Quantification of the effect of amino acids on an integrated mTOR and insulin signaling pathway

Abstract

Integration of nutrient and growth factor signaling pathways through mammalian TOR (mTOR) plays a central role in the regulation of cell growth. However, the mechanism of integration of these two signals in mTOR activation is largely unknown. Moreover, the nutritional input involving amino acids is yet to be characterized. Excess amino acid conditions, such as in obesity and protein-rich diets, are known to regulate insulin signaling through mTOR activation resulting in insulin resistance. Here, we develop a dynamic model to identify the regulatory role of amino acids in mTOR activation and to study its effect on insulin signaling in relation to multiple feedback loops present in the insulin signaling pathway. The analysis revealed that amino acids bring about multiple effects in the regulation of mTOR that might be represented by a single mechanism. Insulin signaling was demonstrated to operate between two extreme conditions involving tumor growth and insulin resistance, with multiple feedback loops tightly controlling and maintaining a robust insulin response. The state of insulin resistance was characterized by a decrease in the time lag or an increase in the magnitude of the negative feedback loop facilitated through perturbations such as excess input of amino acids. Such a condition disturbs the delicate balance between positive and negative feedback loops to yield an insulin-resistant state.

A systems study reveals concurrent activation of AMPK and mTOR by amino acids

“…There are several other systems modelling studies of the mTOR network (for example, Jain and Bhalla, 2009; ref. 41), but only one has attempted to model multiple aa inputs42 and found that a single input via mTORC1 was sufficient to explain a set of reported observations. Using time-course data only, our computational strategy for exploring alternative aa inputs allowed us to comprehensively cover model structures that showed an improvement to the canonical single aa-mTORC1 input.…”

Diets rich in starch improve the efficiency of amino acids use by the mammary gland in lactating Jersey cows

“…Indeed, although AA availability is the main limiting factor for milk protein synthesis (Bequette et al, 1998), the production of milk protein has also been shown to dramatically increase through endocrine signals only (McGuire et al, 1995;Griinari et al, 1997;Mackle et al, 2000). However, AA supply together with endocrine signals prompted by glucogenic nutrients seem to be highly interconnected in pathways involved in milk protein synthesis (Burgos et al, 2010;Bionaz and Loor, 2011), and some interactions between these stimuli have been previously documented at the molecular level (Vinod and Venkatesh, 2009;Burgos et al, 2010;Rius et al, 2010). Hence, a need to assess the effect of CHO on mammary metabolism at different protein intakes levels exists.…”

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

“…However, the lack of time-resolved data is problematic since the authors claim that they describe the dynamics of the insulin signaling network. Despite the shortcomings of the Sedaghat model, it has been extensively used and also further developed [143][144][145] and analyzed [146]. Recently, another more theoretical attempt at constructing a detailed model of insulin signaling was published [141].…”