Leucine, protein intake and macrophage mTOR signalling in heart risk
What it found
In people, a meal with more than about 25 grams of protein switched on a signalling pathway in blood immune cells, and leucine was the amino acid responsible.
In mice, protein above about 22% of energy needs made atherosclerosis worse.
What they found
Studies in people
Protein threshold in people
In people, only meals with protein above about 25 grams, or about 22% of energy, switched on mTOR signalling in blood monocytes. A meal with 16 grams of protein did not.
Animal and lab studies
Leucine is the key amino acid
In lab tests on human macrophages, leucine was by far the strongest activator of mTOR signalling among seven amino acids tested. It activated mTOR nearly 4-fold more than the others.
Leucine threshold in cells
In human macrophages grown in the lab, leucine switched on mTOR signalling and its harmful downstream effects only above a threshold between 100 and 300 micromolar. This range is reached after a high protein meal in people.
Leucine drives the effect in mice
In mice, adding leucine alone to a lower protein diet produced the same mTOR activation as a higher protein diet. This showed that the leucine content explained the whole difference.
Atherosclerosis in mice
In atherosclerosis-prone mice fed Western diets for 8 weeks, the high protein diet increased plaque build-up compared with the low protein diet. The moderate protein diet did not.
Leucine and plaque in mice
Mice given a moderate protein diet with added leucine, or with all amino acids added, had larger plaques. Mice given the same diets but without extra leucine did not.
What the authors conclude
“However, the results from our studies suggest high protein intake should be considered with caution.”
Also in their conclusions
- They say high protein intake should be considered with caution.
- They call for additional mechanistic and prospective clinical trials that evaluate the effects of different amounts and types of dietary proteins on the atherogenic signalling pathways they identified.
- Their findings suggest current dietary guidelines concerning protein intake may need to be revised.
How it was done
High protein intake is common in Western countries and is often promoted as part of a healthy lifestyle, but amino acid driven mTOR signalling in macrophages has been linked to ischaemic heart disease. The authors wanted to find out whether the same mechanism works in people and which amino acid is responsible.
Two clinical studies gave meals with different protein amounts to 14 and 9 overweight participants, and measured amino acids in their blood and mTOR signalling in their monocytes. They also fed mice diets with different protein and leucine levels for 8 weeks and looked at plaque build-up in their aortas.
What it can’t tell you
- The human part of this study was small and short term, so it can show that protein and leucine switch on a signalling pathway in blood cells, but it cannot show whether that leads to heart disease in people.
- The atherosclerosis results come from mice, so they cannot prove that high protein or leucine intake causes plaque build-up in people.
- The study did not include older adults or people with existing heart disease, so the results may not apply to them.
Who paid
- Funding
- Funded by NIDDK NIH HHS; NHLBI NIH HHS; BLRD VA; NCATS NIH HHS (from the PubMed record).
- Conflicts
- DECLARATION OF INTEREST STATEMENT. All authors declare they have no conflict of interest.
- Authors work at
- University of Pittsburgh School of Medicine and UPMC, USA; Pittsburgh VA Medical Center, USA; Washington University School of Medicine, USA
The paper
- Title
- Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk
- Type
- Study
- Evidence
- Studies in people · animals · lab
- Summarised from
- Full text
- Cite
- Zhang X, Kapoor D, Jeong SJ, et al (2024). Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk. Nature metabolism. doi:10.1038/s42255-024-00984-2Free full textPubMed 38409323DOI
Summary written 26 Sep 2026. Check it against the paper before it changes what you eat. How we summarise papers · Report an error