beta-Adrenergic regulation of proinflammatory cytokines in humans.

OBJECTIVES: To investigate the effects of beta-adrenergic stimulation on IL-6 secretion in humans, and to determine the potential contribution to this response of adipocytes and peripheral blood cells (PBC). DESIGN: Experimental study in 8 human volunteers, and in vitro studies on murine adipocyte cell-line, 3T3.L1 and 3T3.F442A, and human PBC. MEASUREMENTS: Plasma IL-6 and TNFalpha responses to isoprenaline infusion. Cytokine secretion from differentiated adipocyte cell-lines and PBC in response to isoprenaline. RESULTS: Plasma IL-6 levels increased ninefold (median) by 180 min (baseline median 0.51 [interquartile range 0.47-1.4] vs 180 mins 4.53 [2.58-5.69] pg ml(-1), P=0.01). One hour after infusion, IL-6 levels (2.9 [1.27-3.98]) were lower than at 180 min (P=0.05), but higher than baseline (P=0.01). TNFalpha levels were unchanged. Differentiated adipocytes incubated in isoprenaline (0-0.1 microM) released significantly increased amounts of IL-6 whereas no response was elicited from PBC. CONCLUSIONS: The induction of IL-6 observed in vivo may be attributed to the beta-adrenergic stimulation of IL-6 release specifically from adipocytes, as opposed to circulating blood cells.

Thyroid and sympathetic influences on plasma leptin in hypothyroidism and hyperthyroidism.

OBJECTIVES: To determine the dependence of plasma leptin concentrations upon circulating noradrenaline (NA) and thyroid hormones (TH) in humans. DESIGN: Cross-sectional study in 40 newly diagnosed untreated patients with primary thyroid disease, and 69 lean and obese euthyroid control subjects. MEASUREMENTS: Plasma leptin, NA, free T3 (fT3) and TSH in the fasting state. Anthropometry and % body fat (electrical bioimpedance). RESULTS: Leptin levels were highest in 37 obese euthyroid and 22 hypothyroid (median [interquartiles]31.5 [19.0- 48.0], 19.2 [11.5-31.5] ng ml(-1)), and lowest in 32 lean euthyroid and 18 hyperthyroid subjects (6.6 [3.9-14.4], 8.9 [5.5-11.1]; ANOVA, P< 0.0001). Plasma NA was similar in all groups (P= n.s.). In obese controls, TSH correlated with % body fat and leptin (r= 0.67, r= 0.61; P< 0.001). Treatment of hypothyroidism (n= 10) with T4 reduced leptin from 20.8 [11.8-31.6] to 12.9[4.6-21.2] (P= 0.005) with no change in BMI. CONCLUSIONS: Thyroid status modifies leptin secretion independently of adiposity and NA. The data suggest leptin-thyroid interactions at hypothalamic and adipocyte level.

Central obesity, depression and the hypothalamo-pituitary-adrenal axis in men and postmenopausal women.

OBJECTIVE: We examined the relationship of adiposity to pituitary-adrenal responses to corticotrophin-releasing hormone (CRH) in men and postmenopausal women, controlling for the influence of depression. DESIGN: Studies of CRH responses, cortisol metabolite levels and depression scores in relation to adiposity in men and postmenopausal women. SUBJECTS: Thirteen men: age (median, interquartile range) 62 y (52-63), body mass index (BMI) 29.0 kg/m2 (26.3-33.1), waist circumference (waist) 105 cm (97-111), waist:hip ratio (WHR) 1.03 (0.98-1.07), subscapular to triceps skinfold thickness ratio (STR) 2.0 (1.2-2.4), total body fat (TBF) 25.4 kg (19.8-28.8); and eight women: age 54 y (53-62), BMI 30 kg/m2 (23-41), waist 86 cm (79-117), WHR 0.94 (0.87-1.10), STR 1.0 (0.85-1.07), TBF 35.0 kg (18.7-48.8). MEASUREMENTS: A standard CRH test was conducted with additional basal samples taken for leptin and interleukin 6 (IL-6). Total urine cortisol metabolites (TCM) and the ratio of urinary cortisol:cortisone (Fm/Em) metabolites were measured. Depression scores were measured by the General Health Questionnaire (GHQ-30) and Hospital Anxiety and Depression Scale (HAD) questionnaire. All subjects completed an overnight dexamethasone suppression test. RESULTS: The basal to peak percentage increments (%inc.) in adrenocorticotrophic hormone (ACTH) and cortisol in men correlated directly with STR (ACTH %inc. r=0.70, P<0.01; cortisol %inc. r=0.55, P=0.05); this relationship was independent of depression scores. In women, the ACTH area under incremental curve (AUIC) correlated negatively with STR (r=-0.81, P<0.05). In men, but not in women, there was a significant correlation between GHQ-30 score and ACTH AUIC (r=0.62, P<0.05) and cortisol AUIC (r=0.72, P<0.01). Depression scores were consistently and directly related to indices of obesity and central obesity. There were no significant relationships in either sex between urinary TCM or Fm/Em ratio and BMI, waist, WHR, TBF, STR or CRH responses. The urinary Fm/Em ratio was higher in men than in women (median 0.74 vs 0.66, P<0.05). In men, but not in women, GHQ-30 scores correlated positively with urinary TCM (r=0.57, P=0.05) and HAD-depression scores were inversely related to the urine Fm/Em ratio (r=-0.65, P<0.05). All subjects suppressed normally with dexamethasone. CONCLUSIONS: Cortisol metabolite levels were increased in depression in men, but were not related to adiposity in either sex. We demonstrate that central obesity in men, but not postmenopausal women, is associated with an enhanced pituitary-adrenal response to CRH and that this relationship is independent of depression score. International Journal of Obesity (2000) 24, 246-251

Leptin production during early starvation in lean and obese women.

We evaluated abdominal adipose tissue leptin production during short-term fasting in nine lean [body mass index (BMI) 21 +/- 1 kg/m(2)] and nine upper body obese (BMI 36 +/- 1 kg/m(2)) women. Leptin kinetics were determined by arteriovenous balance across abdominal subcutaneous adipose tissue at 14 and 22 h of fasting. At 14 h of fasting, net leptin release from abdominal adipose tissue in obese subjects (10.9 +/- 1.9 ng x 100 g tissue x (-1) x min(-1)) was not significantly greater than the values observed in the lean group (7.6 +/- 2.1 ng x 100 g(-1) x min(-1)). Estimated whole body leptin production was approximately fivefold greater in obese (6.97 +/- 1.18 microg/min) than lean subjects (1.25 +/- 0.28 microg/min) (P < 0.005). At 22 h of fasting, leptin production rates decreased in both lean and obese groups (to 3.10 +/- 1.31 and 10.5 +/- 2.3 ng x 100 g adipose tissue(-1) x min(-1), respectively). However, the relative declines in both arterial leptin concentration and local leptin production in obese women (arterial concentration 13.8 +/- 4.4%, local production 10.0 +/- 12.3%) were less (P < 0.05 for both) than the relative decline in lean women (arterial concentration 39.0 +/- 5.5%, local production 56.9 +/- 13.0%). This study demonstrates that decreased leptin production accounts for the decline in plasma leptin concentration observed after fasting. However, compared with lean women, the fasting-induced decline in leptin production is blunted in women with upper body obesity. Differences in leptin production during fasting may be responsible for differences in the neuroendocrine response to fasting previously observed in lean and obese women.

Production of soluble tumor necrosis factor receptors by human subcutaneous adipose tissue in vivo.

To investigate in vivo adipose tissue production of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and their soluble receptors: TNF receptor type I (sTNFR-I), TNF receptor type II (sTNFR-II), and IL-6 receptor (sIL-6R), we determined arteriovenous differences in their levels across abdominal subcutaneous adipose tissue in obese subjects. Subjects had a median (interquartile range) age of 44.5 (27-51.3) yr, body mass index (BMI) of 32.9 (26. 0-46.6) kg/m(2), and %body fat of 42.5 (28.5-51.2) %. Although there was not a significant difference in the arteriovenous concentrations of TNF-alpha (P = 0.073) or sTNFR-II (P = 0.18), the levels of sTNFR-I (P = 0.002) were higher in the vein compared with artery, suggesting adipose tissue production of this soluble receptor. There was a significant arteriovenous difference in IL-6 (P < 0.001) but not in its soluble receptor (P = 0.18). There was no relationship between TNF-alpha levels and adiposity indexes (r(s) = 0.12-0.22, P = not significant); however, levels of both its soluble receptor isomers correlated significantly with BMI and %body fat (sTNFR-I r(s) = 0.42-0.72, P < 0.001; sTNFR-II r(s) = 0.36-0.65, P < 0.05- <0. 001). IL-6 levels correlated significantly with both BMI and %body fat (r(s) = 0.51, P = 0.004, and r(s) = 0.63, P < 0.001), but sIL-6R did not. In conclusion, 1) soluble TNFR-I is produced by adipose tissue, and concentrations of both soluble isoforms correlate with the degree of adiposity, and 2) IL-6, but not its soluble receptor, is produced by adipose tissue and relates to adiposity.

Leptin and the pituitary-thyroid axis: a comparative study in lean, obese, hypothyroid and hyperthyroid subjects.

OBJECTIVE: To study interactions between leptin and the pituitary-thyroid axis, both in euthyroid and dysthyroid states. SUBJECTS AND MEASUREMENTS: We investigated the relationships of plasma leptin to levels of free thyroid hormones and TSH in 18 patients with newly diagnosed hyperthyroidism, 22 with newly diagnosed primary hypothyroidism, and 32 lean (body mass index [BMI] < 30) and 37 obese (BMI > 30 kg/m2) euthyroid subjects. Hypothyroid patients were restudied during thyroxine replacement treatment. RESULTS: Median [interquartile range] plasma leptin concentrations were highest in obese euthyroid subjects (31.5 [19.0-48.0] and in untreated hypothyroid patients (19.2 [11.5-31.5]), and lowest levels in untreated hyperthyroid patients (8.9 [5.5-11.1]) and lean euthyroid control subjects (6.6 [3.9-14.4] micrograms/l (Kruskall-Wallis one-way analysis of variance; P < 0.0001). In euthyroid subjects, plasma leptin levels were higher in obese than in lean subjects (P < 0.00001). In obese subjects plasma levels of TSH correlated with percentage body fat (r = 0.67; P < 0.001) and plasma leptin (r = 0.61; P < 0.001). In untreated hyperthyroid subjects plasma leptin was unrelated to free T3, and in untreated hypothyroidism plasma leptin was unrelated to either free T3 or TSH concentrations (all P = NS). In untreated hyperthyroid, but not hypothyroid, patients plasma leptin concentrations correlated with BMI (r = 0.57; P = 0.02). Treatment of hypothyroidism with thyroxine resulted in a significant reduction in plasma leptin concentrations from 20.8 (11.8 to 31.6) to 12.9 (4.6-21.2) micrograms/l (P = 0.005), but BMI did not change significantly in the hypothyroid subjects being studied prospectively. CONCLUSIONS: (i) In euthyroid subjects, plasma leptin and TSH levels correlate, and both are positively correlated with adiposity. (ii) Plasma leptin was significantly elevated in hypothyroid subjects, to levels similar to those seen in obese euthyroid subjects. (iii) Treatment of hypothyroidism resulted in a reduction in the raised plasma leptin levels. The data are consistent with the hypothesis that leptin and the pituitary-thyroid axis interact in the euthyroid state, and that hypothyroidism reversibly increases leptin concentrations.

Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo.

We measured arterio-venous differences in concentrations of tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) across a sc adipose tissue bed in the postabsorptive state in 39 subjects [22 women and 17 men; median age, 36 yr (interquartile range, 26-48 yr); body mass index, 31.8 kg/m2 (range, 22.3- 38.7 kg/m2); percent body fat, 28.7% (range, 17.6-50.7%)]. A subgroup of 8 subjects had arteriovenous differences measured across forearm muscle. Thirty subjects were studied from late morning to early evening; 19 ate a high carbohydrate meal around 1300 h, and 11 continued to fast. We found a greater than 2-fold increase in IL-6 concentrations across the adipose tissue bed [arterial, 2.27 pg/mL (range, 1.42-3.53 pg/mL); venous, 6.71 pg/mL (range, 3.36-9.62 pg/mL); P < 0.001], but not across forearm muscle. Arterial plasma concentrations of IL-6 correlated significantly with body mass index (Spearman's r = 0.48; P < 0.01) and percent body fat (Spearman's r = 0.49; P < 0.01). Subcutaneous adipose tissue IL-6 production increased by the early evening (1800-1900 h) in both subjects who had extended their fasting and those who had eaten. Neither deep forearm nor sc adipose tissue consistently released TNF alpha [across adipose tissue: arterial, 1.83 pg/mL (range, 1.36-2.34 pg/mL); venous, 1.85 pg/mL (range, 1.44-2.53 pg/mL); P = NS: across forearm muscle: arterial, 1.22 pg/mL (range, 0.74-2.76 pg/mL); venous, 0.99 pg/mL (range, 0.69-1.70 pg/mL); P = NS]. Although both IL-6 and TNF alpha are expressed by adipose tissue, our results show that there are important differences in their systemic release. TNF alpha is not released by this sc depot. In contrast, IL-6 is released from the depot and is thereby able to signal systemically.

Relationships between plasma leptin and insulin concentrations, but not insulin resistance, in non-insulin-dependent (type 2) diabetes mellitus.

In non-diabetic subjects, insulin concentrations and insulin resistance are clearly connected, and both correlate with leptin levels, making interpretations about mechanisms difficult. In non-insulin-dependent (Type 2) diabetes mellitus (NIDDM), however, insulin concentrations and insulin resistance are less closely associated. Therefore, we examined the relationship of plasma leptin concentrations within insulin resistance and insulin levels in 32 subjects with NIDDM, who underwent measurement of insulin resistance with an insulin sensitivity test. Plasma leptin was measured with an in-house monoclonal immunoradiometric assay. Fasting leptin level correlated with BMI (r = 0.78; p < 0.001), metabolic clearance rate of glucose (= -0.44; p = 0.015), and fasting specific insulin (r = 0.58; p = 0.001), but not with age, cholesterol, triglycerides or blood pressure (r = -0.26 to 0.21; p = NS). In linear regression analysis, after adjustment for BMI and gender, leptin concentrations correlated with those of insulin (partial r = 0.42; p = 0.025), but not insulin resistance (partial r = -0.10; p = NS). We conclude that in NIDDM, concentrations of plasma leptin are closely related to those of insulin per se and to obesity, but not to insulin resistance. Insulin may be an important regulator of leptin concentration in NIDDM.