neomycin sulfate The level of estrogens is age dependent in
The level of estrogens is age-dependent in females, whereas the neomycin sulfate of BMP4 might be influenced by genetics and may be highly variable among humans. It was reported that one genetic variant of BMP4 (single nucleotide polymorphism rs8014363) was associated with levels of triglyceride and high-density lipoprotein cholesterol after adjusting for age, gender, and BMI in a study that involved 6822 participants (Tang et al., 2013), supporting a link between BMP4 genetics and adipose tissue metabolism. Our previous study also showed that the level of BMP4 in human adipose tissues of about 32 participants (15 males and 17 females) correlated inversely with BMI (Qian et al., 2013). With more female participants enrolled in this study, we found that the inverse correlation was significant among postmenopausal women rather than premenopausal ones. Estrogens are an important sex hormone in females that decreases with age and in some pathological conditions, and when the regulation of BMP4 becomes dominant, which affect the incidence of obesity (Fig. 7D). This study also suggests that the regulation of BMP4 may offer a new opportunity of intervention in the control of excessive obesity.
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Conflict of interest
Acknowledgments We thank Dr. Brigid Hogan at Department of Cell Biology, Duke University Medical Center for kindly providing BMP4LoxP/LoxP mice.
Introduction Obesity and diabetes are worldwide health burdens. The incidence of obesity has doubled since 1980 with over 1.9 billion adults overweight in 2014, and globally >400 million people have type 2 diabetes. Unfortunately, existing anti-obesity and anti-diabetic therapeutic display insufficient efficacy and adverse effects (Aguiree et al., 2013). Therefore, there is a global need for novel therapeutic targets that regulate excessive adiposity and glycemic pathophysiology to treat those populations challenged by adverse clinical outcomes. The nuclear hormone receptor (NR) superfamily is comprised of hormone-dependent transcription factors that translate physiological signals into gene regulation to control metabolism in an organ-specific manner. In the context of metabolic disease, dysfunctional NR signaling results in dyslipidemia, diabetes, and obesity. There are 48 NRs in humans, all implicated in disease, although not all with identified natural ligands; these NRs are denoted as orphans. The NR, RORα, has been implicated in the regulation of glucose and fat homeostasis, but has historically belonged to the orphan class of NRs. However, interest in this specific receptor has been stimulated by the rapid emergence of small molecule agonist and inverse agonists (Smith and Muscat, 2006; Marciano et al., 2014). Several studies suggest that RORα is a constitutively active receptor. The constitutive recruitment of coactivators such as p300, glutamate receptor interacting protein 1 and steroid receptor coactivator 1 (reviewed in Fitzsimmons et al., 2012) by RORα in the absence of exogenous ligands supports a state of constitutive activation of RORα by a common endogenous ligand (such as cholesterol metabolites and intermediates) (reviewed in Fitzsimmons et al., 2012; Marciano et al., 2014). For example, crystallographic and mass spectrometry studies showed that the RORα-LBD is constitutively bound to endogenous ligands including fatty acids, cholesterol metabolites and all trans retinoic acid (reviewed in Marciano et al., 2014). Furthermore, the basal activity of RORs is highlighted by the observation that natural inverse agonists are exploited (for example ursolic acid) in RORγ reporter assays to identify agonists in reporter assays (Santori, 2015; Chang et al., 2016). Recently, it was confirmed that oxygenated sterols (natural LXR ligands and agonists) function as native ligands, but as inverse agonists for both RORα and RORγ (reviewed in Marciano et al., 2014; Kojetin and Burris, 2014). Moreover, the crosstalk between the (oxysterol activated NR) LXR and RORα/γ signaling pathways is underscored by our recent study demonstrating decreased expression of the cholesterol 25-hydroxylase mRNA (encodes the enzyme that produces the LXR agonist 25-hydroxycholesterol, 25-HC) and aberrant phagocytosis in the Rorα-deficient staggerer mice (sg/sg) (Tuong et al., 2013). New studies (Tuong et al., 2016) implicate Rorα in regulating lipid storage in macrophages in a process modulated by 25-HC levels.