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Background: Hepatokines such as fibroblast growth factor 21 (FGF21), leukocyte cell-derived chemotaxin 2 (LECT2), fetuin-A, fetuin-B, and selenoprotein P (SeP) are liver-derived proteins that are modulated by chronic energy status and metabolic disease. Emerging data from rodent and cell models indicate that hepatokines may be sensitive to acute nutritional manipulation; however, data in humans are lacking., Objective: The aim was to investigate the influence of hyperenergetic, high-fat feeding on circulating hepatokine concentrations, including the time course of responses., Methods: In a randomized, crossover design, 12 healthy men [mean ± SD: age, 24 ± 4 y; BMI (kg/m2), 24.1 ± 1.5] consumed a 7-d hyperenergetic, high-fat diet [HE-HFD; +50% energy, 65% total energy as fat (32% saturated, 26% monounsaturated, 8% polyunsaturated)] and control diet (36% total energy as fat), separated by 3 wk. Whole-body insulin sensitivity was assessed before and after each diet using oral-glucose-tolerance tests. Fasting plasma concentrations of FGF21 (primary outcome), LECT2, fetuin-A, fetuin-B, SeP, and related metabolites were measured after 1, 3, and 7 d of each diet. Hepatokine responses were analyzed using 2-factor repeated-measures ANOVA and subsequent pairwise comparisons., Results: Compared with the control, the HE-HFD increased circulating FGF21 at 1 d (105%) and 3 d (121%; P ≤ 0.040), LECT2 at 3 d (17%) and 7 d (32%; P ≤ 0.004), and fetuin-A at 7 d (7%; P = 0.028). Plasma fetuin-B and SeP did not respond to the HE-HFD. Whole-body insulin sensitivity was reduced after the HE-HFD by 31% (P = 0.021)., Conclusions: Acute high-fat overfeeding augments circulating concentrations of FGF21, LECT2, and fetuin-A in healthy men. Notably, the time course of response varies between proteins and is transient for FGF21. These findings provide further insight into the nutritional regulation of hepatokines in humans and their interaction with metabolic homeostasis. This study was registered at clinicaltrials.gov as NCT03369145., (Copyright © The Author(s) 2020.)

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., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Intermittent energy restriction (IER) involves short periods of severe energy restriction interspersed with periods of adequate energy intake, and can induce weight loss. Insulin sensitivity is impaired by short-term, complete energy restriction, but the effects of IER are not well known. In randomised order, fourteen lean men (age: 25 (sd 4) years; BMI: 24 (sd 2) kg/m2; body fat: 17 (4) %) consumed 24-h diets providing 100 % (10 441 (sd 812) kJ; energy balance (EB)) or 25 % (2622 (sd 204) kJ; energy restriction (ER)) of estimated energy requirements, followed by an oral glucose tolerance test (OGTT; 75 g of glucose drink) after fasting overnight. Plasma/serum glucose, insulin, NEFA, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and fibroblast growth factor 21 (FGF21) were assessed before and after (0 h) each 24-h dietary intervention, and throughout the 2-h OGTT. Homoeostatic model assessment of insulin resistance (HOMA2-IR) assessed the fasted response and incremental AUC (iAUC) or total AUC (tAUC) were calculated during the OGTT. At 0 h, HOMA2-IR was 23 % lower after ER compared with EB (P<0·05). During the OGTT, serum glucose iAUC (P<0·001), serum insulin iAUC (P<0·05) and plasma NEFA tAUC (P<0·01) were greater during ER, but GLP-1 (P=0·161), GIP (P=0·473) and FGF21 (P=0·497) tAUC were similar between trials. These results demonstrate that severe energy restriction acutely impairs postprandial glycaemic control in lean men, despite reducing HOMA2-IR. Chronic intervention studies are required to elucidate the long-term effects of IER on indices of insulin sensitivity, particularly in the absence of weight loss.