Secondary Logo

Journal Logo

Obesity and kidney disease

differential effects of obesity on adipose tissue and kidney inflammation and fibrosis

Declèves, Anne-Emiliea,b; Sharma, Kumara,c

Current Opinion in Nephrology and Hypertension: January 2015 - Volume 24 - Issue 1 - p 28–36
doi: 10.1097/MNH.0000000000000087
CIRCULATION AND HEMODYNAMICS: Edited by Matthew R. Weir and Roland C. Blantz
Free

Purpose of review To provide a perspective by investigating the potential cross-talk between the adipose tissue and the kidney during obesity.

Recent findings It is well established that excessive caloric intake contributes to organ injury. The associated increased adiposity initiates a cascade of cellular events that leads to progressive obesity-associated diseases such as kidney disease. Recent evidence has indicated that adipose tissue produces bioactive substances that contribute to obesity-related kidney disease, altering the renal function and structure. In parallel, proinflammatory processes within the adipose tissue can also lead to pathophysiological changes in the kidney during the obese state.

Summary Despite considerable efforts to better characterize the pathophysiology of obesity-related metabolic disease, there are still a lack of efficient therapeutic strategies. New strategies focused on regulating adipose function with respect to AMP-activated protein kinase activation, NADPH oxidase function, and TGF-β may contribute to reducing adipose inflammation that may also provide renoprotection.

aCenter for Renal Translational Medicine, La Jolla, California, USA

bLaboratory of Experimental Nephrology, Faculty of Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium

cInstitute for Metabolomic Medicine, University of California San Diego, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA

Correspondence to Kumar Sharma, MD, Center for Renal Translational Medicine, University of California San Diego, Veterans Affairs San Diego Healthcare System, Stein Clinical Research Building, 4th Floor, 9500 Gilman Drive, La Jolla, CA 92093-0711, USA. Tel: +1 858 822 0870; fax: +1 858 822 7483; e-mail: kumarsharma@ucsd.edu

Back to Top | Article Outline

INTRODUCTION

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 [1], 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 [2]. 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) [3]. 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.

Box 1

Box 1

Back to Top | Article Outline

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.

Back to Top | Article Outline

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 [47]. 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 [39]. 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.[53] 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 [71].

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 [73]. 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 [74]. 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 [75]. Metabolic stress conditions such as obesity modulate the activity of AMPK. Steinberg et al.[76] 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.[76] 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 [77]. 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 [79]. 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 [80].

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 [81]. 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 [90]. 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 [60]. 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 [87]. 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 [98]. 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 [87]. 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 [99]. 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 [100]. The use of metformin, another AMPK activator, showed similar data in a murine model of HFD-induced renal injury [101]. In another study, activation of AMPK by metformin prevented the decrease of urinary sodium excretion and increased blood pressure (BP) induced by ANG II [102]. In turn, low adiponectin level has been reported to contribute to the development of obesity-related hypertension [103]. 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 [104]. The regulation of Nox by AMPK is also likely because of its effects on NF-κB activation [99].

Back to Top | Article Outline

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.[105] 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 [106]. 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 [87]. 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 [113], or small-interfering RNA for TGF-β type II receptor [114] 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.[117] 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 [117]. 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 [117]. 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 [118]. 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 [118]. 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.

Back to Top | Article Outline

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 [119]. 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 [120]. In that study, transgenic GPR40 knockout mice were protected from hyperinsulinemia and glucose intolerance [121]. 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.[122] 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 [122], 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 [123]. 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 [123]. 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 [124]. 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 [124]. 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 [125]. A more recent study reported opposite effects of GPCR functions [126]. 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 [126]. 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.

Back to Top | Article Outline

CONCLUSION

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.

Back to Top | Article Outline

Acknowledgements

None.

Back to Top | Article Outline

Financial support and sponsorship

This study was supported by the grants from the NIDDK (DP3DK094352), VA Merit Grant (5101BX000277) to K.S.

Back to Top | Article Outline

Conflicts of interest

None.

Back to Top | Article Outline

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
Back to Top | Article Outline

REFERENCES

1. Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell 2012; 148:852–871.
2. Bruce KD, Hanson MA. The developmental origins, mechanisms, and implications of metabolic syndrome. J Nutr 2010; 140:648–652.
3. Collins AJ, Foley RN, Herzog C, et al. US Renal Data System 2010 annual data report. Am J Kidney Dis 2011; 57 (1 Suppl. 1):A8e1–e526.
4. Cao H. Adipocytokines in obesity and metabolic disease. J Endocrinol 2014; 220:T47–T59.
5. Sikaris KA. The clinical biochemistry of obesity – more than skin deep. Heart Lung Circ 2007; 16 (Suppl. 3):S45–S50.
6. Marcussen N. Atubular glomeruli and the structural basis for chronic renal failure. Lab Invest 1992; 66:265–284.
7. Taft JL, Nolan CJ, Yeung SP, et al. Clinical and histological correlations of decline in renal function in diabetic patients with proteinuria. Diabetes 1994; 43:1046–1051.
8. Gilbert RE, Cooper ME. The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury? Kidney Int 1999; 56:1627–1637.
9. Chagnac A, Weinstein T, Korzets A, et al. Glomerular hemodynamics in severe obesity. Am J Physiol Renal Physiol 2000; 278:F817–F822.
10. Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature 2006; 444:847–853.
11. Hotamisligil GS. Inflammatory pathways and insulin action. Int J Obes Relat Metab Disord 2003; 27 (Suppl. 3):S53–S55.
12. Bluher M. Adipose tissue dysfunction in obesity. Exp Clin Endocrinol Diabetes 2009; 117:241–250.
13▪. Makki K, Froguel P, Wolowczuk I. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm 2013; 2013:139239.

This review highlights the central role of adipose tissue regarding insulin resistance in obesity.

14. Liao MT, Sung CC, Hung KC, et al. Insulin resistance in patients with chronic kidney disease. J Biomed Biotechnol 2012; 2012:691369.
15. Chen J, Muntner P, Hamm LL, et al. Insulin resistance and risk of chronic kidney disease in nondiabetic US adults. J Am Soc Nephrol 2003; 14:469–477.
16. Parvanova AI, Trevisan R, Iliev IP, et al. Insulin resistance and microalbuminuria: a cross-sectional, case–control study of 158 patients with type 2 diabetes and different degrees of urinary albumin excretion. Diabetes 2006; 55:1456–1462.
17. Abrass CK, Raugi GJ, Gabourel LS, Lovett DH. Insulin and insulin-like growth factor I binding to cultured rat glomerular mesangial cells. Endocrinology 1988; 123:2432–2439.
18. Kreisberg JI. Insulin requirement for contraction of cultured rat glomerular mesangial cells in response to angiotensin II: possible role for insulin in modulating glomerular hemodynamics. Proc Natl Acad Sci USA 1982; 79:4190–4192.
19. Cusumano AM, Bodkin NL, Hansen BC, et al. Glomerular hypertrophy is associated with hyperinsulinemia and precedes overt diabetes in aging rhesus monkeys. Am J Kidney Dis 2002; 40:1075–1085.
20. Manrique C, Lastra G, Sowers JR. New insights into insulin action and resistance in the vasculature. Ann N Y Acad Sci 2014; 1311:138–150.
21. Gual P, Le Marchand-Brustel Y, Tanti JF. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 2005; 87:99–109.
22. Welsh GI, Hale LJ, Eremina V, et al. Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab 2010; 12:329–340.
23. Amann K, Benz K. Structural renal changes in obesity and diabetes. Semin Nephrol 2013; 33:23–33.
24. Thethi T, Kamiyama M, Kobori H. The link between the renin–angiotensin–aldosterone system and renal injury in obesity and the metabolic syndrome. Curr Hypertens Rep 2012; 14:160–169.
25. Leehey DJ, Singh AK, Alavi N, Singh R. Role of angiotensin II in diabetic nephropathy. Kidney Int Suppl 2000; 77:S93–S98.
26. Praga M, Hernandez E, Morales E, et al. Clinical features and long-term outcome of obesity-associated focal segmental glomerulosclerosis. Nephrol Dial Transplant 2001; 16:1790–1798.
27. Gupte M, Boustany-Kari CM, Bharadwaj K, et al. ACE2 is expressed in mouse adipocytes and regulated by a high-fat diet. Am J Physiol Regul Integr Comp Physiol 2008; 295:R781–R788.
28. Lu H, Boustany-Kari CM, Daugherty A, Cassis LA. Angiotensin II increases adipose angiotensinogen expression. Am J Physiol Endocrinol Metab 2007; 292:E1280–E1287.
29. Ogihara T, Asano T, Ando K, et al. Angiotensin II-induced insulin resistance is associated with enhanced insulin signaling. Hypertension 2002; 40:872–879.
30. Olivares-Reyes JA, Arellano-Plancarte A, Castillo-Hernandez JR. Angiotensin II and the development of insulin resistance: implications for diabetes. Mol Cell Endocrinol 2009; 302:128–139.
31. Prasannarong M, Santos FR, Henriksen EJ. ANG-(1–7) reduces ANG II-induced insulin resistance by enhancing Akt phosphorylation via a Mas receptor-dependent mechanism in rat skeletal muscle. Biochem Biophys Res Commun 2012; 426:369–373.
32. El-Atat FA, Stas SN, McFarlane SI, Sowers JR. The relationship between hyperinsulinemia, hypertension and progressive renal disease. J Am Soc Nephrol 2004; 15:2816–2827.
33. Kim JA, Jang HJ, Martinez-Lemus LA, Sowers JR. Activation of mTOR/p70S6 kinase by ANG II inhibits insulin-stimulated endothelial nitric oxide synthase and vasodilation. Am J Physiol Endocrinol Metab 2012; 302:E201–E208.
34. Lastra G, Habibi J, Whaley-Connell AT, et al. Direct renin inhibition improves systemic insulin resistance and skeletal muscle glucose transport in a transgenic rodent model of tissue renin overexpression. Endocrinology 2009; 150:2561–2568.
35. Lastra-Lastra G, Sowers JR, Restrepo-Erazo K, et al. Role of aldosterone and angiotensin II in insulin resistance: an update. Clin Endocrinol (Oxf) 2009; 71:1–6.
36. Blendea MC, Jacobs D, Stump CS, et al. Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression. Am J Physiol Endocrinol Metab 2005; 288:E353–E359.
37. Sowers JR. Hypertension, angiotensin II, and oxidative stress. N Engl J Med 2002; 346:1999–2001.
38. Sowers JR, Frohlich ED. Insulin and insulin resistance: impact on blood pressure and cardiovascular disease. Med Clin North Am 2004; 88:63–82.
39. Uysal KT, Wiesbrock SM, Hotamisligil GS. Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity. Endocrinology 1998; 139:4832–4838.
40. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 1997; 389:610–614.
41. Taniyama Y, Hitomi H, Shah A, et al. Mechanisms of reactive oxygen species-dependent downregulation of insulin receptor substrate-1 by angiotensin II. Arterioscler Thromb Vasc Biol 2005; 25:1142–1147.
42. Lennon R, Pons D, Sabin MA, et al. Saturated fatty acids induce insulin resistance in human podocytes: implications for diabetic nephropathy. Nephrol Dial Transplant 2009; 24:3288–3296.
43. Chavez JA, Knotts TA, Wang LP, et al. A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. J Biol Chem 2003; 278:10297–10303.
44▪. Decleves AE, Zolkipli Z, Satriano J, et al. Regulation of lipid accumulation by AMP-activated kinase [corrected] in high fat diet-induced kidney injury. Kidney Int 2014; 85:611–623.

This study demonstrates the beneficial effect of AMPK in preventing obesity-induced kidney disease.

45. Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444:860–867.
46. Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res 2005; 96:939–949.
47. Trajcevski KE, O’Neill HM, Wang DC, et al. Enhanced lipid oxidation and maintenance of muscle insulin sensitivity despite glucose intolerance in a diet-induced obesity mouse model. PLoS One 2013; 8:e71747.
48. Weisberg SP, McCann D, Desai M, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112:1796–1808.
49. Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112:1821–1830.
50. Stienstra R, van Diepen JA, Tack CJ, et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc Natl Acad Sci USA 2011; 108:15324–15329.
51. Hivert MF, Sullivan LM, Fox CS, et al. Associations of adiponectin, resistin, and tumor necrosis factor-alpha with insulin resistance. J Clin Endocrinol Metab 2008; 93:3165–3172.
52. Rajkovic N, Zamaklar M, Lalic K, et al. Relationship between obesity, adipocytokines and inflammatory markers in type 2 diabetes: relevance for cardiovascular risk prevention. Int J Environ Res Public Health 2014; 11:4049–4065.
53. Suganami T, Nishida J, Ogawa Y. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol 2005; 25:2062–2068.
54. Bremer AA, Jialal I. Adipose tissue dysfunction in nascent metabolic syndrome. J Obes 2013; 2013:393192.
55. Huber J, Kiefer FW, Zeyda M, et al. CC chemokine and CC chemokine receptor profiles in visceral and subcutaneous adipose tissue are altered in human obesity. J Clin Endocrinol Metab 2008; 93:3215–3221.
56. Kanda H, Tateya S, Tamori Y, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006; 116:1494–1505.
57. Kamei N, Tobe K, Suzuki R, et al. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem 2006; 281:26602–26614.
58. Weisberg SP, Hunter D, Huber R, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 2006; 116:115–124.
59. Hotta K, Funahashi T, Arita Y, et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000; 20:1595–1599.
60. Sharma K, Ramachandrarao S, Qiu G, et al. Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest 2008; 118:1645–1656.
61. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev 2005; 26:439–451.
62. Kadowaki T, Yamauchi T, Kubota N, et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 2006; 116:1784–1792.
63. Yatagai T, Nagasaka S, Taniguchi A, et al. Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus. Metabolism 2003; 52:1274–1278.
64. Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999; 257:79–83.
65. Berg AH, Combs TP, Du X, et al. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001; 7:947–953.
66. Yamauchi T, Kamon J, Waki H, et al. Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem 2003; 278:2461–2468.
67. Combs TP, Pajvani UB, Berg AH, et al. A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity. Endocrinology 2004; 145:367–383.
68. Maeda N, Shimomura I, Kishida K, et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002; 8:731–737.
69. Kubota N, Terauchi Y, Yamauchi T, et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 2002; 277:25863–25866.
70. Nawrocki AR, Rajala MW, Tomas E, et al. Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J Biol Chem 2006; 281:2654–2660.
71. Ruan H, Miles PD, Ladd CM, et al. Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-alpha: implications for insulin resistance. Diabetes 2002; 51:3176–3188.
72. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002; 8:1288–1295.
73. Steinberg GR, Kemp BE. AMPK in health and disease. Physiol Rev 2009; 89:1025–1078.
74. Carling D. The AMP-activated protein kinase cascade – a unifying system for energy control. Trends Biochem Sci 2004; 29:18–24.
75. Hardie DG, Hawley SA, Scott JW. AMP-activated protein kinase – development of the energy sensor concept. J Physiol 2006; 574 (Pt 1):7–15.
76. Steinberg GR, Michell BJ, van Denderen BJ, et al. Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. Cell Metab 2006; 4:465–474.
77. Yu C, Chen Y, Cline GW, et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 2002; 277:50230–50236.
78▪▪. Shibata T, Takaguri A, Ichihara K, Satoh K. Inhibition of the TNF-alpha-induced serine phosphorylation of IRS-1 at 636/639 by AICAR. J Pharmacol Sci 2013; 122:93–102.

This study shows the beneficial effect of AMPK activation in improving insulin resistance. This observation opens a new path toward novel pharmacological therapies.

79. Lihn AS, Jessen N, Pedersen SB, et al. AICAR stimulates adiponectin and inhibits cytokines in adipose tissue. Biochem Biophys Res Commun 2004; 316:853–858.
80. Sell H, Dietze-Schroeder D, Eckardt K, Eckel J. Cytokine secretion by human adipocytes is differentially regulated by adiponectin, AICAR, and troglitazone. Biochem Biophys Res Commun 2006; 343:700–706.
81. Kumashiro N, Erion DM, Zhang D, et al. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci USA 2011; 108:16381–16385.
82. Petersen KF, Befroy D, Dufour S, et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003; 300:1140–1142.
83▪. Taddeo EP, Laker RC, Breen DS, et al. Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle. Mol Metab 2014; 3:124–134.

This study highlights the link between mitochondrial dysfunction and insulin resistance. This study offers new insights into understanding the progression of insulin resistance.

84▪. Turner N, Cooney GJ, Kraegen EW, Bruce CR. Fatty acid metabolism, energy expenditure and insulin resistance in muscle. J Endocrinol 2014; 220:T61–T79.

This review presents a great summary regarding the link between excess of fatty acids and insulin resistance.

85. Hansen ME, Tippetts TS, Anderson MC, et al. Insulin increases ceramide synthesis in skeletal muscle. J Diabetes Res 2014; 2014:765784.
86▪. Wang C, Liu F, Yuan Y, et al. Metformin suppresses lipid accumulation in skeletal muscle by promoting fatty acid oxidation. Clin Lab 2014; 60:887–896.

This study shows that metformin, an AMPK activator, improves insulin resistance by suppressing lipid accumulation.

87. Decleves AE, Mathew AV, Cunard R, Sharma K. AMPK mediates the initiation of kidney disease induced by a high-fat diet. J Am Soc Nephrol 2011; 22:1846–1855.
88. Deji N, Kume S, Araki S, Soumura M. Structural and functional changes in the kidneys of high-fat diet-induced obese mice. Am J Physiol Renal Physiol 2009; 296:F118–F126.
89. Kume S, Uzu T, Araki S, et al. Role of altered renal lipid metabolism in the development of renal injury induced by a high-fat diet. J Am Soc Nephrol 2007; 18:2715–2723.
90. Roubicek T, Bartlova M, Krajickova J, et al. Increased production of proinflammatory cytokines in adipose tissue of patients with end-stage renal disease. Nutrition 2009; 25:762–768.
91. Siew ED, Ikizler TA. Insulin resistance and protein energy metabolism in patients with advanced chronic kidney disease. Semin Dial 2010; 23:378–382.
92. Wilson AC, Schneider MF, Cox C, et al. Prevalence and correlates of multiple cardiovascular risk factors in children with chronic kidney disease. Clin J Am Soc Nephrol 2011; 6:2759–2765.
93▪▪. Adamczak M, Wiecek A. The adipose tissue as an endocrine organ. Semin Nephrol 2013; 33:2–13.

This review highlights the critical role of adipose tissue in the development of obesity-related metabolic disease such as kidney disease, atherosclerosis, and cardiovascular disease.

94. Stemmer K, Perez-Tilve D, Ananthakrishnan G, et al. High-fat-diet-induced obesity causes an inflammatory and tumor-promoting microenvironment in the rat kidney. Dis Model Mech 2012; 5:627–635.
95. Mori J, Patel VB, Ramprasath T, et al. Angiotensin 1–7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity. Am J Physiol Renal Physiol 2014; 306:F812–F821.
96. Peairs A, Radjavi A, Davis S, et al. Activation of AMPK inhibits inflammation in MRL/lpr mouse mesangial cells. Clin Exp Immunol 2009; 156:542–551.
97. Furuichi K, Kaneko S, Wada T. Chemokine/chemokine receptor-mediated inflammation regulates pathologic changes from acute kidney injury to chronic kidney disease. Clin Exp Nephrol 2009; 13:9–14.
98. Tarabra E, Giunti S, Barutta F, et al. Effect of the monocyte chemoattractant protein-1/CC chemokine receptor 2 system on nephrin expression in streptozotocin-treated mice and human cultured podocytes. Diabetes 2009; 58:2109–2118.
99. Wang S, Zhang M, Liang B, et al. AMPKalpha2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes. Circ Res 2010; 106:1117–1128.
100. O’Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 2013; 493:346–355.
101. Kim D, Lee JE, Jung YJ, et al. Metformin decreases high-fat diet-induced renal injury by regulating the expression of adipokines and the renal AMP-activated protein kinase/acetyl-CoA carboxylase pathway in mice. Int J Mol Med 2013; 32:1293–1302.
102. Deji N, Kume S, Araki S, et al. Role of angiotensin II-mediated AMPK inactivation on obesity-related salt-sensitive hypertension. Biochem Biophys Res Commun 2012; 418:559–564.
103. Ohashi K, Kihara S, Ouchi N, et al. Adiponectin replenishment ameliorates obesity-related hypertension. Hypertension 2006; 47:1108–1116.
104. Sanchez AP, Zhao J, You Y, et al. Role of the USF1 transcription factor in diabetic kidney disease. Am J Physiol Renal Physiol 2011; 301:F271–F279.
105. Halberg N, Khan T, Trujillo ME, et al. Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol 2009; 29:4467–4483.
106. Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int 2006; 69:213–217.
107. Ziyadeh FN, Hoffman BB, Han DC, et al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci USA 2000; 97:8015–8020.
108. Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994; 331:1286–1292.
109. Sharma K, Jin Y, Guo J, Ziyadeh FN, et al. Neutralization of TGF-beta by anti-TGF-beta antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes 1996; 45:522–530.
110. Ma LJ, Jha S, Ling H, et al. Divergent effects of low versus high dose anti-TGF-beta antibody in puromycin aminonucleoside nephropathy in rats. Kidney Int 2004; 65:106–115.
111. Guan Q, Li S, Gao S, et al. Reduction of chronic rejection of renal allografts by antitransforming growth factor-beta antibody therapy in a rat model. Am J Physiol Renal Physiol 2013; 305:F199–F207.
112. Chen S, Iglesias-de la, Cruz MC, Jim B, et al. Reversibility of established diabetic glomerulopathy by anti-TGF-beta antibodies in db/db mice. Biochem Biophys Res Commun 2003; 300:16–22.
113. Juarez P, Vilchis-Landeros MM, Ponce-Coria J, et al. Soluble betaglycan reduces renal damage progression in db/db mice. Am J Physiol Renal Physiol 2007; 292:F321–F329.
114. Kushibiki T, Nagata-Nakajima N, Sugai M, et al. Delivery of plasmid DNA expressing small interference RNA for TGF-beta type II receptor by cationized gelatin to prevent interstitial renal fibrosis. J Control Release 2005; 105:318–331.
115▪▪. Meng XM, Chung AC, Lan HY. Role of the TGF-beta/BMP-7/Smad pathways in renal diseases. Clin Sci (Lond) 2013; 124:243–254.

This is a good review describing the balance between TGF-beta/Smad and BMP-7/Smad pathways during the progression of kidney disease.

116. Henegar C, Tordjman J, Achard V, et al. Adipose tissue transcriptomic signature highlights the pathological relevance of extracellular matrix in human obesity. Genome Biol 2008; 9:R14.
117. Khan T, Muise ES, Iyengar P, et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol 2009; 29:1575–1591.
118. Yadav H, Quijano C, Kamaraju AK, et al. Protection from obesity and diabetes by blockade of TGF-beta/Smad3 signaling. Cell Metab 2011; 14:67–79.
119. Bartoov-Shifman R, Ridner G, Bahar K, et al. Regulation of the gene encoding GPR40, a fatty acid receptor expressed selectively in pancreatic beta cells. J Biol Chem 2007; 282:23561–23571.
120. McGarry JD, Dobbins RL. Fatty acids, lipotoxicity and insulin secretion. Diabetologia 1999; 42:128–138.
121. Steneberg P, Rubins N, Bartoov-Shifman R, et al. The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse. Cell Metab 2005; 1:245–258.
122. Xiong Y, Miyamoto N, Shibata K, et al. Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc Natl Acad Sci USA 2004; 101:1045–1050.
123. Hong YH, Nishimura Y, Hishikawa D, et al. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology 2005; 146:5092–5099.
124. Ge H, Li X, Weiszmann J, et al. Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinology 2008; 149:4519–4526.
125. Pluznick JL, Zou DJ, Zhang X, et al. Functional expression of the olfactory signaling system in the kidney. Proc Natl Acad Sci USA 2009; 106:2059–2064.
126. Pluznick JL. Renal and cardiovascular sensory receptors and blood pressure regulation. Am J Physiol Renal Physiol 2013; 305:F439–F444.
Keywords:

AMPK; HIF-1α; NADPH oxidase; nutrient stress; TGF-β

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.