Abstract
The TGF-b superfamily cytokine MIC-1/GDF15 circulates in the blood of healthy humans. Its levels rise substantially in cancer and other diseases and this may sometimes lead to development of an anorexia/cachexia syndrome. This is mediated by a direct action of MIC-1/GDF15 on feeding centres in the hypothalamus and brainstem. More recent studies in germline gene deleted mice also suggest that this cytokine may play a role in physiological regulation of energy homeostasis. To further characterize the role of MIC-1/GDF15 in physiological regulation of energy homeostasis in man, we have examined diurnal and food associated variation in serum levels and whether variation in circulating levels relate to BMI in human monozygotic twin pairs. We found that the within twin pair differences in serum MIC-1/GDF15 levels were significantly correlated with within twin pair differences in BMI, suggesting a role for MIC-1/GDF15 in the regulation of energy balance in man. MIC-1/GDF15 serum levels altered slightly in response to a meal, but comparison with variation its serum levels over a 24hour period suggested that these changes are likely to be due to bimodal diurnal variation which can alter serum MIC-1/GDF15 levels by about plus or minus 10% from the mesor. The lack of a rapid and substantial postprandial increase in MIC-1/GDF15 serum levels suggests that MIC1/GDF15 is unlikely to act as a satiety factor. Taken together, our findings suggest that MIC-1/GDF15 may be a physiological regulator of energy homeostasis in man, most probably due to actions on long-term regulation of energy homeostasis.
Highlights
The regulation of food intake, energy storage and energy expenditure is tightly controlled by complex homeostatic mechanisms
To investigate whether MIC-1/GDF15 may regulate energy homeostasis in humans, as in mice, we examined the relationship between MIC-1/GDF15 serum levels and body mass index (BMI)
The observed correlation between MIC-1/GDF15 serum levels and BMI in humans suggests that the data we have previously obtained in mice, demonstrating that high MIC-1/GDF15 levels lead to weight loss and that absent MIC-1/GDF15 levels leads to weight gain[23], may apply to humans
Summary
The regulation of food intake, energy storage and energy expenditure is tightly controlled by complex homeostatic mechanisms. MIC-1/GDF15 is normally present in the blood of normal adult humans, with a broad normal range of 150 to 1150 pg/mL [16], which may rise substantially further in the elderly [21, 22] This raises questions as to whether MIC-1/GDF15 levels within this normal circulating range may regulate energy homeostasis. When MIC-1-/mice were infused with sufficient recombinant MIC-1/GDF15 to raise their serum levels to the middle of the normal human range, their body weight and food intake were significantly reduced. These findings suggested that, at least in mice, physiological concentrations of MIC1/GDF15 play a role in the regulation of appetite, fat deposition and body weight [23, 24]. Interactions between MIC-1/GDF15 and several currently known gut-derived satiety factors were examined in healthy men
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