Effects of physiological leptin administration on markers of inflammation, platelet activation, and platelet aggregation during caloric deprivation.

CONTEXT: Leptin is a nutritionally regulated adipocyte-derived cytokine. Previous studies in obese patients have demonstrated increased inflammatory markers and increased platelet aggregation in association with leptin. However, the effects of leptin administration on markers of inflammation and platelet aggregation in a human model of undernutrition have not previously been studied. OBJECTIVE: The objective of the study was to investigate markers of inflammation, platelet activation, and platelet aggregation in a model of caloric deprivation and increased leptin sensitivity. DESIGN: This study was a randomized, placebo-controlled study conducted between November 2002 and November 2003. SETTING: The study was conducted at an inpatient care setting at the General Clinical Research Center. PARTICIPANTS: Twenty healthy, young (18-35 yr old), normal-weight (body mass index, 20-26 kg/m2) women were recruited from local advertisements. No subjects withdrew due to adverse effects. INTERVENTION: The effects of physiological recombinant methionyl human leptin or identical placebo administration were investigated over a 4-d fast. MAIN OUTCOME MEASURES: The primary outcome measures for this study were C-reactive protein (CRP) and indices of platelet activity. RESULTS: Leptin administration prevented the fasting-induced decline in leptin (P < 0.05 vs. placebo at each time point). Leptin administration increased CRP (6.3 +/- 2.4 vs. 0.7 +/- 0.3 mg/liter; P = 0.04), circulating P-selectin (11.6 +/- 10.2 vs. -28.9 +/- 15.6 ng/ml; P = 0.04), and induction of platelet aggregation (5.8 +/- 2.6 vs. -2.7 +/- 2.9%, P = 0.04, percent maximum platelet aggregation) relative to placebo administration (change in leptin vs. change in placebo, respectively, for each variable). Leptin tended to increase serum amyloid A [0.1 +/- 0.2 vs. -0.3 +/- 0.1 log10 (ng/ml); P = 0.07], and the changes in serum amyloid A and CRP were highly correlated (r = 0.83; P < 0.0001). No changes in TNFalpha, IL-6, IL-10, plasminogen activator inhibitor-1, haptoglobin, intercellular adhesion molecule, or vascular cell adhesion molecule were seen between the groups. CONCLUSIONS: Our data provide evidence that physiological leptin administration stimulates inflammatory and platelet responses in humans during caloric deprivation.

Reciprocal changes in endogenous ghrelin and growth hormone during fasting in healthy women.

Ghrelin stimulates growth hormone (GH) secretion, but it is unknown whether there is a feedback of GH on ghrelin secretion. In this study, we characterized the relatedness of GH and ghrelin in a model of acute caloric deprivation in 10 healthy women (age 26.7 +/- 1.6 yr) during a 4-day fast in the early follicular phase. GH, ghrelin, and cortisol were assessed every hour over 24 h during an isocaloric diet and after a 4-day complete fast. Sampling during a normal diet at baseline demonstrated that ghrelin decreased 17.9% within 1 h after meals (P < 0.0001), but there was no meal effect on GH. BMI (22.3 +/- 0.4 vs. 21.5 +/- 0.4 kg/m2, P < 0.0001) and IGF-I (312 +/- 28 vs.124 +/- 22 ng/ml, P < 0.0001) decreased during fasting. Mean 24-h GH increased (2.6 +/- 0.5 vs. 5.6 +/- 0.5 ng/ml, P < 0.001), but ghrelin decreased (441.3 +/- 59.7 vs. 359.8 +/- 54.2 pg/ml, P = 0.012). The peak ghrelin level decreased from 483.5 to 375.6 pg/ml (P < 0.0001), and the time of the peak ghrelin changed from 0415 to 1715. In contrast, the diurnal pattern of GH was maintained, with increases in the nadir (1.1 to 3.4 ng/ml) and peak GH concentrations (4.1 to 7.9 ng/ml) from the fed to fasted state (P < 0.0001). The change in morning GH concentrations was inversely related to the change in ghrelin (r = -0.79, P = 0.012). During complete short-term caloric deprivation in healthy women, ghrelin decreases, even as GH rises, and these processes appear to be reciprocal, suggesting that GH exhibits feedback inhibition on ghrelin. Our data provide new evidence of the physiological relationship of GH and ghrelin in response to changes in protein-energy metabolism.

Endocrine and metabolic effects of physiologic r-metHuLeptin administration during acute caloric deprivation in normal-weight women.

Leptin is a nutritionally regulated hormone that may modulate neuroendocrine function during caloric deficit. We hypothesized that administration of low-dose leptin would prevent changes in neuroendocrine function resulting from short-term caloric restriction. We administered physiologic doses of r-metHuLeptin [(0.05 mg/kg sc daily or identical placebo in divided doses (0800, 1400, 2000, and 0200 h)] to 17 healthy, normal-weight, reproductive-aged women during a 4-d fast. Leptin levels were lower in the placebo-treated group during fasting (3.3 +/- 0.2 vs. 9.6 +/- 1.0 ng/ml, P < 0.001, placebo vs. leptin-treated at end of study). Fat mass decreased more in the leptin than the placebo-treated group (-0.6 +/- 0.1 vs. -0.2 +/- 0.1 kg, P = 0.03). Both overnight LH area (38.9 +/- 21.5 vs. 1.2 +/- 11.1 microIU/ml.min, P = 0.05) and LH peak width increased (15.8 +/- 7.1 vs. -2.3 +/- 6.7 min, P = 0.06) and LH pulsatility decreased (-2.0 +/- 0.9 vs. 1.0 +/- 0.8 peaks/12 h, P = 0.03) more in the leptin vs. placebo group. LH pulse regularity was higher in the leptin-treated group (P = 0.02). Twenty-four-hour mean TSH decreased more in the placebo than the leptin-treated group, respectively (-1.06 +/- 0.27 vs. -0.32 +/- 0.18 microIU/ml, P = 0.03). No differences in 24-h mean GH, cortisol, IGF binding protein-1, and IGF-I were observed between the groups. Hunger was inversely related to leptin levels in the subjects randomized to leptin (r = -0.76, P = 0.03) but not placebo (r = -0.18, P = 0.70) at the end of the study. Diminished hunger was seen among subjects achieving the highest leptin levels. Our data provide new evidence of the important role of physiologic leptin regulation in the neuroendocrine response to acute caloric deprivation.

Effects of testosterone administration on growth hormone pulse dynamics in human immunodeficiency virus-infected women.

The effects of testosterone administration on the GH axis in androgen-deficient HIV-infected women are unknown. In this study, we determined the effects of transdermal testosterone administration on GH secretory dynamics and pulse characteristics in this population. GH-IGF-I parameters were determined in response to testosterone (4.1 mg/patch, twice a week; estimated delivery rate, 150 microg/d) vs. placebo over 6 months in 31 HIV-infected women. IGF-I increased significantly in the testosterone-treated compared with the placebo-treated patients [37 (-4, 73) vs. -30 (-98, 39) ng/ml, P = 0.01; 4.8 (-0.5, 9.6) vs. -3.9 (-12.8, 5.1) nmol/liter]. GH pulse frequency increased significantly in the testosterone-treated compared with the placebo-treated subjects [1.0 (1.0, 2.0) vs. 0.0 (-0.5, 1.5) peaks per 12 h, respectively; P = 0.02]. Before testosterone administration, overnight GH pulse amplitude was significantly related to IGF-I in univariate (r = 0.41, P = 0.03) and multivariate regression analysis; however, free testosterone, estradiol, and body mass index were not significantly correlated with baseline IGF-I. In contrast, after 6 months of treatment with testosterone, the change in IGF-I was significantly correlated to the change in free testosterone in univariate (r = 0.40, P = 0.04) and multivariate regression analysis. For each 1.0 pg/ml (3.5 pmol/liter) increase in free testosterone, IGF-I increased 19 ng/ml (2.5 nmol/liter), controlling for estradiol, body mass index, and GH pulse parameters (r(2) = 0.64). We demonstrate that IGF-I increases in response to physiologic, transdermal testosterone in HIV-infected women. The mechanism of this effect is unknown, but may involve a direct effect of testosterone on IGF-I, independent of changes in GH pulse dynamics.

Pharmacotherapy of obesity: an update.

There has been an epidemic of obesity in the last decade. In spite of the rising numbers of people who are overweight and obese, medical treatment of obesity is currently where medical treatment of hypertension was in the 1950s with only two Food and Drug Administration-approved medications for chronic weight loss and maintenance, sibutramine and orlistat. This article reviews these medications and others currently being used for weight loss and weight maintenance. Available medications for obesity include drugs that affect caloric intake and appetite and alter energy expenditure and nutrient absorption, as well as some with an unclear mechanism of action at present. Dozens of drugs in different phases of clinical investigation could be available in the next decade.