2134/11354099.v1 Scott Willis Scott Willis Jack Sargeant Jack Sargeant Tom Yates Tom Yates Toshinari Takamura Toshinari Takamura Hiroaki Takayama Hiroaki Takayama Vinay Gupta Vinay Gupta Emily Brittain Emily Brittain Joe Crawford Joe Crawford Sion Parry Sion Parry Alice Thackray Alice Thackray Veronica Varela-Mato Veronica Varela-Mato David Stensel David Stensel Rachel Woods Rachel Woods Carl Hulston Carl Hulston Guruprasad Aithal Guruprasad Aithal James King James King Acute hyper-energetic, high-fat feeding increases circulating FGF21, LECT2 and fetuin-A in healthy men Loughborough University 2019 Hepatokines overfeeding high-fat diet insulin resistance FGF21 LECT2 Fetuin-B Fetuin-A Selenoprotein-P Nutrition & Dietetics Nutrition and Dietetics Animal Production Food Sciences 2019-12-12 13:09:33 Journal contribution https://repository.lboro.ac.uk/articles/journal_contribution/Acute_hyper-energetic_high-fat_feeding_increases_circulating_FGF21_LECT2_and_fetuin-A_in_healthy_men/11354099 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 which 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: To investigate the influence of hyper-energetic, high-fat feeding on circulating hepatokine concentrations, including the time-course of responses. Methods: In a randomised, crossover design, 12 healthy men (mean ± SD: age, 24 ± 4 years; BMI, 24.1 ± 1.5 kg∙m-2) consumed a seven-day hyper-energetic, 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 three weeks. 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 analysed using two-way repeated-measures ANOVA and subsequent pairwise comparisons. Results: Compared with control, the HE-HFD increased circulating FGF21 at 1 (105%) and 3 d (121%; P  0.040); LECT2 at 3 (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 levels 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.