Obesity and Kidney Disease

Differential Effects of Obesity on Adipose Tissue and Kidney Inflammation and Fibrosis

Anne-Emilie Declèves; Kumar Sharma


Curr Opin Nephrol Hypertens. 2015;24(1):28-36. 

In This Article

Insulin Resistance in Adipose Tissue and Kidney

As already mentioned, adipose tissue is not a passive energy storage, but an active tissue able to produce a number of hormonally and metabolic factor called adipokines. In a healthy state, there is a balance between these adipokines in order to maintain body energy homeostasis. In contrast, during obesity, an excessive caloric intake contributes to adiposity and initiates a cascade of cellular events that leads to progressive obesity-associated diseases.[10–12] In the obese rodent and human, adipose tissue has been demonstrated to be inflamed and to likely contribute to the development of insulin resistance.[11,13] Insulin resistance is a key metabolic risk promoting chronic kidney disease (CKD).[14] Many studies have demonstrated the association between insulin resistance/hyperinsulinemia and CKD. This association was even shown to exist before the onset of diabetes.[15,16] It is known that insulin mediates the mesangial cell growth and modulates the glomerular hemodynamics by stimulating the glomerular cells in response to ANG II.[17,18] Moreover, Cusumano et al.[19] demonstrated a link between hyperinsulinemia and glomerular hypertrophy. In the kidney, insulin promotes its effects by binding and activating its two receptors insulin response substrate 1 (IRS1)/IRS2, which in turn activate molecular signaling pathways to promote, for example, glucose uptake, cell growth, or nitric oxide production.[20] In pathological conditions such as obesity, abnormal modulations of the insulin receptors and signaling have been shown. These alterations were associated with increased levels of many factors such as TNF-α (reported below), ANG II, endothelin, free fatty acids (FFAs), oxidative stress, and amino acids (reviewed in[21]). More recently, Welsh et al.[22] demonstrated the critical role of insulin signaling in normal kidney function, particularly in podocytes. In that study, transgenic mice missing insulin receptors in their podocytes were generated. These mice showed normal glomerular histological features at an early age (3 weeks old). However, later, starting at 5 weeks old, loss of podocyte foot process structures, clear evidence of albuminuria, and increased glomerular matrix were observed.[22] Even though this study demonstrated clear evidence of the role of insulin in glomerular kidney function, which is the chicken and which is the egg in the development of CKD is still elusive. It might be worth admitting that several mechanisms involved in obesity-related organ dysfunction are concomitant. As previously mentioned, insulin resistance is linked to increased levels of ANG II, whereas renal damage progression in obesity is also associated with increased ANG II level. Indeed, ANG II is a crucial mediator in the progression of obesity and diabetes-related kidney disease.[23–25] ANG II participates in hyperfiltration and glomerulosclerosis through hemodynamic and nonhemodynamic effects.[26–31] Many works have demonstrated that insulin can attenuate the effect of ANG II on the vasculature and vice versa.[32–35] Insulin induces vascular relaxation by promoting nitric oxide production through the phosphatidylinositol 3-kinase (PI3K)–protein kinase B (Akt) signaling pathway, whereas ANG II has vasoconstriction effects on the vasculature. The inhibitory effects of ANG II on the insulin action may be mediated by the production of reactive oxygen species (ROS).[33,36,37] In turn, ROS act to induce inflammatory cytokines such as MCP-1 or TNF-α which can then impair the PI3K–Akt pathway of the insulin signaling,[38–41] leading to insulin resistance.

FFAs might also contribute to insulin resistance. Increased FFA flux from overwhelmed adipose tissue to nonadipose organs leads to the increase of lipid accumulation in ectopic organs such as the liver, muscle, and also the kidney. This promotes the impairment of glucose metabolism and insulin sensitivity in these organs. Lennon et al.[42] demonstrated that the exposition of immortalized human podocytes to the FFA palmitate blocked the effect of insulin on glucose uptake. This adverse effect was associated with an increase of ceramide, a highly lipotoxic molecule, that has been reported to play a role in insulin resistance.[43] In addition, dysregulation of the insulin receptor, as well as the impairment of glucose glucose transporter 4 transporter to the cell surface, were observed.[42] We have previously shown that lipid accumulation occurs in the kidney after a high-fat caloric exposure, leading to insulin resistance associated with impairment of tubular cell structure and inflammation as well as fibrosis. In that study, the central energy sensor, AMP-activated protein kinase (AMPK), appears to play a beneficial role.[44]

Thus, there is a strong evidence in support of the important role of insulin resistance as a driver of renal disease. However, whether insulin resistance is critical to the progression of the disease is still under debate and needs more investigation.