Nat. Metab. 2, 110–125 (2020)

High-protein diets induce weight loss. In Nature Metabolism, Razani and colleagues show that hyperlipidemia-prone Apo2–/– mice on a high-protein Western diet (HPWD; 43% fat, 46% protein) develop more atherosclerosis, with more apoptosis and necrosis in the plaques, than mice on a ‘standard’ Western diet (42% fat, 15% protein), despite a reduction in whole-body fat. HPWD increases the amount of amino acids, especially leucine, in macrophages from the sclerotic aortas and increases the activation of the amino acid sensor mTORC1 in these cells. Macrophage-specific deletion of the mTORC1 component Raptor reduces atherosclerosis and plaque complexity in Apo2–/– mice on a HPWD. In cultured macrophages, leucine treatment decreases autophagy of mitochondria in a Raptor-dependent manner, while deletion of the autophagy regulator Atg5 abrogates the protective phenotype of Raptor deficiency in Apo2–/– mice on a HPWD. Thus, high levels of protein can worsen high-fat-diet-induced atherosclerosis, despite the weight loss benefits.