Cytochrome P450 2F2 (CYP2F2) negatively regulates browning in 3T3-L1 white adipocytes.

Cytochromes P450 (CYPs) are a multigene superfamily of constitutively expressed and inducible enzymes responsible for the detoxification of many endogenous and exogenous compounds and for the metabolism of numerous medications. The cytochrome P450 2F2 (CYP2F2) subfamily is preferentially expressed in the respiratory tract, but its functional role in adipocytes has never been explored. We found that CYP2F2 was highly expressed during the differentiation of the C3H10T1/2 murine mesenchymal stem cells to adipocytes and here we have explored its functional role in adipocytes. The expression of thermogenic marker proteins such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), PR domain containing 16 (PRDM16), and uncoupling protein 1 (UCP1) and beige-fat specific genes were significantly increased in Cyp2f2-deficient 3T3-L1 adipocytes. Moreover, Cyp2f2 silencing led to reduced adipogenesis and lipogenesis, and enhanced lipid catabolism through the increased expression of lipolytic and fatty acid oxidative enzymes. A mechanistic study to identify molecular signals for CYP2F2-mediated negative regulation in the browning of white adipocytes revealed that CYP2F2 impairs the beta-3 adrenergic receptor (ß3-AR) activation as well as its downstream regulators including protein kinase A (PKA), p38 mitogen-activated protein kinase (p38 MAPK), and activating transcription factor 2 (ATF2). This data provides evidence that CYP2F2 is a negative regulator of lipid catabolism and browning in white adipocytes, suggesting that inhibitors of CYP2F2 could be potential drugs for the treatment of obesity with a focus on enhancing energy expenditure.

Cytochrome P450 2E1 (CYP2E1) positively regulates lipid catabolism and induces browning in 3T3-L1 white adipocytes.

AIMS: Browning induction (beiging) of white adipocytes is an emerging prospective strategy to defeat obesity and its related metabolic disorders. Cytochrome P450 2E1 (CYP2E1), a membrane protein which belongs to the cytochrome P450 superfamily, reportedly functions in the xenobiotic metabolism in the body, especially ethanol metabolism. Although previous studies have reported the effect of CYP2E1 on obesity in animal models, the data remains controversial. In the current study, we investigate for the first time, the role of CYP2E1 in lipid metabolism in 3T3-L1 white adipocytes, with a focus on fat browning. METHODS: 3T3-L1 white adipocytes and Cyp2e1 siRNA were applied to investigate the role of CYP2E1 in white adipocytes. After that, cells were seperately exposed to ß3-AR agonist, ß3-AR antagonist and p38 inhibitor to identify the pathway which CYP2E1 was involved in to regulate browning event in white adipocytes. KEY FINDINGS: We found that CYP2E1 deficiency results in reduced adipogenesis and lipogenesis as well as brown adipocyte-like phenotype induction. A mechanistic study to identify the molecular signals for CYP2E1 regulation in the browning of white adipocytes revealed that CYP2E1 inhibition deters the ß3-adrenergic receptor activation and its downstream targets. SIGNIFICANCE: Our data unveilved a previously unknown mechanism in the regulation of browning by CYP2E1 in 3T3-L1 white adipocytes, suggesting that CYP2E1 is a promising molecular target for the treatment of obesity and its related diseases.

BMP10 positively regulates myogenic differentiation in C2C12 myoblasts via the Smad 1/5/8 signaling pathway.

BMP10 plays an essential role in regulating cardiac growth, chamber maturation, and maintaining normal expressions of several key cardiogenic factors; however, other functional roles of BMP10 in muscle remain unexplored. This study therefore undertook to investigate the roles of BMP10 in muscle physiology, using mouse-derived C2C12 myoblasts. Bmp10 silencing prevented a number of biological processes such as myogenic differentiation, glucose uptake, and lipid catabolism, whereas exogenous induction of BMP10 in C2C12 cells significantly stimulated the expression of proteins and genes involved in these processes, as well as mitochondrial biogenesis and thermogenesis, resulting in reduced lipid accumulation. A mechanistic study revealed that BMP10 stimulates myogenesis mainly via the Smad 1/5/8 signaling pathway. In conclusion, our data unveiled a previously unknown mechanism in the regulation of lipid metabolisms by BMP10 in muscle cells and identified its significant roles in systemic metabolic homeostasis, shedding light on BMP10 as a pharmacotherapeutic target to treat metabolic disorders.