Abstract
SUMMARYObesity and concomitant comorbidities have emerged as public health problems of the first order. For instance, obese individuals have an increased risk for kidney cancer. However, direct mechanisms linking obesity with kidney cancer remain elusive. We hypothesized that diet-induced obesity (DIO) promotes renal carcinogenesis by inducing an inflammatory and tumor-promoting microenvironment. We compared chow-fed lean Wistar rats with those that were sensitive (DIOsens) or partially resistant (DIOres) to DIO to investigate the impact of body adiposity versus dietary nutrient overload in the development of renal preneoplasia and activation of tumor-promoting signaling pathways. Our data clearly show a correlation between body adiposity, the severity of nephropathy, and the total number and incidence of preneoplastic renal lesions. However, similar plasma triglyceride, plasma free fatty acid and renal triglyceride levels were found in chow-fed, DIOres and DIOsens rats, suggesting that lipotoxicity is not a critical contributor to the renal pathology. Obesity-related nephropathy was further associated with regenerative cell proliferation, monocyte infiltration and higher renal expression of monocyte chemotactic protein-1 (MCP-1), interleukin (IL)-6, IL-6 receptor and leptin receptor. Accordingly, we observed increased signal transducer and activator of transcription 3 (STAT3) and mammalian target of rapamycin (mTOR) phosphorylation in tubules with preneoplastic phenotypes. In summary, our results demonstrate that high body adiposity induces an inflammatory and proliferative microenvironment in rat kidneys that promotes the development of preneoplastic lesions, potentially via activation of the STAT3 and mTOR signaling pathways.
Highlights
Over the last two decades, a worldwide rise in obesity has resulted in 1.46 billion overweight [body mass index (BMI)>25] and 502 million obese (BMI>30) adults (Finucane et al, 2011)
We hypothesized that diet-induced obesity (DIO) promotes the earliest stages of renal carcinogenesis via signal transducer and activator of transcription 3 (STAT3) activation
Using chow-fed lean rats and two groups of high-fat diet (HFD)-fed rats with either pronounced sensitivity to develop DIO (DIOsens rats) or partial resistance to DIO (DIOres rats), we demonstrated a correlation between body adiposity and the severity of kidney pathology: DIO sensitive (DIOsens) and DIO resistant (DIOres) rats had increased renal inflammation and cytokine expression, and higher incidences of nephropathies and preneoplastic lesions
Summary
Over the last two decades, a worldwide rise in obesity has resulted in 1.46 billion overweight [body mass index (BMI)>25] and 502 million obese (BMI>30) adults (Finucane et al, 2011). Co-morbidities for obesity include diabetes mellitus type 2, cardiovascular disease, hepatic steatosis, Alzheimer’s disease, chronic kidney disease and certain cancers (Haslam and James, 2005; Brunt, 2010; Barnes and Yaffe, 2011). A major determinant for many obesity-induced sequelae is the low-grade inflammation of the enlarged adipose tissue, and the persistent release of inflammatory adipocytokines such as tumor necrosis factor- (TNF) and interleukin-6 (IL-6) (Gregor and Hotamisligil, 2011), which can adversely affect various non-adipose target tissues. Such obesity-induced hepatic inflammation was recently shown to promote tumor formation in livers of dietary obese mice (Park et al, 2010). Inhibition of the IL-6 target signal transducer and activator of transcription 3 (STAT3) is currently under investigation as a potential target for kidney cancer therapy (Xin et al, 2009; Horiguchi et al, 2010)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
