The Impact of Overnutrition on Insulin Metabolic Signaling in the Heart and the Kidney

Abstract

Overnutrition characterized by overconsumption of food rich in fat and carbohydrates is a significant contributor to hypertension, type 2 diabetes, and the cardiorenal syndrome. Overnutrition activates the renin-angiotensin-aldosterone system (RAAS) and causes chronic exposure of cardiovascular and renal tissue to increased circulating nutrients, insulin (INS), and angiotensin II (ANG II). Emerging evidence suggests that overnutrition, aldosterone, and ANG II promote INS resistance, a chronic condition that underlies these co-morbidities, through activation of the mammalian target of the rapamycin (mTOR)/S6 kinase 1 (S6K1) signaling pathway in cardiovascular tissue and the kidney. However, a novel ANG II type 2 receptor (AT2R)-mediated cross talk between the RAAS and mTOR pathways ameliorates overnutrition-induced activation of mTOR/S6K1 signaling in cardiovascular tissue of rats, mice, and humans and confers cardioprotection.

Keywords: Hypertension; Insulin metabolic signaling; Overnutrition; Progressive kidney disease.

Fig. 1

Wild-type (WT) and S6K1^−/– mice after 6 months of high-fat diet. Reprinted with permission from Macmillan Publishers Ltd. (Nature[16], Copyright 2004).

Fig. 2

Function/metabolic effects of INS in cardiac muscle cells.

Fig. 3

Micro-PET determination of INS/glucose uptake [Cooper, Am J Physiol Heart Circ Physiol, 2007; American Physiological Society, used with permission].

Fig. 4

Up-regulation of the AT₂R may be a protective feedback mechanism to regulate excess mTOR/S6K1 signaling in cardiomyocytes. Excess nutrients (due to overnutrition) or chronic exposure to ANG II/INS can activate mTOR/S6K1 signaling, increase translation, induce myocardial remodeling and left-ventricular hypertrophy, and up-regulate AT₂R protein levels. AT₂R can be activated by redirected ANG II (due to ANG receptor blocker-mediated inhibition of ANG II binding to the AT₁R) or AT₂R agonist. AT₂R signaling inhibits phosphorylation of RPS6 and regulates excess mTOR/S6K1 signaling and subsequent cardiac pathology.

Fig. 5

Proposed mechanism by which ANG II promotes an exaggerated response on mTOR in the kidney with downstream activation of S6K1 and associated tubulointerstitial fibrosis. FTS-1 = Fibroblast transcription site-1; FSP1 = fibroblast secretory protein-1.