Abstract 079: Hmox1 Activation Reprograms White Fat to Beige Adipose Tissue Through Recruitment of Cyp2C44-derived EET, pAMPK-PGC1α That Enhances Mitochondrial Mfn2 and Opa1

Abstract

Introduction: Hmox1 +/+ is critical in the regulation of insulin sensitivity and mitochondrial bioenergetics by regulating cellular heme-derived CO and bilirubin levels (Hosick and Stec 2015). We have demonstrated that high fat (HF) diets decreased HO-1 and PGC-1α. We examined the role of HO-1 on white and brown-fat like and energy expenditure genes. Methods: C57/B16 female mice, 5 wks old, were fed a HF diet for 24 wks. At 12 wks, when all mice had established pre-diabetic stage, cobalt protoporphyrin, (CoPP) was administered, i.p. (0.3 mg /100, BW), for the last 8 wks. Blood and fat tissues were collected, Cyp-2C44-derived EET, AMPK, HO-1, insulin receptors, and mito-fusion protein markers were determined in the three groups of mice: A) Control, B) HF, C) HF-CoPP. We generated adipoq-HO-1 knockout mouse model and mRNA and protein signaling, adiposity, oxygen consumption were determined and compared to adipocyte culture depressed in HO. Result: CoPP increased HO-1 expression by 20-fold (p<0.02), EETs (p<0.05), PGC-1α (p<0.05), pAMPK (p<0.05) and Mfn1/2 (p<0.05), Opa1 and OXPHOS (p<0.05), oxygen consumption (Vo 2 ), but decreased fasting glucose levels. These was associated with a decreases in VAT, SAT (p<0.02). Adipoq-HO-1 -/- female mice exhibit marked decrease in pAMPK, Cyp2C44, PGC1α, Mfn1/2, Opa1, UCP1 and SIRT1 but increased adipogenic markers including Mest/Peg1 in adipose tissues. Conclusion: Overexpression of HO-1-derived CO and bilirubin enhances UCP1, Cyp2C44, pAMPK-PGC1α to turn on a robust program of energy expenditure genes and reprogrammed white (VAT, SAT) to beige adipose and brown-like adipocytes. Deletion of HO-1 or suppression of HO-1 led to metabolic dysfunction, hyperglycemia as in white fat to exhibit significant low energy expenditure, OXPHOS and VO 2 . Mechanistically, absence of HO-1 decreased AMPK signaling; thereby disrupting EET-PGC-1α expression and mitochondrial oxidative metabolism. These findings offer new insight for the development of obesity treatment strategies through restoration of HO-1 and adipocyte function.