GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans.

GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.This work and authors were funded by the NIHR Cambridge Biomedical Research Centre; NIHR Rare Disease Translational Research Collaboration; Medical Research Council [MC_UU_12012/2 and MRC_MC_UU_12012/3]; MRC Metabolic Diseases Unit [MRC_MC_UU_12012/5 and MRC_MC_UU_12012.1]; Wellcome Trust Strategic Award [100574/Z/12/Z and 100140]; Wellcome Trust [107064 , 095515/Z/11/Z , 098497/Z/12/Z, 106262/Z/14/Z and 106263/Z/14/Z]; British Heart Foundation [RG/12/13/29853]; Addenbrooke’s Charitable Trust / Evelyn Trust Cambridge Clinical Research Fellowship [16-69] US Department of Agriculture: 2010-34323-21052; EFSD project grant and a Royal College of Surgeons Research Fellowship, Diabetes UK Harry Keen intermediate clinical fellowship (17/0005712). European Research Council, Bernard Wolfe Health Neuroscience Endowment, Experimental Medicine Training Initiative/AstraZeneca and Medimmune

Intake of Protein Plus Carbohydrate during the First Two Hours after Exhaustive Cycling Improves Performance the following Day.

Intake of protein immediately after exercise stimulates protein synthesis but improved recovery of performance is not consistently observed. The primary aim of the present study was to compare performance 18 h after exhaustive cycling in a randomized diet-controlled study (175 kJ·kg(-1) during 18 h) when subjects were supplemented with protein plus carbohydrate or carbohydrate only in a 2-h window starting immediately after exhaustive cycling. The second aim was to investigate the effect of no nutrition during the first 2 h and low total energy intake (113 kJ·kg(-1) during 18 h) on performance when protein intake was similar. Eight endurance-trained subjects cycled at 237±6 Watt (~72% VO2max) until exhaustion (TTE) on three occasions, and supplemented with 1.2 g carbohydrate·kg(-1)·h(-1) (CHO), 0.8 g carbohydrate + 0.4 g protein·kg(-1)·h(-1) (CHO+PRO) or placebo without energy (PLA). Intake of CHO+PROT increased plasma glucose, insulin, and branch chained amino acids, whereas CHO only increased glucose and insulin. Eighteen hours later, subjects performed another TTE at 237±6 Watt. TTE was increased after intake of CHO+PROT compared to CHO (63.5±4.4 vs 49.8±5.4 min; p<0.05). PLA reduced TTE to 42.8±5.1 min (p<0.05 vs CHO). Nitrogen balance was positive in CHO+PROT, and negative in CHO and PLA. In conclusion, performance was higher 18 h after exhaustive cycling with intake of CHO+PROT compared to an isocaloric amount of carbohydrate during the first 2 h post exercise. Intake of a similar amount of protein but less carbohydrate during the 18 h recovery period reduced performance

Metabolic data during exhaustive exercise prior to the three diet interventions.

<p>Day 1.</p

Plasma concentrations of lactate, glucose, insulin, FFA, glycerol and glucagon during the first 2 h recovery when provided CHO, CHO+PROT or PLA.

<p>Data are mean and error bars represents SEM. C: p<0.05 compared to CHO; W: p<0.05 compared to CHO+PROT (whey); P: p<0.05 compared to placebo. N = 8 for all data points.</p

Plasma concentrations of uric acid, ornithine, citrulline and 1-methyl-histidine during the first 2 h of recovery when provided CHO, CHO+PROT or PLA.

<p>Data are mean and error bars represents SEM. C: p<0.05 compared to CHO; W: p<0.05 compared to CHO+PROT (whey); P: p<0.05 compared to placebo. N = 8 for all data points.</p

Performance test after 18 h recovery receiving CHO, CHO+PROT or PLA.

<p>The performance test was time to exhaustion cycling at W_72% (237±6 W). Data are mean and error bars represents SEM. N = 8 at all tests. a: p<0.05 compared to CHO+PROT; b: p<0.05 compared to CHO.</p

VO₂, RER, CHO oxidation and HF during the performance test (TTE) after the three diet interventions (Day 2).

<p>VO₂, RER, CHO oxidation and HF during the performance test (TTE) after the three diet interventions (Day 2).</p

Rate of perceived exertion (RPE) during the time to exhaustion (TTE) performance test after the three diet interventions.

<p>Data are mean and error bars represents SEM. C: p<0.05 compared to CHO; W: p<0.05 compared to CHO+PROT (whey); P: p<0.05 compared to placebo. N = 8 for all data points.</p

Concentrations of metabolites and hormones in fasted condition the day after exhaustive exercise and diet interventions, and during and after the performance test.

<p>Data are mean and error bars represents SEM. C: p<0.05 compared to CHO; W: p<0.05 compared to CHO+PROT (whey); P: p<0.05 compared to placebo. N = 8 for all data points.</p

Nitrogen balance and urine excretion of urea and creatinine. a: p<0.05 compared to CHO+PROT; b: p<0.05 compared to CHO.

<p>Data are mean and error bars represents SEM. C: p<0.05 compared to CHO; W: p<0.05 compared to CHO+PROT (whey); P: p<0.05 compared to placebo. N = 8 for all data points.</p