leptin and Respiratory-Insufficiency

Opiate-induced respiratory depression is sexually dimorphic and associated with increased risk among the obese. The mechanisms underlying these associations are unknown. The present study evaluated the two-tailed hypothesis that sex, leptin status, and obesity modulate buprenorphine-induced changes in breathing.. Mice (n = 40 male and 40 female) comprising four congenic lines that differ in leptin signaling and body weight were injected with saline and buprenorphine (0.3 mg/kg). Whole-body plethysmography was used to quantify the effects on minute ventilation. The data were evaluated using three-way analysis of variance, regression, and Poincaré analyses.. Relative to B6 mice with normal leptin, buprenorphine decreased minute ventilation in mice with diet-induced obesity (37.2%; P < 0.0001), ob/ob mice that lack leptin (62.6%; P < 0.0001), and db/db mice with dysfunctional leptin receptors (65.9%; P < 0.0001). Poincaré analyses showed that buprenorphine caused a significant (P < 0.0001) collapse in minute ventilation variability that was greatest in mice with leptin dysfunction. There was no significant effect of sex or body weight on minute ventilation.. The results support the interpretation that leptin status but not body weight or sex contributed to the buprenorphine-induced decrease in minute ventilation. Poincaré plots illustrate that the buprenorphine-induced decrease in minute ventilation variability was greatest in mice with impaired leptin signaling. This is relevant because normal respiratory variability is essential for martialing a compensatory response to ventilatory challenges imposed by disease, obesity, and surgical stress.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Disease Models, Animal; Female; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Respiratory Insufficiency; Sex Factors; Signal Transduction

Obese females are less predisposed to sleep-disordered breathing and have higher serum leptin levels than males of comparable body weight. Because leptin is a powerful respiratory stimulant, especially during sleep, we hypothesized that the elevated leptin level is necessary to maintain normal ventilatory control in obese females. We examined ventilatory control during sleep and wakefulness in male and female leptin-deficient obese C57BL/6J-Lep(ob) mice, wild-type C57BL/6J mice with dietary-induced obesity and high serum leptin levels, and normal weight wild-type C57BL/6J mice. Both male and female C57BL/6J-Lep(ob) mice had depressed hypercapnic ventilatory response (HCVR) in comparison with wild-type animals. In comparison with male C57BL/6J-Lep(ob) mice, female C57BL/6J-Lep(ob) mice had reduced HCVR and respiratory drive (a ratio of tidal volume to inspiratory time) both during non-rapid eye movement (NREM) sleep and wakefulness. In contrast, the HCVR did not differ between sexes in wild-type mice during NREM sleep and wakefulness, but was lower in females during REM sleep. Thus, leptin deficiency in female obesity is even more detrimental to hypercapnic ventilatory control during wakefulness and NREM sleep than in obese, leptin-deficient males.

Topics: Animals; Carbon Dioxide; Female; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Respiratory Insufficiency; Severity of Illness Index; Sex Factors

Previously we reported an impaired energy balance in patients with chronic obstructive pulmonary disease (COPD) during an acute disease exacerbation, but limited data are available on the underlying mechanisms. Experimental and clinical research supports the hypothesis of involvement of the hormone leptin in body weight and energy balance homeostasis. The aim of this study was to investigate the course of the energy balance in relation to leptin and the soluble tumor necrosis factor (TNF) receptors (sTNF-R) 55 and 75, plasma glucose, and serum insulin in patients with severe COPD during the first 7 d of hospitalization for an acute exacerbation (n = 17, 11 men, age mean [SD] 66 [10] yr, FEV(1) 36 [12] %pred). For reference values of the laboratory parameters, blood was collected from 23 (16 men) healthy, elderly subjects. On admission, the dietary intake/resting energy expenditure (REE) ratio was severely depressed (1.28 [0.57]), but gradually restored until Day 7 (1.65 [0. 45], p = 0.005 versus Day 1). Glucose and insulin concentrations were elevated on admission, but on Day 7 only plasma glucose was decreased. The sTNF-Rs were not different from healthy subjects and did not change. Plasma leptin, adjusted for fat mass expressed as percentage of body weight (%FM), was elevated on Day 1 compared with healthy subjects (1.82 [3.85] versus 0.32 [0.72] ng%/ml, p = 0.008), but decreased significantly until Day 7 (1.46 [3.77] ng%/ml, p = 0. 015 versus Day 1). On Day 7, sTNF-R55 was, independently of %FM, correlated with the natural logarithm (LN) of leptin (r = 0.65, p = 0.041) and with plasma glucose (r = 0.81, p = 0.015). In addition, the dietary intake/REE ratio was not only inversely related with LN leptin (-0.74, p = 0.037), but also with sTNF-R55 (r = -0.93, p = 0. 001) on day seven. In conclusion, temporary disturbances in the energy balance were seen during an acute exacerbation of COPD, related to increased leptin concentrations as well as to the systemic inflammatory response. Evidence was found that the elevated leptin concentrations were in turn under control of the systemic inflammatory response, and, presumably, the high-dose systemic glucocorticosteroid treatment.

Topics: Acute Disease; Aged; Blood Glucose; Body Weight; Energy Metabolism; Female; Homeostasis; Humans; Leptin; Lung Diseases, Obstructive; Lung Volume Measurements; Male; Middle Aged; Respiratory Insufficiency; Risk Factors; Systemic Inflammatory Response Syndrome