microRNAs-mediated regulation of insulin signaling in white adipose tissue during aging: Role of caloric restriction.

Caloric restriction is a non-pharmacological intervention known to ameliorate the metabolic defects associated with aging, including insulin resistance. The levels of miRNA expression may represent a predictive tool for aging-related alterations. In order to investigate the role of miRNAs underlying insulin resistance in adipose tissue during the early stages of aging, 3- and 12-month-old male animals fed ad libitum, and 12-month-old male animals fed with a 20% caloric restricted diet were used. In this work we demonstrate that specific miRNAs may contribute to the impaired insulin-stimulated glucose metabolism specifically in the subcutaneous white adipose tissue, through the regulation of target genes implicated in the insulin signaling cascade. Moreover, the expression of these miRNAs is modified by caloric restriction in middle-aged animals, in accordance with the improvement of the metabolic state. Overall, our work demonstrates that alterations in posttranscriptional gene expression because of miRNAs dysregulation might represent an endogenous mechanism by which insulin response in the subcutaneous fat depot is already affected at middle age. Importantly, caloric restriction could prevent this modulation, demonstrating that certain miRNAs could constitute potential biomarkers of age-related metabolic alterations.

Novel Insights in the Physiopathology and Management of Obesity-Related Kidney Disease.

Obesity is recognized as an independent risk factor for the development of kidney disease, which has led to the designation of obesity-related glomerulopathy (ORG). Common renal features observed in this condition include glomerular hypertrophy, glomerulosclerosis, haemodynamic changes and glomerular filtration barrier defects. Additionally, and although less studied, obesity-related kidney disease also involves alterations in renal tubules, including tubule hypertrophy, lipid deposition and tubulointerstitial fibrosis. Although not completely understood, the harmful effects of obesity on the kidney may be mediated by different mechanisms, with alterations in adipose tissue probably playing an important role. An increase in visceral adipose tissue has classically been associated with the development of kidney damage, however, recent studies point to adipose tissue surrounding the kidney, and specifically to the fat within the renal sinus, as potentially involved in the development of ORG. In addition, new strategies for the treatment of patients with obesity-related kidney disease are focusing on the management of obesity. In this regard, some non-invasive options, such as glucagon-like peptide-1 (GLP-1) receptor agonists or sodium-glucose cotransporter-2 (SGLT2) inhibitors, are being considered for application in the clinic, not only for patients with diabetic kidney disease but as a novel pharmacological strategy for patients with ORG. In addition, bariatric surgery stands as one of the most effective options, not only for weight loss but also for the improvement of kidney outcomes in obese patients with chronic kidney disease.

Tackling the effects of extracellular vesicles in fibrosis.

Fibrosis is a physiological process of tissue repair that turns into pathological when becomes chronic, damaging the functional structure of the tissue. In this review we outline the current status of extracellular vesicles as modulators of the fibrotic process at different levels. In adipose tissue, extracellular vesicles mediate the intercellular communication not only between adipocytes, but also between adipocytes and other cells of the stromal vascular fraction. Thus, they could be altering essential processes for the functionality of adipose tissue, such as adipocyte hypertrophy/hyperplasia, tissue plasticity, adipogenesis and/or inflammation, and ultimately trigger fibrosis. This process is particularly important in obesity, and may eventually, influence the development of obesity-associated alterations. In this regard, obesity is now recognized as an independent risk factor for the development of chronic kidney disease, although the role of extracellular vesicles in this connection has not been explored so far. Nonetheless, the role of extracellular vesicles in the onset and progression of renal fibrosis has been highlighted due to the critical role of fibrosis as a common feature of kidney diseases. In fact, the content of extracellular vesicles disturbs cellular signaling cascades involved in fibrosis in virtually all types of renal cells. What is certain is that the study of extracellular vesicles is complex, as their isolation and manipulation is still difficult to reproduce, which complicates the overview of their physiopathological effects. Nevertheless, new strategies have been developed to exploit the potential of extracellular vesicles and their cargo, both as biomarkers and as therapeutic tools to prevent the progression of fibrosis towards an irreversible event.

Lipidomic and Metabolomic Signature of Progression of Chronic Kidney Disease in Patients with Severe Obesity.

Severe obesity is a major risk for chronic kidney disease (CKD). Early detection and careful monitoring of renal function are critical for the prevention of CKD during obesity, since biopsies are not performed in patients with CKD and diagnosis is dependent on the assessment of clinical parameters. To explore whether distinct lipid and metabolic signatures in obesity may signify early stages of pathogenesis toward CKD, liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-high resolution accurate mass-mass spectrometry (GC-HRAM-MS) analyses were performed in the serum and the urine of severely obese patients with and without CKD. Moreover, the impact of bariatric surgery (BS) in lipid and metabolic signature was also studied, through LC-MS and GC-HRAM-MS analyses in the serum and urine of patients with severe obesity and CKD before and after undergoing BS. Regarding patients with severe obesity and CKD compared to severely obese patients without CKD, serum lipidome analysis revealed significant differences in lipid signature. Furthermore, serum metabolomics profile revealed significant changes in specific amino acids, with isoleucine and tyrosine, increased in CKD patients compared with patients without CKD. LC-MS and GC-HRAM-MS analysis in serum of patients with severe obesity and CKD after BS showed downregulation of levels of triglycerides (TGs) and diglycerides (DGs) as well as a decrease in branched-chain amino acid (BCAA), lysine, threonine, proline, and serine. In addition, BS removed most of the correlations in CKD patients against biochemical parameters related to kidney dysfunction. Concerning urine analysis, hippuric acid, valine and glutamine were significantly decreased in urine from CKD patients after surgery. Interestingly, bariatric surgery did not restore all the lipid species, some of them decreased, hence drawing attention to them as potential targets for early diagnosis or therapeutic intervention. Results obtained in this study would justify the use of comprehensive mass spectrometry-based lipidomics to measure other lipids aside from conventional lipid profiles and to validate possible early markers of risk of CKD in patients with severe obesity.

Renoprotective role of bariatric surgery in patients with established chronic kidney disease.

BACKGROUND: Bariatric surgery (BS) has been postulated as the most effective measure for weight reduction. Weight loss improves metabolic parameters and exerts changes in renal function that lead to the amelioration of absolute or relative glomerular hyperfiltration, a condition that may be renoprotective in the long term. However, few studies have demonstrated the influence of BS in patients with severe obesity and chronic kidney disease (CKD). Our objective was to analyse the evolution of renal function, adipose tissue-derived molecules and inflammatory parameters in patients with CKD after BS. METHODS: This is an observational and prospective study. Thirty patients were screened and 12 were included between January 2016 and January 2018 with a 24-month follow-up. Glomerular filtration rate (GFR) was determined by plasma iohexol clearance. Adipokines, cytokines, circulating hormones and fibrotic parameters were evaluated before and 12 months after BS using the Bioplex system. RESULTS: The mean age was 50.6 years and 58.3% were males. Seven patients had a body mass index >40 kg/m2 and 66.7% were diabetic. Twenty-four months following BS there was a significant decrease in body weight (36.4%). Proteinuria decreased by 63.7 ± 28.2%. Measured GFR significantly diminished from before surgery to Month 24 after surgery (94 ± 44 to 79 ± 44 mL/min, P = 0.03). There was a significant decrease in adipocyte-derived molecules (leptin and vifastin) as well as in pro-inflammatory cytokines [interleukin (IL)-1ß, tumour necrosis factor α, IL-6 and monocyte chemoattractant protein-1] and other circulating factors (vascular endothelial growth factor and transforming growth factor ß isoforms). CONCLUSIONS: BS is an effective option to prevent kidney damage in obese subjects with CKD due to the improvement of glomerular hyperfiltration, adipocyte cytokines metabolic and inflammatory parameters.

From Obesity to Chronic Kidney Disease: How Can Adipose Tissue Affect Renal Function?

Obesity is directly associated with an increased risk of developing CKD, regardless of other comorbid conditions. Although the molecular mechanisms that link both diseases are not well established, the role of adipose tissue (AT) is becoming increasingly important in obesity-associated kidney damage. In the context of obesity, lipotoxicity and the alteration of AT secretion profile promote inflammation, oxidative stress, and fibrosis in the kidney, which ultimately leads to impaired renal function. Different studies have highlighted the importance of body weight loss in the improvement of renal function markers. In this regard, bariatric surgery, rather than low-calorie diets, has been accepted as the most effective option to lose weight. In fact, a significant reduction in proteinuria and hyperfiltration has been observed in association with surgically induced weight loss. Detection of early signs of kidney dysfunction in patients with obesity has not been accomplished yet, though. Therefore, understanding the harmful effects within the adipo-renal axis is essential to prevent the progression to the irreversible renal insufficiency. MicroRNAs have recently been described as important modulators of normal kidney function. Some of these microRNAs could be potential early markers of kidney damage, which would help with the diagnosis and the prevention of CKD.