Inflammation Related to Obesity in Adipose Tissue and Kidney
As previously mentioned, insulin resistance is a common adverse process related to the development of obesity and its related metabolic syndrome.[11,45,46] Rapid expansion of adipose tissue results in an aberrant production of proinflammatory adipokines that leads to a state of low-grade inflammation. Evidence of macrophage infiltration into adipose tissue has been reported in obese human and experimental models.[48–50] Among the large number of proinflammatory adipokines, TNF-α has been recognized as one of the most critical mediators of adipose tissue inflammation and insulin resistance development. It has been demonstrated that TNF-α knockout mice were protected from obesity-induced insulin resistance. In patients, the correlation between circulating TNF-α and insulin resistance has also been reported.[51,52] In an experimental model of obesity using a co-culture system, Suganami et al. postulated a paracrine loop involving FFAs and TNF-α between macrophages and adipocytes, generating a vicious cycle that maintains or even increases the chronic inflammatory state. An increased TNF-α level is usually associated with increased production of MCP-1, a chemokine produced by adipocytes and macrophages, which has been reported to be increased with excessive fat storage.[54,55] Both these proinflammatory adipokines are upregulated, whereas anti-inflammatory adipokines such as adiponectin are downregulated. MCP-1 is also now recognized as a key mediator of adipose tissue inflammation and insulin resistance development. Many studies have demonstrated its effects on macrophage recruitment into the adipose tissue.[56,57] In contrast, deficiency of MCP-1 or its receptor was shown to induce a reduction of macrophage infiltration in the adipose tissue and to improve insulin resistance in the obese experimental models.[56,58]
It has been clearly demonstrated that adiponectin (also called Acrp30) is one of the most abundant adipokines produced by the adipocytes and is downregulated in obesity.[59–62] Adiponectin is an insulin-sensitizing factor and has anti-inflammatory effects. Reduced plasma adiponectin level has been inversely correlated with insulin resistance in obese patients.[63,64] The role of adiponectin in obesity-related disease has been extensively investigated using transgenic mice or pharmacological globular Acrp30 compound.[65–70] Although a deficiency in adiponectin was associated with insulin resistance, globular adiponectin transgenic mice, or treatment with exogenous gAcrp30, showed a beneficial effect regarding insulin resistance and glucose tolerance.[65,66,68] Adiponectin is an important regulator of lipid and glucose metabolism and a key link between TNF-α, MCP-1, and insulin resistance. As already noted, TNF-α plays a critical role in the induction of insulin resistance as suggested by the protection of TNF-α knockout mice against insulin resistance induction.[39,40] The infusion of TNF-α in rats was reported to induce rapid changes in adipocyte gene expression, favoring proinflammatory cytokine production along with a reduction of adiponectin. These changes were associated with the increase of lipolysis, leading to the rise of plasma FFA and the induction of insulin resistance.
Although increased TNF-α level is usually associated with a decreased adiponectin level, a potential role of AMPK has also been considered in the insulin resistance process. The effects of adiponectin are tightly linked to the activation of AMPK.[60,72] AMPK is a ubiquitous heterotrimeric enzyme that is considered to be the master energy sensor in all eukaryotic cells. As a cellular energy sensor, its activity is highly linked to the change in the intracellular AMP/ATP ratio. Increase of the AMP/ATP ratio stimulates AMPK activity, whereas a reduction of the AMPK/ATP ratio results in its inhibition. Hence, its activation results in a change of energy utilization involving the stimulation of energy-producing pathways and reduced energy-requiring cell processes in order to restore energy balance. Metabolic stress conditions such as obesity modulate the activity of AMPK. Steinberg et al. demonstrated that TNF-α could suppress AMPK activation through the TNF receptor 1 (TNFR1), suppressing fatty acid (FA) oxidation and promoting insulin resistance in skeletal muscle. This negative effect of TNF-α on AMPK activation was prevented in transgenic TNFR1 and TNFR2 knockout mice or after treatment with exogenous TNF-α neutralizing antibody. The mechanisms involved in the inhibition of AMPK activation by TNF-α are still unclear. However, Steinberg et al. showed that this process might involve the upregulation of protein phosphatase 2C (PP2C) by TNF-α, with the subsequent suppression of AMPK activation. Hence, TNF-α treatment showed a decrease of AMPK activation along with an elevated PP2C activity in wildtype mice but not in the transgenic ob/ob TNFR–/– mice. This change was associated with a reduction of FA oxidation and an increase of diacylglycerol (DAG) and triacylglycerol (TAG) in the skeletal muscle. DAG is known to be involved in insulin resistance through the activation of the protein kinase C. In contrast, the activation of AMPK was shown to reduce TNF-α action and positively regulate insulin signaling. Shibata et al. showed that AMPK activation by 5-aminoimidazole-4-carboxamide-1-D-ribofuranoside (AICAR), a potent AMPK activator, could inhibit the effect of TNF-α to induce insulin resistance in 3T3L1 adipocytes. Similarly, in human adipose tissue, AMPK activation reduced the level of TNF-α and increased adiponectin level, improving insulin sensitivity. A similar link has been observed regarding AMPK activation and MCP-1 level. An increased level of MCP-1 by human adipocytes was accompanied by a decrease in adiponectin and AMPK activation, which was prevented by treatment with AICAR.
Although adipose tissue has a clear role in obesity, excessive fat deposition has been also reported to induce lipid accumulation in ectopic sites, especially in liver and muscle. Indeed, nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease associated with insulin resistance. In muscle, lipid accumulation has been related to impaired glucose and insulin metabolism as well as mitochondrial function.[82,83,84,85,86] Although the impact of lipid accumulation in the liver and muscle has been widely investigated, less is known regarding other organs such as the kidney. More recently, studies showing ectopic lipid deposition in kidney have emerged, suggesting the role of fat accumulation in the development of CKD.[44,87–89] It has been reported that the adipose tissue of patients with ESRD exhibits higher amounts of proinflammatory cytokines TNF-α and MCP-1, and an increase in macrophage infiltration. Even though it is well-known that patients with renal disease are more susceptible to develop insulin resistance,[91,92] the direct link between adipose tissue dysfunction, insulin resistance, and kidney disease in obesity is becoming more apparent. One likely explanation is that the decreased adiponectin level associated with reduced insulin sensitivity leads to the increase of proinflammatory process in the kidney. Studies have shown the correlation between elevated expressions of proinflammatory cytokines or chemokine (TNF-α, IL-6, IL-1β, and MCP-1) in adipose tissue with renal inflammation (increased TNF-α, MCP-1, IL-6, and infiltrated macrophages) in the rodent models of obesity.[94,95]
We have previously identified that low levels of circulating adiponectin correlate with low-grade albuminuria in obese African Americans and that the adiponectin knockout mouse developed low-grade albuminuria without obesity. Adiponectin was found to have a protective effect on podocytes, primarily via stimulating the enzyme AMPK. In another study, we demonstrated an early reduction of AMPK activity in a model of high-fat diet (HFD)-induced kidney disease. This was associated with reduced plasma adiponectin level, increased renal inflammation, and increased plasma insulin level. Interestingly, the decrease in AMPK activity was associated with the upregulation of MCP-1. Indeed, renal MCP1 was increased as early as 1 week after the HFD at the gene expression and protein level in the renal tissue and in the urine. MCP-1 and its receptor C-C chemokine receptor 2 (CCR2) has been receiving greater recognition for its role in mediating CKD.[96,97] MCP-1 was found to regulate nephrin expression via CCR2 in human podocytes, and mice lacking MCP-1 had resistance to diabetes-induced albuminuria. Studies in the mesangial cells demonstrated a marked stimulation of MCP-1 secretion by palmitate, suggesting that exposure of circulating saturated FAs, such as palmitate, may be a trigger of MCP-1 production in the setting of HFD and obesity. We also showed that the early increase in MCP-1 could contribute to the subsequent recruitment of macrophages and enhancement of proinflammatory factors such as TNF-α. Importantly, we demonstrated that AMPK activation is able to completely inhibit MCP-1 stimulation both in vivo with HFD and in vitro in response to palmitic acid.
The mechanism by which AMPK activation inhibits MCP-1 in renal cells is unclear, but is likely because of the inhibition of nuclear factor kappa B (NF-κB) activation. AMPK has been recently shown to affect the proteolysis of inhibitory kappa B in endothelial cells and regulate NF-κB. AMPK also seems to play a prominent role in regulating macrophage infiltration and activation. The overall numbers of macrophages infiltrating the kidney with HFD was completely normalized with AMPK activation. A role for AMPK in regulating macrophage activation has been highlighted recently. The use of metformin, another AMPK activator, showed similar data in a murine model of HFD-induced renal injury. In another study, activation of AMPK by metformin prevented the decrease of urinary sodium excretion and increased blood pressure (BP) induced by ANG II. In turn, low adiponectin level has been reported to contribute to the development of obesity-related hypertension. Finally, we showed that AMPK activation is a key regulator of lipid storage in kidney. Indeed, our results revealed a significant lipid accumulation in vacuolated proximal tubular cells along with impaired brush border, increased nitrotyrosine and nadph oxidase 4 (Nox4) levels, suggesting tubular dysfunction. These changes were prevented with AMPK activation. The regulation of Nox4 and NADPH oxidase activity has now been demonstrated in the podocytes and proximal tubular cells. We previously found that high-glucose-induced stimulation of Nox4 can be blocked by adiponectin or AMPK activation. Similarly, NADPH oxidase activity by ANG II was completely blocked by adiponectin and AMPK activators. The regulation of Nox by AMPK is also likely because of its effects on NF-κB activation.
Curr Opin Nephrol Hypertens. 2015;24(1):28-36. © 2015 Lippincott Williams & Wilkins