The growing epidemic of obesity, particularly in the western world, is a major factor in reducing the expected life-expectancy, and is an added serious health and economic burden. The epidemic of obesity is related to the combination of sedentary lifestyle, usually associated with a high caloric intake and a lack of exercise. A possible scenario is that when the energy intake exceeds the storage capacity of white adipose tissue (WAT), ectopic lipid accumulation in ectopic organs is induced , promoting metabolic disturbances such as insulin resistance and alteration in the control of glucose and lipid metabolisms, contributing to hyperglycemia, dyslipidemia, hypertension, insulin resistance, glucose intolerance, and atherosclerosis . Moreover, central obesity is a major risk factor for diabetes and hypertension, which together account for about 70% of all cases of end-stage renal disease (ESRD) . However, a full understanding of the mechanisms involved in progressive renal disease is still absent.
WAT is not only a simple fat storage organ, but also now recognized as a dynamic tissue involved in the production of adipokines such as leptin, adiponectin, tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), transforming growth factor-beta (TGF-β), and angiotensin II (ANG II) [4,5]. The balance between these adipokines allows the adipose tissue to regulate the appetite, food intake, glucose clearance, and energy expenditure. The perturbation of this balance during obesity promotes a proinflammatory environment and leads to insulin resistance. Obesity-related kidney disease is associated with renal hemodynamic abnormalities, endothelial and podocyte dysfunction, glomerular basement membrane thickening and mesangial expansion, tubular atrophy, interstitial fibrosis, and a progressive decrease in renal function [increased albuminuria and decreased glomerular filtration rate (GFR)], leading to ESRD [6–9]. Assuming that common factors exist between obesity-induced adipose tissue and kidney disease, here we will discuss the potential cross-talk between both tissues during obesity.
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) . 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. 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 . 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 ). More recently, Welsh et al. 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 . 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. 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 . In addition, dysregulation of the insulin receptor, as well as the impairment of glucose glucose transporter 4 transporter to the cell surface, were observed . 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.
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.[78▪▪] 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 [93▪▪]. 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 [44▪]. 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 [44▪]. 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 .
ADIPOSE AND KIDNEY MATRIX ACCUMULATION
Hypoxia-inducible factor 1α (HIF-1α), a key mediator of hypoxia, has been also reported to act in adipose tissue fibrosis. As mentioned previously, an excessive metabolic challenge in adipose tissue induces a hypoxia in the tissue that leads to the initiation of inflammation and, in turn, to fibrosis. Halberg et al. demonstrated that local adipose tissue hypoxia results in the stabilization of the transcription factor HIF-1α that is an important driving force to induce fibrosis.
However, the mechanisms underlying the adipose tissue fibrosis are still unclear.
The kidney is susceptible to fibrosis with a HFD and obesity. Renal fibrosis is marked by progressive tissue scarring, leading to glomerulosclerosis and tubulointerstitial fibrosis . TGF-β is the major driver of matrix synthesis, inhibition of matrix degradation and stimulator of myofibroblast activation, and has been considered as the major mediator of chronic fibrosis in kidney disease. Recent studies demonstrate that with diet-induced obesity there is induction of TGF-β in the kidney in association with the upregulation of extracellular matrix (ECM) molecules, including fibronectin, type IV and type I collagens . Inhibition of TGF-β as an interventional agent results in reduced matrix accumulation in diabetes, puromycin nephropathy, unilateral ureteral obstruction, anti-glomerular basement membrane disease, and hypertensive renal disease [107–110]. Many therapeutic approaches have been tested to inhibit TGF-β, such as the administration of neutralizing anti-TGF-β [107,109,111,112], soluble TGF-β receptor , or small-interfering RNA for TGF-β type II receptor  in the experimental model of CKD.
Similar to adipose tissue, mothers against decapentaplegic 3 (Smad3) has emerged as a key receptor-regulated phospho-Smad that has been tightly linked to matrix accumulation. It has been reported that deletion of Smad3 protects against diabetic kidney disease, hypertensive kidney disease, and obstructive nephropathy [115▪▪]. Smad4 is a co-Smad that mediates all Smad-mediated signaling and has emerged as a necessary co-factor to initiate the transcription of Smad3-targeted genes. Deletion of Smad4 in tubular epithelial cells, tubulointerstitial fibroblasts, and mesangial cells protects cells against TGF-β-induced matrix stimulation. Recently, we have found several interactions between the AMPK pathway and TGF-β. TGF-β1 gene stimulation by high glucose has been found to be regulated by the upstream stimulatory factor (USF) family of transcription factors. Upon exposure to high glucose, USF1 translocated to the nucleus; however, this nuclear translocation is blocked by AMPK activation. Similar findings were noted with Smad4, in that nuclear translocation stimulated by elevated glucose or TGF-β1 itself was blocked by AMPK activation (AJP in submission).
However, the role of fibrosis and TGF-β likely has potent effects in many organs outside the kidney, especially in obesity. In obesity-induced adipose tissue dysfunction, increased ECM has been demonstrated in rodent and in human WAT [105,116], even though the role of the ECM of adipose tissue has received limited attention to date. Nevertheless, Khan et al. demonstrated that adipose tissue exhibited an increased collagen content in the ECM, and especially collagen VI, a predominant component of adipose matrix, in obese mice as well as in Asian Indian patients. The role of collagen VI was then evaluated by the use of a genetic ob/ob mice model with collagen VI disruption. These mice presented an improved fasting blood glucose, insulin sensitivity, and lipid metabolism along with an altered level of many key fibrotic genes in adipose tissue. Luminican, involved in the epithelial–mesenchyme transition during fibrosis, was downregulated, whereas decorin, an antagonist of TGF-β-induced fibrosis, was upregulated . TGF-β, itself, was downregulated in the mice with collagen VI deletion. This was associated with a reduced activation of downstream TGF-β signaling mediators, Smad2 and Smad3. These changes were accompanied by a decrease of adipose tissue inflammation . Therefore, the decreased levels of TGF-β and its downstream mediators suggest a potential role of TGF-β in adipose tissue fibrosis.
A more recent study demonstrated the crucial role of TGF-β and Smad3 in regulating glucose and energy homeostasis using a Smad3 knockout mice . Obesity was found to correlate with the circulating TGF-β1 levels in mice and humans. Upon exposure to diet-induced obesity, there was an increase in adipose tissue TGF-β and increased Smad3 phosphorylation. Interestingly, when mice were treated with anti-TGF-β neutralizing antibody (1D11), the mice had less weight gain, less insulin resistance and the WAT had features of brown fat, with increased uncoupling protein 1 (UCP1) and mitochondrial biogenesis . The Smad3 knockout mice on the HFD exhibited an increase of insulin sensitivity, a reduced adipocyte size, reduced pro-inflammatory cytokines, and macrophage infiltration in adipose tissue compared with wildtype mice on the HFD.
ORPHAN G-PROTEIN-COUPLED RECEPTORS IN THE KIDNEY AND ADIPOSE TISSUE
More recently, orphan G-protein-coupled receptors (GPCRs) have been shown to play a role in the progression of obesity-related disease. These receptors function as receptors for short-chain fatty acids (SCFAs), such as acetate and propionate. The source of FA can be diverse. They can come from the digestion and lipolysis of triglycerides in the liver and adipose tissue, or be obtained from food intake. The GPCRs are expressed in many tissues such as the pancreas, adipose tissue, and kidney. In the pancreas, the orphan GPCRs, especially GPR40, have been found to interact with insulin signaling . A recent study showed that an acute exposure of FFA stimulated insulin release from the β cells, whereas chronic stimulation by FFA impaired the β-cell insulin secretion and led to lipotoxicity . In that study, transgenic GPR40 knockout mice were protected from hyperinsulinemia and glucose intolerance . It is thus easy to conclude that excess food intake, and especially fat food, lead to an increase of FFAs that, in turn, promote abnormal response in their orphan GPCRs, promoting impaired insulin secretion. In adipose tissue, GPR43 and GPR41 have been identified. Their exact role is not fully elucidated. Xiong et al. found that the activation of GPR41 by SCFAs induced leptin expression in both mouse adipocyte cell line and mouse adipose tissue in primary culture. The increased level of circulating leptin was also measured in mice after acute oral administration of propionate, a well-known SCFA, ligand of the GPCRs , therefore suggesting that SCFA via a specific GPC receptor could play a role in the cellular signaling pathway and regulate metabolic factor such as leptin. In another study, increased expression of GPR43 but not GPR41 was demonstrated in adipose tissue from mice fed a HFD . Moreover, the inhibition of GPR43 in 3T3-L cells by specific siRNA was found to significantly reduce lipid accumulation after stimulation with the SCFA, propionate . The role of GPR43 activation in the inhibition of lipolysis was then confirmed using an in-vitro model of adipocytes isolated from GPR43 knockout mice . Furthermore, in vivo, activating GPR43 by SCFA resulted in a reduced level of plasma FFA, reinforcing the role of GPR43 in inhibiting lipolysis and reducing plasma FFA . In the kidney, the evidence for a role of GPCR has been reported. Indeed, GPCRs were detected in distal tubular cells and in the macula densa, suggesting a sensory role in the regulation of the tubuloglomerular feedback by regulating the renin release . A more recent study reported opposite effects of GPCR functions . In this study, the olfactory receptor78 (Olfr78) and the GPR41 knockout mice models were used to determine the role of the SCFA and their receptors in the regulation of renal vascular tone and release of renin. Both Olfr78 and GPR41 were detected in the renal vasculature . However, whereas Olfr 78 knockout mice presented a lower BP associated with a lower plasma level of renin, the opposite was observed in GPR41 knockout mice. That study revealed that Olfr78 activation promotes an increase of BP, whereas the activation of GPR41 contributes to the hypotensive effect of propionate. This opposite effect may act to buffer BP modulation. The role of these receptors in insulin resistance is uncertain. However, SCFAs released in the bloodstream can modulate diverse cellular signaling such as the renal renin–angiotensin system, which may in turn promote the impairment of insulin signaling. Clearly, further investigations are needed to delineate the exact role of these orphan GPCRs.
Thus, it is becoming increasingly clear that there is an important cross-talk between adipose tissue and the kidney, especially in obesity-related kidney disease, although similar cross-talk is likely also important with diabetes and possibly hypertension-associated kidney disease. The use of systemic AMPK activation is likely to have profound effects on adipose tissue, which could contribute to the reduced inflammation and fibrosis observed in the kidney. Nevertheless, there are likely kidney-specific effects of AMPK activators as well. In addition, the use of systemic anti-inflammatory and anti-TGF-β antibodies likely also has profound effects on the adipose tissue, which are beneficial systemically and for the improvement in renal structure and function. In future studies, further understanding and elucidation of the key pathways linking adipose tissue to the kidney will suggest improved treatment approaches, which will likely have widespread application and implications for progressive CKD of many causes.
Financial support and sponsorship
This study was supported by the grants from the NIDDK (DP3DK094352), VA Merit Grant (5101BX000277) to K.S.
Conflicts of interest
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