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Metformin Improves Metabolic Memory in High Fat Diet (HFD)-induced Renal Dysfunction.

ABSTRACT: Recently, we have shown that high fat diet (HFD) in vivo and in vitro generates metabolic memory by altering H3K36me2 and H3K27me3 on the promoter of FOXO1 (transcription factor of gluconeogenic genes) (Kumar, S., Pamulapati, H., and Tikoo, K. (2016) Mol. Cell. Endocrinol. 422, 233-242). Here we checked the hypothesis whether concomitant diet reversal and metformin could overcome HFD-induced metabolic memory and renal damage. Male adult Sprague-Dawley rats were rendered insulin-resistant by feeding high fat diet for 16 weeks. Then the rats were subjected to diet reversal alone and along with metformin for 8 weeks. Biochemical and histological markers of insulin resistance and kidney function were measured. Blood pressure and in vivo vascular reactivity to angiotensin II (200 ng kg^-1) were also checked. Diet reversal could improve lipid profile but could not prevent renal complications induced by HFD. Interestingly, metformin along with diet reversal restored the levels of blood glucose, triglycerides, cholesterol, blood urea nitrogen, and creatinine. In kidney, metformin increased the activation of AMP-activated protein kinase (AMPK) and decreased inflammatory markers (COX-2 and IL-1β) and apoptotic markers (poly(ADP-ribose) polymerase (PARP) and caspase 3). Metformin was effective in lowering elevated basal blood pressure and acute change in mean arterial pressure in response to angiotensin II (Ang II). It also attenuated tubulointerstitial fibrosis and glomerulosclerosis induced by HFD feeding in kidney. Here we report, for the first time, that metformin treatment overcomes metabolic memory and prevents HFD-induced renal damage.

SUBMITTER: Tikoo K

PROVIDER: S-EPMC5063970 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aims/hypothesisDespite a similar fat storing function, visceral (intra-abdominal) white adipose tissue (WAT) is detrimental, whereas subcutaneous WAT is considered to protect against metabolic disease. Recent findings indicate that thermogenic genes, expressed in brown adipose tissue (BAT), can be induced primarily in subcutaneous WAT. Here, we investigate the hypothesis that the Wilms tumour gene product (WT1), which is expressed in intra-abdominal WAT but not in subcutaneous WAT and BAT, suppresses a thermogenic program in white fat cells.MethodsHeterozygous Wt1 knockout mice and their wild-type littermates were examined in terms of thermogenic and adipocyte-selective gene expression. Glucose tolerance and hepatic lipid accumulation in these mice were assessed under normal chow and high-fat diet conditions. Pre-adipocytes isolated from the stromal vascular fraction of BAT were transduced with Wt1-expressing retrovirus, induced to differentiate and analysed for the expression of thermogenic and adipocyte-selective genes.ResultsExpression of the thermogenic genes Cpt1b and Tmem26 was enhanced and transcript levels of Ucp1 were on average more than tenfold higher in epididymal WAT of heterozygous Wt1 knockout mice compared with wild-type mice. Wt1 heterozygosity reduced epididymal WAT mass, improved whole-body glucose tolerance and alleviated severe hepatic steatosis upon diet-induced obesity in mice. Retroviral expression of WT1 in brown pre-adipocytes, which lack endogenous WT1, reduced mRNA levels of Ucp1, Ppargc1a, Cidea, Prdm16 and Cpt1b upon in vitro differentiation by 60-90%. WT1 knockdown in epididymal pre-adipocytes significantly lowered Aldh1a1 and Zfp423 transcripts, two key suppressors of the thermogenic program. Conversely, Aldh1a1 and Zfp423 mRNA levels were increased approximately five- and threefold, respectively, by retroviral expression of WT1 in brown pre-adipocytes.Conclusion/interpretationWT1 functions as a white adipocyte determination factor in epididymal WAT by suppressing thermogenic genes. Reducing Wt1 expression in this and other intra-abdominal fat depots may represent a novel treatment strategy in metabolic disease.

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Metformin Improves Metabolic Memory in High Fat Diet (HFD)-induced Renal Dysfunction.

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