Stefan Riedl, Michael Kluge, Katharina Schweitzer, Thomas Waldhör, and Herwig Frisch
High altitude (HA) provokes a variety of endocrine adaptive processes. We investigated the impact of HA on ghrelin levels and the GH/IGF axis.
Observational study as part of a medical multidisciplinary project in a mountainous environment.
Thirty-three probands (12 females) were investigated at three timepoints during ascent to HA (A: d −42, 120 m; B: d +4, 3440 m; C: d +14, 5050 m). The following parameters were obtained: ghrelin; GH; GH-binding protein (GHBP); IGF1; IGF2; IGF-binding proteins (IGFBPs) -1, -2, and -3; acid-labile subunit (ALS); and insulin. Weight was monitored and general well being assessed using the Lake Louise acute mountain sickness (AMS) score.
Ghrelin (150 vs 111 pg/ml; P<0.01) and GH (3.4 vs 1.7 μg/l; P<0.01) were significantly higher at timepoint C compared with A whereas GHBP, IGF1, IGF2, IGFBP3, ALS, and insulin levels did not change. IGFBP1 (58 vs 47 μg/l; P<0.05) and, even more pronounced, IGFBP2 (1141 vs 615 μg/l; P<0.001) increased significantly. No correlation, neither sex-specific nor in the total group, between individual weight loss (females: −2.1 kg; males: −5.1 kg) and rise in ghrelin was found. Five of the subjects did not reach investigation point C due to AMS.
After 14 days of exposure to HA, we observed a significant ghrelin and GH increase without changes in GHBP, IGF1, IGF2, IGFBP3, ALS, and insulin. Higher GH seems to be needed for acute metabolic effects rather than IGF/IGFBP3 generation. Increased IGFBP1 and -2 may reflect effects from HA on IGF bioavailability.
Michael Kluge, Stefan Riedl, Manfred Uhr, Doreen Schmidt, Xiaochi Zhang, Alexander Yassouridis, and Axel Steiger
Ghrelin promotes a positive energy balance, e.g. by increasing food intake. Stimulation of the activity of the hypothalamus–pituitary–thyroid (HPT) axis promotes a negative energy balance, e.g. by increasing energy expenditure. We therefore hypothesized that ghrelin suppresses the HPT axis in humans, counteracting its energy-saving effect.
Design and methods
In this single-blind, randomized, cross-over study, we determined secretion patterns of free triiodothyronine (fT3), free thyroxine (fT4), TSH, and thyroid-binding globulin (TBG) between 2000 and 0700 h in 20 healthy adults (10 males and 10 females, 25.3±2.7 years) receiving 50 μg ghrelin or placebo at 2200, 2300, 0000, and 0100 h.
FT4 plasma levels were significantly higher after ghrelin administration than after placebo administration from 0000 h until 0620 h except for the time points at 0100, 0520, and 0600 h. TSH plasma levels were significantly lower from 0200 until the end of the study at 0700 h except for the time points at 0540, 0600, and 0620 h. The relative increase of fT4 (area under the curve (AUC) 0130–0700 h (ng/dl×min): placebo: 1.31±0.03; ghrelin: 1.39±0.03; P=0.001) was much weaker than the relative decrease of TSH (AUC 0130–0700 h (mIU/ml×min): placebo: 1.74±0.12; ghrelin: 1.32±0.12; P=0.007). FT3 and TBG were not affected.
This is the first study to report that ghrelin affects the HPT axis in humans. The early fT4 increase was possibly induced by direct ghrelin action on the thyroid where ghrelin receptors have been identified. The TSH decrease might have been caused by ghrelin-mediated inhibition at hypothalamic level by feedback inhibition through fT4, or both.
Dirk Alexander Wittekind, Markus Scholz, Jürgen Kratzsch, Markus Löffler, Katrin Horn, Holger Kirsten, Veronica Witte, Arno Villringer, and Michael Kluge
Ghrelin is an orexigenic peptide hormone involved in the regulation of energy homeostasis, food intake and glucose metabolism. Serum levels increase anticipating a meal and fall afterwards. Underlying genetic mechanisms of the ghrelin secretion are unknown.
Total serum ghrelin was measured in 1501 subjects selected from the population-based LIFE-ADULT-sample after an overnight fast. A genome-wide association study (GWAS) was performed. Gene-based expression association analyses (transcriptome-wide association study (TWAS)) are statistical tests associating genetically predicted expression to a certain trait and were done using MetaXcan.
In the GWAS, three loci reached genome-wide significance: the WW-domain containing the oxidoreductase-gene (WWOX; P = 1.80E-10) on chromosome 16q23.3-24.1 (SNP: rs76823993); the contactin-associated protein-like 2 gene (CNTNAP2; P = 9.0E-9) on chromosome 7q35-q36 (SNP: rs192092592) and the ghrelin And obestatin prepropeptide gene (GHRL; P = 2.72E-8) on chromosome 3p25.3 (SNP: rs143729751). In the TWAS, the three genes where the expression was strongest associated with serum ghrelin levels was the ribosomal protein L36 (RPL36; P = 1.3E-06, FDR = 0.011, positively correlated), AP1B1 (P = 1.1E-5, FDR = 0.048, negatively correlated) and the GDNF family receptor alpha like (GFRAL), receptor of the anorexigenic growth differentiation factor-15 (GDF15), (P = 1.8E-05, FDR = 0.15, also negatively correlated).
The three genome-wide significant genetic loci from the GWA and the genes identified in the TWA are functionally plausible and should initiate further research.