Role of Glucocorticoids in the Response of the Hypothalamo-Corticotrope, Immune and Adipose Systems to Repeated Endotoxin Administration

Abstract

The present study was designed to determine whether the glucocorticoid inhibitory feedback mechanism plays a role in the well-known tolerance of the neuroendocrine-immune axis response to repeated endotoxemia. Adult male rats underwent adrenalectomy (ADX) and were implanted with a subcutaneous corticosterone (compound B, CB, 75 mg) pellet, or sham operated and implanted with a placebo pellet. On the morning of day 8 after surgery (experimental day, D1), all rats received an intravenous injection of lipopolysaccharide (LPS) (25 µg/kg body weight) which was repeated daily until D5. Blood was drawn via intravenous indwelling catheters before (sample time zero) as well as 1, 2, 3 and 4 h after LPS treatment on D1, 3 and 5 for measurements of corticotropin (ACTH), CB, tumor necrosis factor-α (TNF-α) and leptin. In sham animals, tolerance to repeated LPS administration was complete by D5 for the corticotrope axis and the immune response. In addition, LPS was found to stimulate leptin secretion on day 1 in intact rats, an effect that also disappeared thereafter. ADX + CB rats showed only a partial tolerance of the corticotrope axis on D5, whereas tolerance of the immune response was similar to that found in sham animals. Interestingly, the acute stimulation of leptin secretion by LPS in ADX + CB rats was qualitatively similar to that of intact controls on D1, but plasma leptin levels were significantly reduced on D3 and 5 compared to controls. Our results demonstrate that the adrenal response tolerance of the hypothalamo-pituitary-adrenal axis to repeated endotoxemia. In addition, our finding that TNF-α secretion follows the same pattern in sham-operated and in adrenalectomized animals suggests that unlike the corticotrope axis, tolerance of the immune response does not depend upon stimulated CB levels. The decrease in circulating levels of leptin following ADX is consistent with the stimulatory effects of glucocorticoids on leptin secretion. However, our finding of an acute stimulation of leptin secretion by LPS in ADX + CB animals demonstrates that this effect of endotoxemia is at least partially glucocorticoid independent.

Food Intake-Induced Leptin Secretion Modulates Hypothalamo-Pituitary-Adrenal Axis Response and Hypothalamic Ob-Rb Expression to Insulin Administration

“…In the present study we found that 24-hour fasting mice injected with insulin displayed a significant increase in plasma leptin levels 45 min posttreatment. This increase in leptin levels could well be due to an insulin effect [33], but a contribution of glucocorticoids cannot be discarded [38, 39]since the rise in leptin was preceded by a marked increase in plasma glucocorticoid levels. It has been reported [30]that both adipocyte ob and hypothalamic Ob-Rb mRNAs anticipate (in coincidence with the time of lights off and maximal plasma glucocorticoid levels) the feeding-induced increase in plasma leptin levels by 4 h in freely fed rats.…”

Neuroendocrine, Metabolic, and Immune Functions during the Acute Phase Response of Inflammatory Stress in Monosodium <i>L</i>-Glutamate-Damaged, Hyperadipose Male Rat

“…injection of bacterial lipopolysaccharide (LPS; 150 µg/kg) [27]. This protocol is similar to the one previously validated by our group, although with minor modifications [28]. Blood samples taken were replaced by a similar volume of red blood cells resuspended in artificial plasma.…”

“…Plasma samples were split in several aliquots and kept frozen (–80°C) until assayed. Plasma concentrations of glucose [27], triglycerides [27], ACTH [29], corticosterone (B) [30], leptin [27], insulin [31], TNFα [28], IL-10 [28], estradiol [32] and testosterone [32] were determined by specific, previously validated assays.…”

Leptin: At the crossroads of energy balance and systemic inflammation

“…In 1996, Grunfeld and colleagues [80] reported that hamsters respond to intraperitoneal LPS with increases in both the expression of the leptin gene in white fat and the circulating level of leptin. Since then, the effect of LPS on leptin production has been well characterized in mice and rats [81][82][83][84][85][86][87][88][89][90]. It is now known that: (i) a rise in plasma leptin may occur as early as 1 h post-LPS; (ii) the rise may last for several hours; (iii) the magnitude of the rise is directly proportional to the LPS dose until a ceiling level of leptin is reached; (iv) as in non-inflammatory states, the ceiling level of leptin is ∼20 ng/ml in lean animals, but it may be higher in obese animals; and (v) the leptin response to LPS occurs in both fasted and fed animals, but the peak leptin level achieved in fasted animals is lower, possibly due to their already reduced basal production of leptin.…”