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.
FUNDING. The research was supported by UK Medical Research Council grants MR/P011705/1, MC_
UP_A090_1006 and MR/P01836X/1. JLG is supported by the Imperial Biomedical Research Centre,
National Institute for Health Research (NIHR).