Preprint: cystine deficiency altered metabolism in mice lacking CTH, a cysteine-synthesizing enzyme
Preprint: cystine deficiency altered metabolism in mice lacking CTH, a cysteine-synthesizing enzyme
The authors dissected the familiar methionine-restricted diet into its two components: methionine and cystine, the form of cysteine present in feed. In a short-term comparison, cystine-free diets raised FGF21 in mice lacking CTH, while a diet containing normal cystine kept this hormone close to control levels. Ten months of cystine reduction produced different outcomes in mice with functional CTH and in animals that lacked the enzyme.
On September 9 a preprint appeared on bioRxiv examining which of the two amino acids drives the metabolic response in these diets. In a classic methionine-restricted diet, both methionine and cystine are typically reduced at the same time, so the traditional name conceals two simultaneous dietary changes.
When dietary cysteine is scarce, the body can assemble it from intermediates of methionine metabolism; this requires the enzyme CTH. The authors knocked out the Cth gene in mice to eliminate this backup pathway and compared three diets: reduced methionine, no cystine, and reduction of both. Over four days, the diet with reduced methionine but a normal amount of cystine kept body weight in CTH-intact mice close to control and did not raise FGF21 in either this line or in CTH-knockout mice. FGF21 is a hormone the liver secretes under nutritional stress. In CTH-knockout mice, cystine-free diets reduced fat mass, raised FGF21, and gave subcutaneous adipose tissue properties of a tissue that expends energy to generate heat. In this model, the metabolic response appeared when the diet was deprived of cystine.
Complete removal of cystine in CTH-knockout mice rapidly reduced body weight by roughly 30%, so for the long-term experiment the amount was cut by 70% instead. In aging CTH-knockout mice, this diet over ten months restrained age-related weight gain and loss of lean mass, improved glucose tolerance, and in males increased grip strength. In animals with functional CTH, the same diet kept weight gain, coordination, grip strength, and glucose tolerance at control levels; in males, however, fat mass increased.
In the roundworm Caenorhabditis elegans, a cth-1 mutation that eliminated the ability to synthesize cysteine extended lifespan on a standard diet. In a separate heat-stress experiment, worms were fed bacteria unable to synthesize either cysteine or methionine: both conditions improved survival, but cysteine deficiency had a stronger effect. When cysteine was restored to the diet, survival returned to control levels.