Hypothalamic roles of mTOR complex I: integration of nutrient and hormone signals to regulate energy homeostasis

Abstract

Mammalian or mechanistic target of rapamycin (mTOR) senses nutrient, energy, and hormone signals to regulate metabolism and energy homeostasis. mTOR activity in the hypothalamus, which is associated with changes in energy status, plays a critical role in the regulation of food intake and body weight. mTOR integrates signals from a variety of "energy balancing" hormones such as leptin, insulin, and ghrelin, although its action varies in response to these distinct hormonal stimuli as well as across different neuronal populations. In this review, we summarize and highlight recent findings regarding the functional roles of mTOR complex 1 (mTORC1) in the hypothalamus specifically in its regulation of body weight, energy expenditure, and glucose/lipid homeostasis. Understanding the role and underlying mechanisms behind mTOR-related signaling in the brain will undoubtedly pave new avenues for future therapeutics and interventions that can combat obesity, insulin resistance, and diabetes.

Keywords: energy homeostasis; hormones; hypothalamus; mTOR; nutrients.

Fig. 1.

Mammalian or mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. The mTORC1 activate can be induced by hormones and growth factors (e.g., insulin, IGF-I, etc.) through a PI3K/Akt-mediated pathway, and by amino acids (mainly leucine) through Rag GTPases. On the other hand, activation of mTORC1 can be suppressed by rapamycin, mTORC1 downstream substrate Grb10, and energy deprivation-induced AMPK activation. Activated mTORC1 subsequently activates downstream S6K or inhibits 4E-BP1, resulting in protein translation, cellular proliferation, autophagy, or lipid metabolism.

Fig. 2.

Schematic model for hypothalamic mTORC1 in the regulation of whole body energy homeostasis. Current evidence shows that, in response to various hormone and nutrient signals, mTORC1 activities can be detected in the neurons of the arcuate nucleus (ARC) and ventromedial (VMH), lateral (LH), and paraventricular (PVH) hypothalamus. In the proopiomelanocortin (POMC) and agouti-reated peptide (AgRP) neurons of hypothalamic ARC, the bidirectional negative regulation between mTORC1and AMPK may regulate activity of neurons that project to and act on distinct downstream neuron populations to suppress or increase food intake as well as insulin sensitivity and glucose homeostasis in the liver and muscle. mTORC1 in hypothalamic neurons may also integrate energy signals to regulate energy expenditure by modulating sympathetic nervous system (SNS) firing to the brown adipose tissue (BAT) and white adipose tissue (WAT). Solid lines and arrows indicate the known pathways; dashed lines and arrows indicate the unknown pathways.