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.

Mitochondria and Oxidative Stress in the Cardiorenal Metabolic Syndrome

“…In either case, diminished mitochondrial electron transport activity is partly attributable to the reduced mitochondrial content, but the decrement in mitochondrial function is greater than can be solely explained by mitochondrial content. Alterations in mitochondrial number and/or function that lead to decreased capacity to oxidize fat may be the underlying cause of lipid accumulation in skeletal muscle, heart, and liver which are characteristic of impaired insulin metabolic signaling and other functional abnormalities of the CRS [1,6,[22][23][24] . Despite the overwhelming evidence depicting altered expression and activity for the PGC-1 ␣ gene regulatory circuit under pathological conditions such as cardiac hypertrophy and ischemic insult, the jury is still out with regard to whether such changes in PGC-1 ␣ are a cause or a consequence of these pathological changes.…”

Over-nutrition contributes to tubulointerstitial fibrosis by targeting nutrient-sensing kinases

“…It is also known that absorption of fructose in the proximal tubule occurs specifically through the glucose transporter isoform 5 (GLUT5), and metabolism by fructokinase has been localized to the S 3 segment of the proximal tubule, wherein fibrotic pathways occur. 1 Moreover, in response to a high fructose diet, but not a high glucose diet, fructokinase expression has been shown to increase in rodent tissues. Recent work in cultured proximal tubular cells corroborates in vivo work demonstrating that fructose induces production of connective tissue proteins, supporting that a diet high in fructose has a specific effect on eliciting TIF.…”

“…1,2 The presence of obesity is associated with the development of chronic kidney disease (CKD) and also hastens its progression and complicates its management. 2,3 In this context, obesity contributes to altered intra-renal physical forces that result in inappropriate activation of the renal renin-angiotensin system (RAS), leading to proximal tubule sodium (Na + ) retention despite a state of relative volume expansion and associated tubulointerstitial damage.…”

“…2,3 In this context, obesity contributes to altered intra-renal physical forces that result in inappropriate activation of the renal renin-angiotensin system (RAS), leading to proximal tubule sodium (Na + ) retention despite a state of relative volume expansion and associated tubulointerstitial damage. 1 Considering the composition of modern western diets, the impact that over-nutrition has on tubulointerstitial fibrosis (TIF) is an important translational research area. The western diet is composed of a high concentration of fat and refined carbohydrates, such as fructose and the disaccharide sucrose (which is composed of fructose + glucose).…”

Interaction between Adiponectin and Aldosterone

“…In this study, obese Zucker rats were also treated with irbesartan, which prevented cellular adiponectin protein depletion [26] . Conversely, stimulation of the Ang type-2 receptor (AT2R) by Ang II results in beneficial actions, such as vasodilatation and tissue regeneration [28,29] , and, in fact, stimulation of AT2R induces adiponectin expression [26] . These studies point to a potential therapy with ARBs, via PPAR-␥ activation, or AT2R agonists in raising adiponectin levels [30] .…”