Association of plasma epinephrine level with insulin sensitivity in metabolically healthy but obese individuals

Autonomic Neuroscience: Basic and Clinical 167 (2012) 66–69

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Association of plasma epinephrine level with insulin sensitivity in metabolically healthy but obese individuals Xing-Ping Dai a, Zhao-Qian Liu b, Lin-Yong Xu b, Zhi-Cheng Gong b, Qiong Huang b, Min Dong b, Xi Huang a,⁎ a

Department of Ethnopharmacology, Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Traditional Chinese Medicine Gan Organ of SATCM, Xiangya Hospital, Central South University, Changsha 410008, PR China Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University Xiangya School of Medicine, Changsha, Hunan 410078, PR China

b

a r t i c l e

i n f o

Article history: Received 20 September 2011 Received in revised form 20 October 2011 Accepted 25 October 2011 Keywords: Epinephrine Obesity Insulin sensitivity Diabetes mellitus Cardiovascular disease

a b s t r a c t In the present study, we explored the association of catecholamines with insulin sensitivity in “metabolically healthy but obese” (MHO) individuals, by examining the metabolic characteristics and plasma catecholamine levels in 100 obese, sedentary postmenopausal women. Subjects were classified as MHO (n = 25) or at-risk (n = 25) based on the upper and lower quartiles of insulin sensitivity as measured by the hyperinsulinemic– euglycemic clamp technique. The MHO group presented a significantly higher range of plasma epinephrine levels (73 ± 21 pg/mL) than the at-risk group (39 ± 20 pg/mL) (P b 0.05), though both within the normal basal range of plasma epinephrine (56 ± 30 pg/mL). Multivariate regression analysis showed that high-sensitivity C-reactive protein, plasma epinephrine, triglycerides and lean body mass index were independent predictors of glucose disposal. The plasma epinephrine level was positively correlated with the glucose disposal rate, insulin sensitivity and the HDL-cholesterol level, and negatively correlated with the triglycerides level (P b 0.05). In conclusion, this study for the first time demonstrates a positive association between plasma epinephrine level and insulin sensitivity in MHO individuals. © 2011 Elsevier B.V. All rights reserved.

1. Introduction Catecholamines are hormones mainly released by the adrenal glands in response to stress. In the human body, the most abundant catecholamines are epinephrine, norepinephrine, and dopamine. They can cause changes in human body metabolism by elevating the blood glucose level, promoting fat metabolism, and stimulating thermogenic responses (Cryer, 1993; Cannon and Nedergaard, 2004). Obesity is a major risk factor for type 2 diabetes, cardiovascular disease, and several types of cancer (Calle et al., 2003; Samanic et al., 2006; Schelbert, 2009), and lies at the core of a cluster of metabolic abnormalities defined as the metabolic syndrome, which includes insulin resistance and hyperinsulinemia, hypertension, impaired glucose tolerance, and type 2 diabetes (Ukkola and Bouchard, 2001). Interestingly, 20%–30% of the adult obese population remains “metabolically healthy but obese” (MHO) (Ruderman et al., 1981); they display an absence of impaired glucose tolerance, dyslipidemia, hyperuricemia, and hypertension (Bonora et al., 1991; Wildman et al., 2008). Their metabolic and cardiovascular disease risk factors

are relatively low (Ruderman et al., 1981; Succurro et al., 2008). Several studies have examined characteristics associated with the protective profile of the MHO individual (Brochu et al., 2001; Karelis et al., 2005). Brochu et al. (2001) reported that two factors, including an early age of obesity onset and low amounts of visceral adipose tissue, explained 35% of the variance in insulin sensitivity in MHO postmenopausal women. Karelis et al. (2005) reported that a lower inflammation state, as attested by low C-reactive protein (CRP) levels, could play a role in the protective profile of the MHO postmenopausal women. In multiple regression analysis, CRP, triglycerides, and the lean body mass index were identified as independent predictors of glucose disposal, collectively explaining 32.0% of the variance in insulin sensitivity. Therefore, there remains a substantial unexplained variance (33%) in the metabolic profile of the MHO individual. In the present study, we explored the association of catecholamines with the MHO phenotype in obese postmenopausal women. 2. Materials and methods 2.1. Subjects

⁎ Corresponding author at: Laboratory of Ethnopharmacology, Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Traditional Chinese Medicine Gan Organ of SATCM, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, PR China. Tel.: + 86 731 89753742; fax: + 86 731 84327401. E-mail address: [email protected] (X. Huang). 1566-0702/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2011.10.006

One hundred non-diabetic obese postmenopausal women aged between 48 and 76 years old were enrolled in this study by the following criteria: (1) body mass index (BMI) >27 kg/m2; (2) cessation of menstruation for more than 1 year and a follicle-stimulating hormone

X.-P. Dai et al. / Autonomic Neuroscience: Basic and Clinical 167 (2012) 66–69

level of ≥30 U/L; (3) sedentary (b2 h of structured exercise per week); (4) nonsmokers; (5) low to moderate alcohol consumers (less than two drinks per day); (6) free of known inflammatory disease; (7) no use of hormone replacement therapy. On physical examination or biological testing, all participants had no history or evidence of the following: (1) cardiovascular disease, peripheral vascular disease, or stroke; (2) diabetes (2 hour plasma glucose b11.0 mmol/L after a 75-gram oral glucose tolerance test); (3) orthopedic limitations; (4) body weight fluctuation within 2 kg in the last 6 months; (5) thyroid or pituitary disease; (6) infection by medical questionnaire examination and complete blood count; (7) medication that could affect cardiovascular function and/or metabolism. Informed consent was obtained from all subjects before the start of the study. After a 4-week period of weight stabilization, patients underwent a 3-hour hyperinsulinemic– euglycemic (HE) clamp. A blood draw was performed for determination of a fasting lipid profile and analyses of insulin and glucose. Body composition was assessed by dual-energy X-ray absorptiometry a few days after the HE clamp. This study was approved by the Ethic Committee of Xiangya Hospital. 2.2. HE clamp The study began at 8:00 AM after a 12-h overnight fast following a procedure described by Karelis et al. (2005). Briefly, an antecubital vein was cannulated for the infusion of 20% dextrose and insulin (Novolin R; Novo-Nordisk, Beijing, China). The other arm was cannulated for sampling of blood. Three basal samples of plasma glucose and insulin were taken over 40 min. Then, an insulin infusion was started at the rate of 75 mU/m2/min for 180 min. Plasma glucose was measured each 10 min with a glucose analyzer (Beckman Coulter, Fullerton, CA) and maintained at fasting level with a variable infusion rate of 20% dextrose. Glucose disposal (M(clamp)) was calculated as the mean rate of glucose infusion measured during the last 30 min of the clamp (steady-state) and is expressed as milligrams per minute per kilogram body weight or as milligrams per minute per kilogram fat-free mass (FFM). Insulin sensitivity (IS(clamp)) was determined as follows: IS(clamp) = GIRss/Gss ∗ ΔIss, where GIRss was the steady-state (milligrams per minute per kilogram), Gss was the steady-state blood glucose concentration (milligrams per deciliter), and ΔIss is the difference between the steady-state and basal insulin concentration (microunits per milliliter) (16). The homeostasis model assessment for insulin resistance (HOMA-IR) was calculated by the formula: HOMA-IR = fasting insulin level (μU/mL) × fasting glucose level (mmol/l)/22.5. 2.3. Identifying MHO and at-risk subjects As previously described by Karelis et al. (2005), we identified MHO and at-risk subjects by dividing the entire cohort into quartiles based on glucose disposal rates (M values/FFM). Women with M/FFM values in the upper quartile (M ≥ 12.84) (n = 25) were classified as having high insulin sensitivity and placed in the MHO group, whereas women with M/FFM values in the lower quartiles (M ≤ 9.05) (n = 25) were classified as low insulin sensitivity and categorized as at-risk subjects. The at risk group is defined as a group that present metabolically abnormalities (i.e. insulin resistance and dyslipidemia), which may be associated with an increase risk of type 2 diabetes and/or cardiovascular disease. 2.4. Laboratory analysis Before the HE clamp, blood samples were drawn from subjects who have been resting quietly for 30 min in a recumbent position after insertion of a venous catheter. Subjects must refrain from eating, using tobacco, or drinking coffee or tea for at least 4 h before venipuncture. The procedure room must be kept quiet and comfortable at a temperature of 23 °C–24 °C. Total cholesterol, triglyceride, high-

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density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol levels were measured as previously described (Eberle et al., 2004). Serum high-sensitivity CRP (hsCRP) and α-1 anti-trypsin were assessed with ELISA kits from antibodies-online.com (Atlanta, GA, USA) and Bethyl Laboratories, Inc (Montgomery, TX, USA), respectively. Basal plasma epinephrine, norepinephrine and dopamine levels were assessed with a 3-CAT RIA kit from Rocky Mountain Diagnostics, Inc (Colorado Springs, CO, USA). In our calibration tests, the RIA kit showed a sensitivity of detecting diluted epinephrine standard at a minimum of 15 pg/mL. 2.5. Body composition Lean body mass and fat mass were evaluated by dual-energy X-ray absorptiometry (Lunar Corporation, Madison, Wisconsin). BMI = body weight (kg) / [height (m)] 2; fat mass index = fat mass / [height (m)] 2; lean body mass index= lean body mass/ [height (m)]2. 2.6. Statistical analysis All continuous variable values were expressed as Mean ± SD. Comparison of means between two groups was performed with Student's t tests upon test of normality and equality of variances. Comparisons of means among multiple groups were performed with one-way ANOVA followed by post hoc pairwise comparisons using the least significant difference method. Categorical variables were compared with Chi-square tests. A stepwise multi-linear regression model determined which variables explained unique variance in glucose disposal values. Statistical analyses were performed with SAS 9.1.3. The significance level of this study was set at two-sided α = 0.05. 3. Results As shown in Table 1, the MHO and the at-risk groups of obese postmenopausal women were comparable in age, BMI, fat mass index and waist circumference. However, the MHO group had lower lean body mass index than the at-risk group (P b 0.01). While there were no significant group differences in total cholesterol, LDLcholesterol and resting systolic and diastolic pressure, the MHO group showed higher HDL-cholesterol and lower triglycerides than the at-risk group (P b 0.01). By design (MHO, top quartile of IS vs. at-risk, lower quartile of IS), the two groups were significantly different in absolute and relative levels of glucose disposal rates and insulin sensitivity (IS(clamp)) (P b 0.01). In addition, the MHO group showed significantly lower levels of hsCRP and α-1 anti-trypsin than the at-risk group (P b 0.01). Basal plasma catecholamine levels were determined for both groups. Mean basal plasma catecholamine levels measured in 500 healthy female volunteers were used as a normal reference. As shown in Table 2, the MHO group and the at-risk group respectively showed higher and lower basal plasma epinephrine level than the normal reference, but without statistical significance. The epinephrine level, but not the norepinephrine and the dopamine levels, was significantly higher in the MHO group than in the at-risk group (P b 0.05). The distribution of plasma epinephrine values in the MHO and the at-risk groups is shown in Fig. 1. The results indicate that the MHO group presented a significantly higher range of plasma epinephrine levels than the at-risk group, though both within the normal basal range of plasma epinephrine. Statistical analyses were performed for the entire cohort (n = 100) of obese postmenopausal women for stepwise multilinear regression analysis and correlation analyses. As shown in Table 3, multivariate regression analysis showed that among all variables listed in Table 1, hsCRP, plasma epinephrine, triglycerides and lean body mass index were independent predictors of glucose disposal, collectively

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Table 1 Characteristics of MHO and at-risk subjects. Characteristics Physical characteristics Age (years) Age group (years) n (%)

b 50 50–59 60–69 ≥ 70

BMI (kg/m2) Fat mass index (kg/m2) Lean body mass index (kg/m2) Waist circumference (cm) Metabolic characteristics Total cholesterol (mmol/L) LDL-cholesterol (mmol/L) HDL-cholesterol (mmol/L) Triglycerides (mmol/L) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Insulin sensitivity index Fasting glucose (mmol/L) Fasting insulin (μU/mL) HOMA-IR IS(clamp) M(clamp) (mg/min/kg) M/FFM(clamp) (mg/min/kg FFM) Inflammation markers hsCRP (mg/L) α-1 anti-trypsin (g/L)

MHO (n = 25)

At-risk (n = 25)

58.2 ± 7.1 4 (16) 9 (36) 9 (36) 3 (12) 32.7 ± 4.2 15.7 ± 3.2 15.9 ± 2.1a 95.4 ± 8.2

60.5 ± 5.8 3 (12) 10 (40) 8 (32) 4 (16) 35.0 ± 4.1 15.6 ± 2.7 18.5 ± 2.3 100.6 ± 8.7

5.7 ± 0.9 3.4 ± 0.6 1.8 ± 0.3a 1.3 ± 0.5a 122.5 ± 19.2 77.2 ± 8.9

5.6 ± 1.0 3.2 ± 0.8 1.4 ± 0.3 2.4 ± 1.0 120.4 ± 14.5 80.1 ± 7.5

4.8 ± 0.5 11.3 ± 3.9a 2.5 ± 1.2a 301.3 ± 77.8a 8.1 ± 1.2a 15.6 ± 2.1a

5.2 ± 0.6 19.5 ± 6.9 4.3 ± 1.8 170.9 ± 41.5 4.1 ± 0.7 7.5 ± 1.4

2.3 ± 2.5a 1.6 ± 0.2a

5.2 ± 4.2 1.9 ± 0.4

Note: For continuous variables, all values were expressed as Mean ± SD. Upon test of normality and equality of variances, Student's t tests were performed to compare means between the groups. For categorical variables, all values were expressed as n(%) and comparisons were performed with Chi-square tests. HOMA-IR, homeostasis model assessment for insulin resistance; FFM, fat free mass; hsCRP, high-sensitivity C-reactive protein. a P b 0.05 compared with the at-risk group.

explaining 39.4% of the variance (Pb 0.01). Pearsons' correlation analyses showed that the plasma epinephrine level was positively correlated with the glucose disposal rate (M(clamp) and M/FFM(clamp)), insulin sensitivity (IS(clamp)) and the HDL-cholesterol level, and negatively correlated with the triglyceride level (P b 0.05) (Table 4). No statistically significant correlation was noted between the plasma epinephrine level and the hsCRP or α-1 anti-trypsin level.

4. Discussion MHO individuals are insulin sensitive, normotensive, and have normal lipid profiles, despite having excessive fatness (Bonora et al., 1991; Wildman et al., 2008). Several studies have reported association of metabolic and inflammatory characteristics with the protective profile of the MHO individual (Brochu et al., 2001; Romano et al., 2003; Karelis et al., 2005). In the present study, we for the first time explored the association of plasma catecholamines with insulin sensitivity in MHO individuals.

Table 2 Plasma catecholamine levels of MHO and at-risk subjects.

Epinephrine (pg/mL) Norepinephrine (pg/mL) Dopamine (pg/mL)

MHO

At-risk

Normal reference

73 ± 21a 321 ± 36 61 ± 23

39 ± 20 316 ± 26 58 ± 30

56 ± 30 313 ± 43 52 ± 42

Note: All values are expressed as Mean ± SD. Mean plasma catecholamine levels measured in 500 healthy female volunteers were used as a normal reference. Comparisons of means among the groups were performed with one-way ANOVA followed by post hoc pairwise comparisons using the least significant difference method. a P b 0.05 compared with the at-risk group.

Fig. 1. Distribution of plasma epinephrine values in MHO and at-risk groups. The mean plasma epinephrine level is marked by a horizontal bar in each group.

Although the acute effect of pharmacologic doses of epinephrine is to increase blood glucose and diminish insulin sensitivity (Westfall and Westfal, 2010), the long-term effect of endogenous epinephrine is reportedly protection against hyperglycemia and insulin insensitivity in a high-fat-diet-induced obesity mouse model (Ziegler et al., 2011). Our results are in agreement with this report, because when we classified obese, postmenopausal women into MHO and at-risk groups (MHO, high insulin sensitivity vs. at-risk, low insulin sensitivity), the MHO subjects exhibited higher plasma epinephrine level than the at-risk subjects. In our study, the multivariate regression analysis results indicate that elevated plasma epinephrine level is associated with increased glucose disposal rate (Table 3). This is probably due to epinephrine stimulation of the β2 adrenoceptor. Though with similar potency at α, β1 and βs receptors, epinephrine stimulates β2 receptors far better than norepinephrine (Westfall and Westfal, 2010). Epinephrine can stimulate intracellular AMP-activated protein kinase (AMPK) through β receptors, which may lead to improved insulin sensitivity (Steinberg and Jorgensen, 2007). Miura et al. (2007) reported that β2 receptors may mediate an increase in proliferator-activated receptorγ coactivator-1α (PGC-1α) by exercise, which can result in improved insulin sensitivity (Lira et al., 2010). In addition, while short-acting β2-agonist terbutaline worsen glucose tolerance, long-acting β2agonist clenbuterol improves insulin sensitivity by increasing glucose uptake in skeletal muscle (Castle et al., 2001). On the other hand, chronic use of β-blockers decreases insulin sensitivity in humans (Sharma et al., 2001). Thus, chronic stimulation of β2 receptors by an elevated plasma level of epinephrine may increase insulin sensitivity. This is in agreement with our results that the plasma epinephrine level was positively correlated with the glucose disposal rate and insulin sensitivity (Table 4). Ward et al. reported that epinephrine excretion was positively correlated with the HDL-cholesterol level and negatively correlated with the triglycerides level, showing a favorable effect of epinephrine on serum lipids. The results were replicated in our study (Table 4). Thus, in the long term, an elevated level of endogenous Table 3 Multivariate regression analysis of independent predictors of glucose disposal in obese postmenopausal women. Dependent variable

Independent variable

Partial r2

Total r2

β coefficient

P value

Glucose disposal (mg/min/kg)

hsCRP Epinephrine Triglycerides Lean body mass index

0.171 0.156 0.042 0.025

0.171 0.327 0.369 0.394

− 0.267 0.251 − 0.218 − 0.193

0.009 0.007 0.012 0.044

Note: Stepwise multi-linear regression analysis was performed using data from the entire cohort (n = 100) of obese postmenopausal women. hsCRP, high-sensitivity C-reactive protein.

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Table 4 Correlation of plasma epinephrine level with glucose disposal rate and blood lipids and inflammation markers levels.

Epinephrine (pg/mL)

M(clamp) (mg/min/kg)

M/FFM (clamp) (mg/min/kg FFM)

IS(clamp)

HDL-cholesterol (mmol/L)

Triglycerides (mmol/L)

hsCRP (mg/L)

α-1 anti-trypsin (g/L)

r = 0.23 p = 0.025⁎

r = 0.24 p = 0.017⁎

r = 0.21 p = 0.038⁎

r = 0.20 p = 0.047⁎

r = − 0.22 p = 0.030⁎

r = 0.17 p = 0.092

r = 0.15 p = 0.135

Note: Pearson's correlation analyses were performed using data from the entire cohort (n = 100) of obese postmenopausal women. Glucose disposal rate is represented by M(clamp) and M/FFM(clamp). Insulin sensitivity is represented by IS(clamp). FFM, fat free mass; IS, insulin sensitivity; hsCRP, high-sensitivity C-reactive protein. ⁎ P b 0.05.

epinephrine is not only associated with increased insulin sensitivity and decreased risk of type 2 diabetes, but also associated with improved serum lipid levels and decreased risk of cardiovascular diseases. This may partly account for the contribution of endogenous epinephrine to the protective profile of the MHO phenotype. Obesity, insulin resistance syndrome, and atherosclerosis are closely linked phenomena, often connected with a chronic low-level inflammatory state (Festa et al., 2000). Karelis et al. (2005) reported that a lower inflammation state, as attested by low C-reactive protein (CRP) and α-1 anti-trypsin levels, could play a role in the protective profile of the MHO postmenopausal women. Our study replicated the results (Table 1). However, the plasma epinephrine level was not correlated with the inflammation markers, suggesting that plasma epinephrine was an independent predictor of the MHO phenotype. This was confirmed in the multivariate regression analysis (Table 3). Since the rate of both epinephrine release and plasma clearance is reduced with age and beta-adrenergic function may change with age (Ebstein et al., 1985; Rutledge and Steinberg, 1991; Begin-Heick, 1996; Seals and Esler, 2000), age could be a confounding factor of the plasma epinephrine level in MHO individuals. However, the MHO and the at-risk groups showed comparable mean age as well as age composition (Table 1), and age as an independent variable did not enter the multivariate regression model (Table 3), thereby excluding possible confounding effects of age on our results. Clutter et al. (1980) reported that acute intravenous epinephrine infusion would lead to increments in plasma glucose at 150–200 pg/mL and early decrements in plasma insulin at >400 pg/mL. In our study, endogenous plasma epinephrine level is positively associated insulin sensitivity in MHO individuals at a lower magnitude (Table 2). This discrepancy could be due to a number of differences in the two studies: (1) acute vs. chronic effect of epinephrine; (2) exogenous infusion vs. endogenous release of epinephrine; (3) normal vs. obese subjects. Nevertheless, further studies are needed to uncover the mechanisms underlying the long-term effects of elevated plasma epinephrine level on insulin sensitivity in MHO individuals. There are several limitations to the present study. First, our cohort only consisted of non-diabetic sedentary obese postmenopausal women. Therefore, our findings are limited to this population. Second, we used a cross-sectional approach, which does not allow us to draw any causal connection between insulin sensitivity and the plasma epinephrine level. Despite the limitations, our results are strengthened by using gold standard techniques as well as a wellcharacterized cohort in a relatively large sample size. In conclusion, this study demonstrates for the first time a positive association between plasma epinephrine level and insulin sensitivity in MHO individuals. Further studies are needed to reveal a causal relationship and the underlying mechanisms. References Begin-Heick, N., 1996. Beta-adrenergic receptors and G-proteins in the ob/ob mouse. Int. J. Obes. Relat. Metab. Disord. 20 (Suppl. 3), S32–S35. Bonora, E., Willeit, J., Kiechl, S., Oberhollenzer, F., Egger, G., Bonadonna, R., Muggeo, M., 1991. U-shaped and Jshaped relationships between serum insulin and coronary heart disease in the general population. The Bruneck Study. Diab. Care 21 (2), 221–230. Brochu, M., Tchernof, A., Dionne, I.J., Sites, C.K., Eltabbakh, G.H., Sims, E.A., Poehlman, E.T., 2001. What are the physical characteristics associated with a normal metabolic

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