Serum Levels of Human MIC-1/GDF15 Vary in a Diurnal Pattern, Do Not Display a Profile Suggestive of a Satiety Factor and Are Related to BMI

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 24 hour 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.

Fig 1. Correlation of monozygotic within-pair differences in MIC-1/GDF15 serum levels and within-pair differences in BMI.

Correlation between within twin-pair difference in serum MIC-1/GDF15 levels and within twin-pair difference in BMI (n = 72 twins), performed by Spearman regression, identifies a highly significant correlation. In general the twin of the twin pair with a higher serum MIC-1/GDF15 level generally had a lower BMI than their identical twin pair. The reverse was also true.

Fig 2. Fasting diurnal variation of human MIC-1/GDF15 serum levels.

Serum MIC-1/GDF15 levels were measured on blood sample taken from participants every 30min during a 24h period. The oscillatory pattern of serum MIC-1/GDF15 levels for each individual subject was fitted to a cosine curve function.

Fig 3. Postprandial changes in human MIC-1/GDF15 serum levels.

Changes in serum MIC-1/GDF15 levels over time were measured in 17 subjects that received 5 different isocaloric meals on 5 separate occasions. (A) Changes in MIC-1/GDF15 serum levels do not differ for the 5 subjects fed the 5 different meals (n = 17, p = 0.26 repeated measure ANOVA). (B) When average data from all meals was pooled and normalised to baseline concentrations, there was significant time dependent alteration in circulating MIC-1/GDF15 levels (n = 5 meal; 17 subject/meal, p < 0.001 one-way ANOVA). (C) The postprandial profile of MIC-1/GDF15 serum levels (red) described in panel B were not significantly from its 24 h oscillatory pattern (p = 0.28, repeated measure ANOVA). Data represented as mean ± s.e.m.

Fig 4. Effect of satiety factor infusions on serum levels of human MIC-1/GDF15.

(A) Subjects receiving CCK-8 infusion alone had significant time dependent increase in serum levels of MIC-1/GDF15 with significant increases at 120, 150 and 180 minutes of infusion. Infusion of GLP-1 or CCK plus GLP-1 had no significant effect on serum MIC-1/GDF15 level (n = 9, vehicle vs GLP-1, p = 0.2; vehicle vs CCK-8 + GLP-1, p = 0.06). (B) PYY1-36 or PYY3-36 or saline was infused in subjects that were fasted overnight and had a 310-Kcal meal. Neither PYY1-36 nor PYY3-36 infusions had a significant effect on serum MIC-1/GDF15 levels (n = 8, vehicle vs PYY1-36, p = 0.18; vehicle vs PYY3-36, p = 0.34). Data were analysed by ANOVA with Bonferroni correction and are presented as mean ± s.e.m. * represents p < 0.05.