The role of hypothalamic mTORC1 and adipose tissue mTORC2 in organismal energetics

Mammalian Target of Rapamycin (mTOR) signaling is a crucial regulator of cell growth and metabolism. The highly conserved serine/threonine protein kinase mTOR is activated by growth factors, such as insulin and insulin-like growth factor 1 (IGF-1), nutrients, and it is sensitive to the cellular energy state. mTOR forms two structurally and functionally distinct multi-protein complexes, termed mTOR complex 1 (mTORC1) and mTORC2, through which it regulates distinct downstream processes, such as protein synthesis, lipogenesis, nucleotide biosynthesis, glucose metabolism, autophagy and cell survival. Deregulation of mTOR signaling is often associated with metabolic diseases, such as diabetes, obesity and cancer. While the role of mTOR signaling in regulating growth and metabolism in single cells is quite well understood, the non-cell autonomous effects of mTOR signaling are still only poorly characterized.
In order to better understand the role of tissue-specific mTOR signaling in organismal energetics, we investigated the role of mTORC1 signaling in hypothalamic orexigenic Agrp neurons and its influence on systemic energy homeostasis and feeding behavior. We therefore generated Agrp neuron-specific raptor knockout (Agrp-raptor KO) mice, which display inactive mTORC1 signaling in Agrp neurons. Agrp-raptor KO mice exhibited a decrease in the circadian expression of orexigenic neuropeptides, but they did not show any defects in energy homeostasis and feeding behavior when fed either a standard diet or a high fat diet. Thus, our findings demonstrate that mTORC1 signaling in Agrp neurons is dispensable for the regulation of systemic energy homeostasis and feeding behavior.
In the second part of this thesis, we investigated the role of mTORC2 signaling in adipose tissue with particular focus on how adipose mTORC2 affects non-shivering thermogenesis (NST) and cold-induced glucose uptake. We found that mTORC2 signaling was induced in brown adipocytes by beta-adrenergic stimulation via cAMP, Epac1 and PI3K. Furthermore, mTORC2 signaling in adipose tissue was required for temperature homeostasis, since mice lacking mTORC2 signaling in mature adipocytes (adipose tissue specific rictor knockout (AdRiKO) mice) were hypothermic and sensitive to cold stress. While lipid store mobilization and induction of oxidative metabolism and mitochondrial uncoupling were not impaired in AdRiKO mice, inactivation of mTORC2 signaling in adipose tissue resulted in a significant impairment in cold-induced glucose uptake and glycolysis in brown adipose tissue (BAT). Interestingly, restoration of glucose metabolism in BAT via introduction of a constitutively active form of Akt2 or via over-expression of hexokinase II increased body temperature and improved cold tolerance of AdRiKO mice. Hence, our findings identify mTORC2 in BAT as a novel regulator of systemic energy homeostasis upon NST by affecting cold-induced glucose uptake and glycolysis.
Taken together, this thesis provides new insights into the non-cell autonomous functions of mTORC1 in Agrp neurons and mTORC2 in BAT. These findings could facilitate the development of novel drugs to treat metabolic disorders, such as obesity and diabetes.