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

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.

Rats Genetically Selected for High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin by Upregulation of Hepatic Biliverdin Reductase-A (BVRA) and Suppression of UGT1A1

“…The PPARα-target gene Gys2 (glycogen synthase-2) [30,37], was significantly (p < 0.05) higher in the HCR rats, but not the glucose and fat scavenger Cd36 (Figure 5C,D). We have shown that bilirubin activation of PPARα induces mitochondrial function [20], and that mice with the loss of BVRA have reduced mitochondrial function [38]. Therefore, we measured citric acid and acetic acid in the HCR and LCR rats, two metabolites associated with mitochondrial activity [39][40][41].…”

“…These data indicate that HCR rats may have a higher running capacity by increasing hepatic BVRA, decreasing UGT1A1, elevating plasma bilirubin that activates PPARα for glycogen storage, and improvement of mitochondria function (Figure 7). We have shown that bilirubin activation of PPARα induces mitochondrial function [20], and that mice with the loss of BVRA have reduced mitochondrial function [38]. Therefore, we measured citric acid and acetic acid in the HCR and LCR rats, two metabolites associated with mitochondrial activity [39][40][41].…”

“…We have shown that bilirubin activation of PPARα induces mitochondrial function [ 20 ], and that mice with the loss of BVRA have reduced mitochondrial function [ 38 ]. Therefore, we measured citric acid and acetic acid in the HCR and LCR rats, two metabolites associated with mitochondrial activity [ 39 , 40 , 41 ].…”

“…Low intrinsic running capacity is associated with reduced skeletal muscle substrate oxidation and lower mitochondrial content in white skeletal muscle [61]. Adipose-specific BVRA knockout mice fed a high-fat diet exhibited increased fat mass and significantly fewer mitochondria in WAT than floxed control fed the same diet [38]. A liver to muscle or liver to adipose circuit may exist via BVRA mediated production of bilirubin, enhancing aerobic exercise capacity due to the mitochondrial effects of bilirubin [19,20,38,62], which might contribute to the high aerobic capacity of the HCR rats.…”

BVR-A Deficiency Leads to Autophagy Impairment through the Dysregulation of AMPK/mTOR Axis in the Brain—Implications for Neurodegeneration

“…BVR-A was shown to be a Ser/Thr/Tyr kinase able to regulate a number of pathways involved in cell growth, differentiation and survival [1,3,12]. In particular, BVR-A was identified as a novel regulator of the insulin/IGF1 signaling in vitro [13][14][15] and recent studies showing that loss of BVR-A impairs insulin signaling activation and cell metabolism also in vivo support this hypothesis [16][17][18][19].…”