Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates

Objective: Fibroblast-growth factor 21 (FGF21) is thought to be important in metabolic regulation. Recently, low protein diets have been shown to increase circulating FGF21 levels. However, when energy contribution from dietary protein is lowered, other macronutrients, such as carbohydrates, must be increased to meet eucaloric balance. This raises the possibility that intake of a diet rich in carbohydrates may induce an increase in plasma FGF21 levels per se. Here we studied the role of dietary carbohydrates on the levels of circulating FGF21 and concomitant physiologic effects by feeding healthy men a carbohydrate rich diet without reducing protein intake. Methods: A diet enriched in carbohydrates (80 E% carbohydrate; CHO) and a eucaloric control diet (CON) were provided to nine healthy men for three days. The energy intake during the CHO diet was increased (+75% energy) to ensure similar dietary protein intake in CHO and CON. To control for the effect of caloric surplus, we similarly overfed (+75% energy) the same subjects for three days with a fat-rich diet (78 E% fat; FAT), consisting of primarily unsaturated fatty acids. The three diets were provided in random order. Results: After CHO, plasma FGF21 concentration increased 8-fold compared to CON (329 ± 99 vs. 39 ± 9 pg ml−1, p < 0.05). In contrast, after FAT only a non-significant tendency (p = 0.073) to an increase in plasma FGF21 concentration was found. The increase in FGF21 concentration after CHO correlated closely (r = 0.88, p < 0.01) with increased leg glucose uptake (62%, p < 0.05) and increased hepatic glucose production (17%, p < 0.01), indicating increased glucose turnover. Plasma fatty acid (FA) concentration was decreased by 68% (p < 0.01), supported by reduced subcutaneous adipose tissue HSL Ser660 phosphorylation (p < 0.01) and perilipin 1 protein content (p < 0.01), pointing to a suppression of adipose tissue lipolysis. Concomitantly, a 146% increase in the plasma marker of hepatic de novo lipogenesis C16:1 n−7 FA (p < 0.01) was observed together with 101% increased plasma TG concentration (p < 0.001) in association with CHO intake and increased plasma FGF21 concentration. Conclusion: Excess dietary carbohydrate, but not fat, led to markedly increased FGF21 secretion in humans, notably without protein restriction, and affected glucose and lipid homeostais. Keywords: FGF21, Diet, Carbohydrates, Lipolysis, Live

Exercise Alleviates Lipid-Induced Insulin Resistance in Human Skeletal Muscle–Signaling Interaction at the Level of TBC1 Domain Family Member 4

Excess lipid availability causes insulin resistance. We examined the effect of acute exercise on lipid-induced insulin resistance and TBC1 domain family member 1/4 (TBCD1/4)-related signaling in skeletal muscle. In eight healthy young male subjects, 1 h of one-legged knee-extensor exercise was followed by 7 h of saline or intralipid infusion. During the last 2 h, a hyperinsulinemic-euglycemic clamp was performed. Femoral catheterization and analysis of biopsy specimens enabled measurements of leg substrate balance and muscle signaling. Each subject underwent two experimental trials, differing only by saline or intralipid infusion. Glucose infusion rate and leg glucose uptake was decreased by intralipid. Insulin-stimulated glucose uptake was higher in the prior exercised leg in the saline and the lipid trials. In the lipid trial, prior exercise normalized insulin-stimulated glucose uptake to the level observed in the resting control leg in the saline trial. Insulin increased phosphorylation of TBC1D1/4. Whereas prior exercise enhanced TBC1D4 phosphorylation on all investigated sites compared with the rested leg, intralipid impaired TBC1D4 S341 phosphorylation compared with the control trial. Intralipid enhanced pyruvate dehydrogenase (PDH) phosphorylation and lactate release. Prior exercise led to higher PDH phosphorylation and activation of glycogen synthase compared with resting control. In conclusion, lipid-induced insulin resistance in skeletal muscle was associated with impaired TBC1D4 S341 and elevated PDH phosphorylation. The prophylactic effect of exercise on lipid-induced insulin resistance may involve augmented TBC1D4 signaling and glycogen synthase activation

The effects of resistance exercise training on macro- and micro-circulatory responses to feeding and skeletal muscle protein anabolism in older men

The anabolic effects of dietary protein on skeletal muscle depend on adequate skeletal muscle perfusion, which is impaired in older people. This study explores fed state muscle microvascular blood flow, protein metabolism and exercise training status in older men. We measured leg blood flow (LBF), muscle microvascular blood volume (MBV) and muscle protein turnover under post-absorptive and fed state (i.v. Glamin to double amino acids, dextrose to sustain glucose ∼7–7.5 mmol l−1) conditions in two groups: 10 untrained men (72.3 ± 1.4 years; body mass index (BMI) 26.5 ± 1.15 kg m2) and 10 men who had undertaken 20 weeks of fully supervised, whole-body resistance exercise training (RET) (72.8 ± 1.4 years; BMI 26.3 ± 1.2 kg m2). We measured LBF by Doppler ultrasound and muscle MBV by contrast-enhanced ultrasound. Muscle protein synthesis (MPS) was measured using [1, 2-13C2] leucine with breakdown (MPB) and net protein balance (NPB) by ring-[D5] phenylalanine tracers. Plasma insulin was measured via ELISA and indices of anabolic signalling (e.g. Akt/mTORC1) by immunoblotting from muscle biopsies. Whereas older untrained men did not exhibit fed-state increases in LBF or MBV, the RET group exhibited increases in both LBF and MBV. Despite our hypothesis that enhanced fed-state circulatory responses would improve anabolic responses to nutrition, fed-state increases in MPS (∼50–75%; P < 0.001) were identical in both groups. Finally, whereas only the RET group exhibited fed-state suppression of MPB (∼–38%; P < 0.05), positive NPB achieved was similar in both groups. We conclude that RET enhances fed-state LBF and MBV and restores nutrient-dependent attenuation of MPB without robustly enhancing MPS or NPB

Enhanced Fatty Acid Oxidation and FATP4 Protein Expression after Endurance Exercise Training in Human Skeletal Muscle

FATP1 and FATP4 appear to be important for the cellular uptake and handling of long chain fatty acids (LCFA). These findings were obtained from loss- or gain of function models. However, reports on FATP1 and FATP4 in human skeletal muscle are limited. Aerobic training enhances lipid oxidation; however, it is not known whether this involves up-regulation of FATP1 and FATP4 protein. Therefore, the aim of this project was to investigate FATP1 and FATP4 protein expression in the vastus lateralis muscle from healthy human individuals and to what extent FATP1 and FATP4 protein expression were affected by an increased fuel demand induced by exercise training. Eight young healthy males were recruited to the study. All subjects were non smokers and did not participate in regular physical activity (<1 time per week for the past 6 months, VO2peak 3.4±0.1 l O2 min−1). Subjects underwent an 8 week supervised aerobic training program. Training induced an increase in VO2peak from 3.4±0.1 to 3.9±0.1 l min−1 and citrate synthase activity was increased from 53.7±2.5 to 80.8±3.7 µmol g−1 min−1. The protein content of FATP4 was increased by 33%, whereas FATP1 protein content was reduced by 20%. Interestingly, at the end of the training intervention a significant association (r2 = 0.74) between the observed increase in skeletal muscle FATP4 protein expression and lipid oxidation during a 120 min endurance exercise test was observed. In conclusion, based on the present findings it is suggested that FATP1 and FATP4 proteins perform different functional roles in handling LCFA in skeletal muscle with FATP4 apparently more important as a lipid transport protein directing lipids for lipid oxidation

A new method to study changes in microvascular blood volume in muscle and adipose tissue: real-time imaging in humans and rat

new method to study changes in microvascular blood volume in muscle and adipose tissue: real-time imaging in humans and rat. A

GLP-1 increases microvascular recruitment but not glucose uptake in human and rat skeletal muscle

The insulinotropic gut hormone glucagon-like peptide-1 (GLP-1) has been proposed to have effects on vascular function and glucose disposal. However, whether GLP-1 is able to increase microvascular recruitment (MVR) in humans has not been investigated. GLP-1 was infused in the femoral artery in overnight-fasted, healthy young men. Microvascular recruitment was measured with real-time contrast-enhanced ultrasound and leg glucose uptake by the leg balance technique with and without inhibition of the insulinotropic response of GLP-1 by coinfusion of octreotide. As a positive control, MVR and leg glucose uptake were measured during a hyperinsulinemic-euglycemic clamp. Infusion of GLP-1 caused a rapid increase (P < 0.05) of 20 ± 12% (mean ± SE) in MVR in the vastus lateralis muscle of the infused leg after 5 min, and MVR further increased to 60 ± 8% above preinfusion levels by 60 min infusion. The effect was slightly slower but similar in magnitude in the noninfused contralateral leg, in which GLP-1 concentration was within the physiological range. Octreotide infusion did not prevent the GLP-1-induced increase in MVR. GLP-1 infusion did not increase leg glucose uptake with or without octreotide coinfusion. GLP-1 infusion in rats increased MVR by 28% (P < 0.05) but did not increase muscle glucose uptake. During the hyperinsulinemic clamp, MVR increased ∼40%, and leg glucose uptake increased 35-fold. It is concluded that GLP-1 in physiological concentrations causes a rapid insulin-independent increase in muscle MVR but does not affect muscle glucose uptake