Tryptophan restriction partially recapitulates the age-dependent effects of total amino acid restriction on energy balance in diet-induced obese rats.

Moderate dietary protein restriction promotes hyperphagia and thermogenesis; however, little is known of whether these responses are due to restriction of the essential amino acids tryptophan and histidine. Here, we determined whether restriction of tryptophan and histidine alone recapitulate the effects of total amino acid restriction on energy balance, and whether the metabolic responses are age-dependent. We fed young (12 weeks old) and older (29 weeks old) diet-induced obese rats with one of four high-fat diets: control (CON, 100% amino acid requirement), total amino acid restriction (TAA, 67% amino acid restriction), tryptophan restriction (TRP, 67% tryptophan restriction) or histidine restriction (HIS, 67% histidine restriction) for 21 days. Energy balance, hormones, and key markers of hepatic nutrient sensing and brown adipose thermogenesis were measured. We found that TAA increased food intake in both young and older rats, with TRP, but not HIS, transiently simulating the hyperphagia. TAA promoted sympathetically mediated increase in energy expenditure in young rats partly through increased β2-adrenergic and FGF21 signaling in brown fat; TRP partially emulated these responses. TRP and HIS transiently increased fat mass in young rats, and TAA promoted adiposity in older rats. TAA, TRP and HIS increased postprandial FGF21 concentrations in older rats. TAA induced age-dependent differential changes in markers of hepatic amino acid sensing; TRP and HIS partially mimicked these responses. Collectively, restriction of tryptophan, but not histidine, partially recapitulated the age-dependent metabolic effects of total amino acid restriction, in concert with distinct changes in hepatic amino acid sensing and signaling mechanisms.