title: Metformin Improves Metabolic Memory in High Fat Diet (HFD)-induced Renal Dysfunction.
abstract: Recently, we have shown that high fat diet (HFD)in vivoandin vitrogenerates metabolic memory by altering H3K36me2 and H3K27me3 on the promoter ofFOXO1(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 andin vivovascular 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.
authors.affiliation: From the Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab-160062, India tikoo.k@gmail.com.
authors.forename: Kulbhushan
authors.initials: K
authors.lastname: Tikoo
authors.affiliation: From the Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab-160062, India.
authors.forename: Ekta
authors.initials: E
authors.lastname: Sharma
authors.affiliation: From the Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab-160062, India.
authors.forename: Venkateswara Rao
authors.initials: VR
authors.lastname: Amara
authors.affiliation: From the Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab-160062, India.
authors.forename: Himani
authors.initials: H
authors.lastname: Pamulapati
authors.affiliation: From the Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab-160062, India.
authors.forename: Vaibhav Shrirang
authors.initials: VS
authors.lastname: Dhawale
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology; D007333:Insulin Resistance; D053583:Interleukin-1beta / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D053583:Interleukin-1beta; D000804:Angiotensin II; D008687:Metformin; D051546:Cyclooxygenase 2; D011065:Poly(ADP-ribose) Polymerases; D055372:AMP-Activated Protein Kinases; D053148:Caspase 3
keywords: AMP-activated kinase (AMPK); Metabolic memory; diet reversal; fibronectin; high fat diet (HFD); insulin resistance; kidney; metformin