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The effect of pegylated human recombinant leptin (PEG-OB) on neuroendocrine adaptations to semi-starvation in overweight men.
Hukshorn, CJ, Menheere, PP, Westerterp-Plantenga, MS, Saris, WH
European journal of endocrinology. 2003;148(6):649-55
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Plain language summary
Starvation results in a response in neuroendocrine system including suppression of some systems (such as thyroid and reproduction) and stimulation of others (such as the stress response). The mechanisms that cause these system responses remain unclear. Research has suggested that the hormone leptin (secreted by adipose tissue) may have a role in the physiological response to fasting. During periods of fasting, leptin levels can drop steeply and leptin given to starved rodents has shown an impact on the neuroendocrine system (such as the thyroid, adrenal and reproductive). This study explored whether raised leptin levels (administered in the form of long-acting pegylated recombinant leptin (PEG-OB)) had an impact on the neuroendocrine system responses to semi-starvation. In this randomised, double blind, placebo controlled trial, 24 overweight men (BMI 25-32) were prescribed a very low energy diet (500 kilocalorie) over 46 days to induce semi-starvation. Subjects either received 80mg of PEG-OB or a placebo. Hormones were measured (including those key to the thyroid, adrenal, somatotropic and sympathetic nervous system) using blood and urine samples. The results showed that men in the PEG-OB achieved significantly more weight loss (2.8kg). However, this did not reverse the fasting induced changes in key hormonal systems. The exception was luteinising hormone (LH) which was lower in the PEG-OB group compared to the placebo. The authors concluded that a lower level of leptin resulting from starvation may be a component of fasting induced changes in the reproductive system.
Abstract
OBJECTIVE Starvation induces a complex neuroendocrine response in humans thought to have evolved to defend against reduced energy intake. The drop in leptin levels observed during fasting has been implicated as a factor that triggers this adaptive response. To explore this hypothesis, we executed a randomized, double-blind, placebo-controlled study to investigate whether elevated leptin levels using long-acting pegylated human recombinant leptin (PEG-OB) influenced the neuroendocrine responses to semi-starvation in human subjects. DESIGN Twenty-four overweight male subjects (mean+/-s.e.m.; 34.8+/-1.3 yrs; 28.8+/-0.5 kg/m(2)) were prescribed a very low energy diet (2.1 MJ/day) to induce a state of semi-starvation for the next 46 days. In addition, all subjects received a weekly treatment of 80 mg PEG-OB or matching placebo. Hormone measurements were performed throughout the study period and included 5-h frequent hormone samplings and 24-h urine collections. RESULTS Weekly subcutaneous administration of PEG-OB led to significant additional weight loss (2.8 kg) but it did not reverse the fasting-induced changes in the thyroid, corticotropic, somatotropic axes and sympathetic nervous system activity. However, after adjustment for weight loss, the drop in mean luteinizing hormone levels was attenuated in the PEG-OB group compared with the placebo group. CONCLUSIONS These results suggest that a reduced level of leptin accompanying food restriction might be a component of the fasting-induced neuroendocrine inhibition of the human reproductive axis.