Overnutrition, mTOR signaling, and cardiovascular diseases

Abstract

The prevalence of obesity and associated medical disorders has increased dramatically in the United States and throughout much of the world in the past decade. Obesity, induced by excess intake of carbohydrates and fats, is a major cause of Type 2 diabetes, hypertension, and the cardiorenal metabolic syndrome. There is emerging evidence that excessive nutrient intake promotes signaling through the mammalian target of rapamycin (mTOR), which, in turn, may lead to alterations of cellular metabolic signaling leading to insulin resistance and obesity-related diseases, such as diabetes, cardiovascular and kidney disease, as well as cancer. While the pivotal role of mTOR signaling in regulating metabolic stress, autophagy, and adaptive immune responses has received increasing attention, there remain many gaps in our knowledge regarding this important nutrient sensor. For example, the precise cellular signaling mechanisms linking excessive nutrient intake and enhanced mTOR signaling with increased cardiovascular and kidney disease, as well as cancer, are not well understood. In this review, we focus on the effects that the interaction between excess intake of nutrients and enhanced mTOR signaling have on the promotion of obesity-associated diseases and potential therapeutic strategies involving targeting mTOR signaling.

Keywords: cardiorenal metabolic syndrome; cardiovascular disease; insulin resistance; mammalian target of rapamycin; obesity.

Fig. 1.

Cross talk of mTOR, ANG II, aldosterone, and nutrients in insulin signaling on cardiovascular cells.

Fig. 2.

Proposed model for the regulation of mTOR signaling in conditions of overnutrition and the cardiorenal syndrome (CRS). Accordingly, mTORC1 relies upon Raptor to enable mTORC1 to bind to its substrates and regulate autophagy, ribosome biogenesis, and protein synthesis. Factors affecting mTORC1 activation include growth factors, amino acids, energy availability, and hypoxia. For example, the mTORC2 pathway can be activated by both insulin and insulin-like growth factor one (IGF1). In turn, mTORC2 regulates cell survival, metabolism, and proliferation by mediating the Akt, PKC, and glucocorticoid-regulated kinase (SGK) signaling.

Fig. 3.

Mechanisms by which mTOR/S6K signaling pathways mediate overnutrition-induced cardiovascular diseases in the cardiorenal syndrome (CRS). Overnutrition activates mTOR/S6K signaling pathways and renin-angiotensin-aldosterone-system (RAAS), resulting in insulin resistance, autophagic inhibition, and reduced T regulatory cell (Treg) differentiation and maturation, which promote endothelial dysfunction, arterial stiffness, hypertension, atherosclerosis, and left ventricular diastolic dysfunction. In contrast, increased ANG type 2 receptor (AT₂R) activation serves as a protective feedback mechanism to balance enhanced mTORC1 signaling. EC, endothelial cell; IRS, insulin receptor substrate; MR, mineralocorticoid receptor.