Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice.

David E Stec,Andrea L Nestor-Kalinoski,Zachary L Mitchell,Matthew C Donald,Terry D Hinds,Darren M Gordon,Justin F Creeden

doi:10.3390/biom10030387

David E Stec, Andrea L Nestor-Kalinoski + Show 5 more

Open Access

https://doi.org/10.3390/biom10030387

Copy DOI

Abstract

Biliverdin reductase (BVR) is an enzymatic and signaling protein that has multifaceted roles in physiological systems. Despite the wealth of knowledge about BVR, no data exist regarding its actions in adipocytes. Here, we generated an adipose-specific deletion of biliverdin reductase-A (BVRA) (BlvraFatKO) in mice to determine the function of BVRA in adipocytes and how it may impact adipose tissue expansion. The BlvraFatKO and littermate control (BlvraFlox) mice were placed on a high-fat diet (HFD) for 12 weeks. Body weights were measured weekly and body composition, fasting blood glucose and insulin levels were quantitated at the end of the 12 weeks. The data showed that the percent body fat and body weights did not differ between the groups; however, BlvraFatKO mice had significantly higher visceral fat as compared to the BlvraFlox. The loss of adipocyte BVRA decreased the mitochondrial number in white adipose tissue (WAT), and increased inflammation and adipocyte size, but this was not observed in brown adipose tissue (BAT). There were genes significantly reduced in WAT that induce the browning effect such as Ppara and Adrb3, indicating that BVRA improves mitochondria function and beige-type white adipocytes. The BlvraFatKO mice also had significantly higher fasting blood glucose levels and no changes in plasma insulin levels, which is indicative of decreased insulin signaling in WAT, as evidenced by reduced levels of phosphorylated AKT (pAKT) and Glut4 mRNA. These results demonstrate the essential role of BVRA in WAT in insulin signaling and adipocyte hypertrophy.

Highlights

Current estimates put the world’s obese population at one-third; that figure may be an underestimate of the global obesity epidemic [1,2,3]
Western blot analysis of the levels of biliverdin reductase-A (BVRA) expressed in va3rioof u14s tissues, including spleen, heart, white adipose (WAT), brown adipose (BAT), and kidney showed that BlvraFatKO mice exhibited near-complete loss of BVRA in the white adipose tissue (WAT) and BATcayslicnodmerpwariethdatocythliendBrlivcraalFploxlamstiiccein(Fseigrtutrhea1tBfu).nBcVtioRnAedletvoellisminit oththeemr otivsesumeesnstuocfhthaes mthiecespwleheilne, thheeayrtw, aenrediknitdhneeEycwhoerMeRnIoitndsitfrfuemreennttb. etween the two groups of mice
Western blot analysis of the levels of BVRA expressed in various tissues, including spleen, heart, white adipose (WAT), brown adipose (BAT), and kidney showed that BlvraFatKO mice exhibited near-complete loss of BVRA in the WAT and brown adipose tissue (BAT) as compared to the BlvraFlox mice (Figure 1B)

Summary

Introduction

Current estimates put the world’s obese population at one-third; that figure may be an underestimate of the global obesity epidemic [1,2,3]. Obesity is a co-morbidity for numerous pathological conditions, including cardiovascular disease, some cancers, increased traumatic injury, and inflammation [4,5,6]. To combat this epidemic, a better understanding of the factors that promote and protect against the harmful effects of obesity are needed. Obesity increases insulin resistance and adipocyte size and reduces mitochondria number [7,8,9]. The visceral fat releases more harmful adipokines than subcutaneous fat, resulting in worsened insulin resistance and inflammation, promoting complications such as type II diabetes and non-alcoholic fatty liver disease (NAFLD) [10,11]. Recent investigations have shown that biliverdin reductase-A (BVRA) can bind to the insulin receptor and increase sensitivity for glucose uptake [12,13], implicating it may be a potential therapeutic for reversing glucose intolerance

Methods

Results

Discussion

Conclusion