Ablation of adipose-HO-1 expression increases white fat over beige fat through inhibition of mitochondrial fusion and of PGC1α in female mice

Abstract

Abstract:Background: Hmox1 plays an important role in the regulation of mitochondrial bioenergetics and function by regulating cellular heme-derived CO and bilirubin. Previous studies have demonstrated that global disruption of HO-1 in humans and mice resulted in severe organ dysfunction. Methods: We investigated the potential role of adipose-specific-HO-1 genetic ablation on adipose tissue function, mitochondrial quality control and energy expenditure by generating an adipo-HO-1 knockout mouse model (Adipo-HO-1 −/− ) and, in vitro, adipocyte cells in which HO activity was inhibited. Adiposity, signaling proteins, fasting glucose and oxygen consumption were determined and compared to adipocyte cultures with depressed levels of both HO-1/HO-2. Results: Adipo-HO-1 −/− female mice exhibited increased adipocyte size, and decreases in the mitochondrial fusion to fission ratio, PGC1, and SIRT3. Importantly, ablation of HO-1 in adipose tissue resulted in fat acquiring many properties of visceral fat such as decreases in thermogenic genes including pAMPK and PRDM16. Deletion of HO-1 in mouse adipose tissue led to complete metabolic dysfunction, an increase in white adipose tissue, a reduction of beige fat and associated increases in FAS, aP2 and hyperglycemia. Mechanistically, genetic deletion of HO-1 in adipose tissues decreased the mitochondrial fusion to fission ratio; disrupted the activity of the PGC1 transcriptional axis and thermogenic genes both in vitro and in vivo. Conclusion: Ablation of adipose tissue-HO-1 abridged PGC1 expression promoted mitochondrial dysfunction and contributed to an increase of pro-inflammatory visceral fat and abrogated beige-cell like phenotype.

CYP-450 Epoxygenase Derived Epoxyeicosatrienoic Acid Contribute To Reversal of Heart Failure in Obesity-Induced Diabetic Cardiomyopathy via PGC-1α Activation

“…For Western blot, tissues were first lysed in RIPA buffer supplemented with protease and phosphatase inhibitors (Complete™ Mini and PhosSTOP™, Roche Diagnostics, Indianapolis, IA) and total protein content was analyzed by the Bradford method (BIO-RAD, Hercules, CA). Immunoblotting was performed for select proteins [ 18 , 36 ].…”

“…Obesity and ROS induction contributes to a reduction in HO-1 levels by either inherited or sedentary lifestyle-induced dyslipidemia, a decline in respiratory capacity, OXPHOS machinery, and ATP production [ 12 – 14 ], contributing to mitochondrial dysfunction and reduced energy expenditure [ 15 – 17 ]. Moreover, oxidative mutations of mitochondrial fusion and fission proteins disable the capability of mitochondrial dynamics to maintain mtDNA integrity, further enhancing ROS-mediated oxidative stress [ 18 , 19 ].…”

Cardioprotective Heme Oxygenase‐1‐PGC1α Signaling in Epicardial Fat Attenuates Cardiovascular Risk in Humans as in Obese Mice

“…We have previously shown that ablation of HO-1 is associated with a reduction in PGC1α, which, itself, is responsible for a decrease in MFN2 and a resulting increase in white fat over brown-like fat (6,44). As noted, HO-1 expression is also mediated via PGC1α activation and, indirectly, can further increase PGC1α by enhancing EET activity.…”

Heme Oxygenase 1 and 2 Differentially Regulate Glucose Metabolism and Adipose Tissue Mitochondrial Respiration: Implications for Metabolic Dysregulation

“…This is supported by a study showing that HO-1 levels are reduced in adipocytes isolated from visceral fat tissues of obese mice compared to lean mice [ 30 ]. Ablation of Hmox1 in adipose tissue increases pro-inflammatory visceral fat and abrogates a beige-cell like phenotype, a comparable thermogenic potential to brown fat cells [ 32 ]. This is in contrast to our findings that global deletion of Hmox1 had no effect on the weight of gonadal fat tissue (WAT).…”