolic function including cytokines (Trayhurn, 2005). Circulating levels of the hormone-like cytokine leptin are markedly elevated in obese humans and animals and correlate with adiposity measures in non-obese healthy individuals (Considine et al., 1996 and Trayhurn and Bing, 2006). Leptin is secreted into the blood stream in proportion to adipose tissue mass, and binds to receptors on specific hypothalamic nuclei to regulate energy balance by reducing appetite and stimulating SNS activity (Trayhurn and Bing, 2006). In rodents, acute systemic or central leptin infusion increases sympathetic nerve activity (SNA) to thermogenic tissues such as brown adipose tissue (BAT) as well as non-thermogenic organs including kidneys and adrenal glands (Ren, 2004). Similarly, chronic leptin infusion increases heart rate, arterial blood pressure and circulating catecholamines, and these effects are inhibited by α1 and β1/β2 adrenergic antagonists (Ren, 2004 and da Silva et al., 2006). The relationship between leptin and SNS activity in humans is less clear. Elevated plasma leptin levels have been reported in patients with hypertension, compared to normotensive individuals (Thomopoulos et al., 2009). Similarly, cross-sectional studies have found positive associations between circulating leptin and sympathetic activity indexed by blood pressure, heart rate and heart rate variability in obese and lean normotensive humans (Bravo et al., 2006, Flanagan et al., 2007 and Ma et al., 2009), and a recent prospective analyses of 489 normotensive men showed that individuals with high serum leptin levels had a 33% increased risk of developing hypertension over 8 years, independent of BMI (Galletti et al., 2008). Nevertheless, most intervention studies have found no effect of either acute or chronic leptin infusion on SNS activity in humans (Hukshorn et al., 2003, Brook et al., 2007, Mackintosh and Hirsch, 2001 and Chan et al., 2007). It is conceivable that the sympatho-activating effects of leptin in humans may be more apparent under conditions of heightened SNS activation induced by factors such as psychological stress. We set out to investigate the relationship between adiposity, leptin and physiological responses to acute psychological stress in a sample of healthy young women. We predicted that women with greater adiposity would have heightened or prolonged cardiovascular, neuroendocrine and inflammatory responses to stress. We also predicted that leptin would potentiate sympathetic cardiovascular reactivity to stress, so that women with higher basal plasma leptin levels would have larger cardiovascular stress responses.

3. Results 3.1. Participant characteristics Sample characteristics at baseline are presented in Table 1. Participants were relatively young with a mean age of 21. The majority were White non-smokers. All were normotensive and had glycated haemoglobin (HbA1c) levels in the normal range. Although they were not overweight on average, there were large individual differences in adiposity measures; BMI ranged from 18.4 to 34.0 kg m−2, waist circumference ranged from 57.0 to 95.0 cm and percentage body fat ranged from 10.1 to 40.5%. Participants also varied widely in basal plasma leptin levels, ranging from 5.7 to 105.5 ng/ml, with a mean concentration of 35.7 ng/ml, s.d. 22.0. These levels are in the expected physiological range for non-fasting women (Rosenbaum et al., 1996). Table 1. Participant characteristics (n = 67). Mean s.d. Range Age 21.3 2.1 18–25 Smoker (%) 17.9 Ethnicity (% white) 66.7 Weight (kg) 62.0 10.3 47.3–93.8 Waist (cm) 70.3 7.9 57.0–95.0 BMI (kg/m2) 23.2 3.1 18.4–34.0 Body fat (%) 25.7 5.4 10.1–40.5 Subjective stress rating 2.0 1.1 1.0–6.0 Salivary cortisol (nmol/l) 5.5 2.5 1.8–13.7 Systolic BP (mmHg) 111.5 10.1 90.0–132.0 Diastolic BP (mmHg) 65.0 8.8 41.3–88.0 Heart rate (bpm) 72.2 8.7 51.8–91.7 HRV (ms) 56.0 29.1 19.4–174.2 Cardiac PEP (ms) 123.2 8.8 106.8–148.0 Plasma leptin (ng/ml) 35.7 22.0 5.7–105.5 Plasma IL-6 (pg/ml) 0.71 0.46 0.27–1.72 Plasma IL-1Ra (pg/ml) 176.9 73.0 98.7–480.1 HbA1c 4.77 0.27 3.9–5.2 Abbreviations: BP, blood pressure; HbA1c, glycated haemoglobin; HRV, heart rate variability; PEP, pre-ejection period; IL-6, interleukin-6; IL-1Ra, interleukin-1 receptor antagonist. Table options 3.2. Subjective, cardiovascular and neuroendocrine responses to stress Participants rated tasks as stressful with a mean score of 4.64 ± 1.1 and 4.42 ± 1.4 during the Stroop and speech task respectively. Subjective stress ratings returned to baseline levels during recovery, falling below baseline at 45 min post-task (F (3, 196) = 174.4, p < 0.001). Participants’ blood pressure and heart rate increased significantly during the tasks, with mean increases of 13.3 mmHg (F (3, 167) = 38.2, p < 0.001) and 10.3 mmHg (F (4, 221) = 44.5, p < 0.001) in systolic BP and diastolic BP respectively, and an average rise of 11.5 bpm in heart rate (F (2, 149) = 116.3, p < 0.001). At the same time, tasks induced a substantial decrease in participants’ HRV and cardiac PEP; HRV decreased by 18.6 ms on average during tasks (F (2, 149) = 42.4, p < 0.001), and cardiac PEP decreased by 6.0 ms on average (F (2, 131) = 44.7, p < 0.001). There were large individual differences in all cardiovascular responses. For example, changes in heart rate ranged from −1.8 bpm to +30.3 bpm, changes in HRV ranged from −99.4 ms to +4.8 ms, and changes in cardiac PEP ranged from −28.0 ms to +13.0 ms, during tasks. In addition, there was a small but significant (14.5%) rise in salivary cortisol in response to tasks, returning to baseline levels during the rest period (F (2, 122) = 9.96, p < 0.001). 3.3. Cytokine stress responses Tasks induced a small but significant increase in participants’ plasma levels of IL-6 (F (1, 78) = 21.1, p < 0.001) and leptin (F (2, 105) = 26.3, p < 0.001), with maximum levels detected at 45 min post-tasks. Plasma levels of IL-6 increased by 37% on average at 45 min, with responses ranging from −0.45 pg/ml to +1.72 pg/ml. Similarly, plasma leptin levels increased by 14% on average at 45 min, with responses ranging from −6.7 ng/ml to +20.2 ng/ml. IL-1Ra levels were not altered by stress in the sample as a whole. However, there were large individual differences in this response, with changes in plasma IL-1Ra ranging from −148.1 pg/ml to +124.2 pg/ml at 45 min post-task. Plasma concentrations of IL-1Ra and leptin were positively correlated immediately post-stress (r = 0.30, p = 0.023) and at 45 min post-stress (r = 0.32, p = 0.020). 3.4. Adiposity and cardiovascular, neuroendocrine and immune measures There was a significant relationship between adiposity and diastolic BP. Baseline diastolic BP was associated with BMI, waist circumference and percentage body fat (β = 0.29–0.37, s.e. = 0.13–0.14, all p < 0.05), independent of age, ethnicity and smoking status. Similarly, stress-induced increases in diastolic BP at 45 min were related to percentage body fat (β = 0.33, s.e. = 0.13, p = 0.014) and waist (β = 0.26, s.e. = 0.14, p = 0.059 ns trend), independent of age, ethnicity, smoking and baseline diastolic BP. There were no associations between adiposity and any other cardiovascular or neuroendocrine measures. Basal plasma cytokine levels were related to adiposity, independent of age, ethnicity and smoking. Baseline leptin was associated with BMI, waist and percentage body fat (β = 0.49–0.62, s.e. = 0.11–0.13, all p < 0.001). Similarly, IL-6 levels were related to BMI and percentage body fat (β = 0.28–0.29, s.e. = 0.13–0.14, p < 0.05), and basal plasma IL-1Ra was associated with waist (β = 0.41, s.e. = 0.13, p = 0.003). There was also a significant relationship between central adiposity and cytokine stress responses. Waist circumference was associated with individual differences in stress-induced increases in plasma leptin immediately post-task (β = 0.34, s.e. = 0.15, p = 0.022) and stress-induced increases in plasma IL-1Ra at 45 min post-task (β = 0.32, s.e. = 0.15, p = 0.040), independent of age, ethnicity, smoking and baseline levels of the respective cytokine. The relationship between waist and IL-1Ra responses is illustrated in Fig. 1, showing mean plasma IL-1Ra concentrations in individuals in the lowest and highest tertiles of waist circumference. People with greater central adiposity had 15% higher IL-1Ra levels at 45 min post-task. Mean plasma concentrations of interleukin-1 receptor antagonist (IL-1Ra) at ... Fig. 1. Mean plasma concentrations of interleukin-1 receptor antagonist (IL-1Ra) at 45 min post-tasks, in relation to waist circumference. Waist circumference was divided into tertiles and data are presented for individuals with low (<67 cm) and high (>70 cm) waist measures. Values are adjusted for age, ethnicity, smoking status and baseline plasma IL-1Ra. Error bars are SEM. Figure options 3.5. Basal leptin and cardiovascular, neuroendocrine and immune measures Plasma levels of leptin at baseline were significantly related to participants’ cardiovascular and inflammatory stress responses, independent of age, smoking, adiposity and baseline measures of the respective dependent variable. Specifically, basal leptin was associated with stress-induced increases in heart rate (β = 0.53, s.e. = 0.18, p = 0.006) and with decreases in HRV (β = −0.44, s.e. = 0.18, p = 0.015) and cardiac PEP (β = −0.51, s.e. = 0.17, p = 0.004) during tasks, independent of covariates. There was also a positive association between basal leptin levels and stress-induced increases in IL-6 at 45 min (β = 0.35, s.e. = 0.17, p = 0.042). These effects are illustrated in Fig. 2 (A–D). Women in the highest versus lowest tertile of basal leptin had a 2.2-fold greater IL-6 response to stress at 45 min. Similarly, during tasks, women in the highest leptin tertile had 187% greater increases in heart rate, 86% greater reductions in HRV and >11-fold larger decreases in cardiac PEP. All associations remained significant when controlling for ethnicity (p < 0.05). There was no relationship between basal leptin and measures of diastolic or systolic BP, salivary cortisol or plasma IL-1Ra. Basal circulating leptin and cardiovascular and inflammatory stress responses. ... Fig. 2. Basal circulating leptin and cardiovascular and inflammatory stress responses. Mean stress-induced changes in (A) plasma interleukin-6 (IL-6), (B) heart rate, (C) heart rate variability and (D) cardiac PEP in relation to baseline plasma leptin levels. Leptin levels were skewed and were square root transformed prior to analyses. Baseline plasma leptin was divided into tertiles and data are presented for individuals with low (<4.8 ng/ml) and high (>6.4 ng/ml) transformed leptin levels. Values are adjusted for age, smoking status, BMI, waist circumference, % body fat, and baseline levels of the appropriate dependent variable. Error bars are SEM. RMSSD, root mean square of successive R–R interval differences; PEP, pre-ejection period.