A randomized 3-way crossover study indicates that high-protein feeding induces de novo lipogenesis in healthy humans

Evelina Charidemou, Tom Ashmore, Xuefei Li, Ben D. McNally, James A. West, Sonia Liggi, Matthew Harvey, Elise Orford, Julian L. Griffin

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26 Citations (Scopus)


BACKGROUND. Dietary changes have led to the growing prevalence of type 2 diabetes and nonalcoholic fatty liver disease. A hallmark of both disorders is hepatic lipid accumulation, derived in part from increased de novo lipogenesis. Despite the popularity of high-protein diets for weight loss, the effect of dietary protein on de novo lipogenesis is poorly studied. We aimed to characterize the effect of dietary protein on de novo lipid synthesis. METHODS. We use a 3-way crossover interventional study in healthy males to determine the effect of high-protein feeding on de novo lipogenesis, combined with in vitro models to determine the lipogenic effects of specific amino acids. The primary outcome was a change in de novo lipogenesis–associated triglycerides in response to protein feeding. RESULTS. We demonstrate that high-protein feeding, rich in glutamate, increases de novo lipogenesis–associated triglycerides in plasma (1.5-fold compared with control; P < 0.0001) and liver-derived very low-density lipoprotein particles (1.8-fold; P < 0.0001) in samples from human subjects (n = 9 per group). In hepatocytes, we show that glutamate-derived carbon is incorporated into triglycerides via palmitate. In addition, supplementation with glutamate, glutamine, and leucine, but not lysine, increased triglyceride synthesis and decreased glucose uptake. Glutamate, glutamine, and leucine increased activation of protein kinase B, suggesting that induction of de novo lipogenesis occurs via the insulin signaling cascade. CONCLUSION. These findings provide mechanistic insight into how select amino acids induce de novo lipogenesis and insulin resistance, suggesting that high-protein feeding to tackle diabetes and obesity requires greater consideration.
Original languageEnglish
Article numbere124819
Pages (from-to)1-22
Number of pages22
JournalJCI Insight
Issue number12
Early online date30 May 2019
Publication statusPublished - 20 Jun 2019

Bibliographical note

We thank Sara Wassell for assistance during study days, Michelle Venables and Les Bluck for study design, as well as Sumantra Ray for expert technical support in the human study. The research was supported by grants MR/P011705/1, MC_UP_A090_1006 and MR/P01836X/1 from the UK Medical Research Council. JLG is supported by the Imperial Biomedical Research Centre, NIHR.


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