mTORC1 signaling in energy balance and metabolic disease

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) pathway regulates cellular responses to fuel availability. Recent studies have demonstrated that within the central nervous system, and in particular the hypothalamus, mTORC1 represents an essential intracellular target for the actions of hormones and nutrients on food intake and body weight regulation. By being at the crossroads of a nutrient-hormonal signaling network, mTORC1 also controls important functions in peripheral organs, such as muscle oxidative metabolism, white adipose tissue differentiation and b-cell-dependent insulin secretion. Notably, dysregulation of the mTORC1 pathway has been implicated in the development of obesity and obesity-related conditions, such as type 2 diabetes. This manuscript will therefore review recent progress made in understanding the role of the mTORC1 pathway in the regulation of energy balance and peripheral metabolism. Furthermore, we will critically discuss the potential relevance of this intracellular pathway as a therapeutic target for the treatment of metabolic disease.

Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells

“…Effects of PRAS40 knockdown on mTORC1 signalling Hyperactivation of the mTORC1-signalling pathway has been associated with inhibition of insulin action via p70S6K-mediated serine phosphorylation and subsequent degradation of IRS1 [1][2][3], as well as through stabilisation of the protein levels of an inhibitor of insulin action, GRB10 [9][10][11]. Because some studies have hinted at an inhibitory role for PRAS40 within mTORC1 [16,17], we next evaluated whether the effects of PRAS40-KD could be ascribed to hyperactivation of the mTORC1 pathway.…”

“…The nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of multiple anabolic responses [1][2][3]. Activation of mTORC1 enhances the synthesis of proteins and lipids, promotes mitochondrial function and inhibits autophagy [1][2][3].…”

“…Activation of mTORC1 enhances the synthesis of proteins and lipids, promotes mitochondrial function and inhibits autophagy [1][2][3]. In rodent models of obesity and hyperinsulinaemia, hyperactivation of mTORC1 signalling in liver and skeletal muscle has been linked to inhibition of insulin signalling [4][5][6][7][8].…”

“…In rodent models of obesity and hyperinsulinaemia, hyperactivation of mTORC1 signalling in liver and skeletal muscle has been linked to inhibition of insulin signalling [4][5][6][7][8]. This involves the induction of serine phosphorylation of IRS1 by the mTORC1 substrate p70S6 kinase (p70S6K), which may result in degradation of IRS1 and thereby inhibition of insulin-mediated activation of the phosphatidylinositol-3′-kinase (PI3K)/Akt pathway [1][2][3]. In addition, stabilisation of the levels of growth factor receptor binding protein (GRB)10 by mTORC1-mediated phosphorylation has been linked to inhibition of insulin action at the level of the insulin receptor [9][10][11].…”

In situ characterization of the mTORC1 during adipogenesis of human adult stem cells on chip

“…In fact, rapamycin inhibits the activity and expression of transcription factor peroxisome proliferator-activated receptor γ (PPARγ) (19), which is the master regulator of adipogenesis. The central importance of mTORC1 in the signaling network of adipocyte stem cell differentiation was fueled by the accumulating knowledge that mTORC1 integrates and transduces signals regulating energy balance (20). Specifically, mTORC1 is involved in the regulation of lipolysis (21) and lipogenesis (22), which are the central functions of adipocytes.…”