Search

Background: Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from lean mass, the metabolically detrimental abdominal obesity has been estimated using waist-hip ratio (WHR). Waist-hip ratio adjusted for body mass index (WHRadjBMI) in turn is a well-established sex-specific marker for abdominal fat and adiposity, and a predictor of adverse metabolic outcomes, such as T2D. However, the underlying genes and regulatory mechanisms orchestrating the sex differences in obesity and body fat distribution in humans are not well understood. Methods: We searched for genetic master regulators of WHRadjBMI by employing integrative genomics approaches on human subcutaneous adipose RNA sequencing (RNA-seq) data (n ~ 1400) and WHRadjBMI GWAS data (n ~ 700,000) from the WHRadjBMI GWAS cohorts and the UK Biobank (UKB), using co-expression network, transcriptome-wide association study (TWAS), and polygenic risk score (PRS) approaches. Finally, we functionally verified our genomic results using gene knockdown experiments in a human primary cell type that is critical for adipose tissue function. Results: Here, we identified an adipose gene co-expression network that contains 35 obesity GWAS genes and explains a significant amount of polygenic risk for abdominal obesity and T2D in the UKB (n = 392,551) in a sex-dependent way. We showed that this network is preserved in the adipose tissue data from the Finnish Kuopio Obesity Study and Mexican Obesity Study. The network is controlled by a novel adipose master transcription factor (TF), TBX15, a WHRadjBMI GWAS gene that regulates the network in trans. Knockdown of TBX15 in human primary preadipocytes resulted in changes in expression of 130 network genes, including the key adipose TFs, PPARG and KLF15, which were significantly impacted (FDR < 0.05), thus functionally verifying the trans regulatory effect of TBX15 on the WHRadjBMI co-expression network. Conclusions: Our study discovers a novel key function for the TBX15 TF in trans regulating an adipose co-expression network of 347 adipose, mitochondrial, and metabolically important genes, including PPARG, KLF15, PPARA, ADIPOQ, and 35 obesity GWAS genes. Thus, based on our converging genomic, transcriptional, and functional evidence, we interpret the role of TBX15 to be a main transcriptional regulator in the adipose tissue and discover its importance in human abdominal obesity. [ABSTRACT FROM AUTHOR]

C16H11BF2N2, monoclinic, P21/c (no. 14), a = 9.0978(14) Å, b = 18.580(3) Å, c = 15.476(2) Å, β = 99.516(5)°, V = 2580.0(7) Å3, Z = 8, Rgt(F) = 0.0406, wRref(F2) = 0.1307, T = 193 K. [ABSTRACT FROM AUTHOR]

C18H15BN2O2, monolinic, P21/n (no. 14), a = 13.61(2) Å, b = 7.389(11) Å, c = 16.34(2) Å, β = 113.91(2)°, V = 1502(4) Å3, Z = 4, Rgt(F) = 0.0544, wRref(F2) = 0.1651, T = 273 K. [ABSTRACT FROM AUTHOR]

C18H17BN2O2, monoclinic, P21/c (no. 14), a = 12.5782(14) Å, b = 13.6724(14) Å, c = 8.7113(9) Å, β = 97.819(6)°, V = 1484.2(3) Å3, Z = 4, Rgt(F) = 0.0482, wRref(F2) = 0.1357, T = 193 K. [ABSTRACT FROM AUTHOR]

C18H15BN2O2, monoclinic, P21/c (no. 14), a = 6.8522(9) Å, b = 8.4333(11) Å, c = 13.1908(18) Å, β = 95.880(5)°, V = 758.24(17) Å3, Z = 2, Rgt(F) = 0.0381, wRref(F2) = 0.1068, T = 193 K. CCDC no.: 2045109 [ABSTRACT FROM AUTHOR]

C17H13BN2O2, orthorhombic, Pbca (no. 61), a = 10.0820(14) Å, b = 13.1135(19) Å, c = 20.644(3) Å, V = 2729.4 Å3, Z = 8, Rgt(F) = 0.0373, wRref(F2) = 0.1005, T = 193 K. [ABSTRACT FROM AUTHOR]

B Correction to: Genome Med 13, 123 (2021) b B https://doi.org/10.1186/s13073-021-00939-2 b It was highlighted that in the original article [[1]] the UK Biobank Resource Application Number was incorrect (3934). Identification of TBX15 as an adipose master trans regulator of abdominal obesity genes. [Extracted from the article]

C21H25EuN2O10, monoclinic, P21/n (no. 14), a = 14.1635(8) Å, b = 12.1381(6) Å, c = 14.4528(7) Å, β = 104.361(2)°, V = 2407.1(2) Å3, Z = 4, Rgt(F) = 0.0304, wRref(F2) = 0.0893, T = 296 K. [ABSTRACT FROM AUTHOR]

Ischemic stroke poses a significant health risk due to its high rate of disability and mortality. To address this problem, several therapeutic approaches have been proposed, including interruption targeting programmed cell death (PCD). Ferroptosis is a newly defined PCD characterized by iron-dependent accumulation of lipid peroxidation, and is becoming a promising target for treating numerous diseases. To explore the underlying mechanisms of the initiation and execution of ferroptosis in ischemic stroke, we established stroke models in vivo and in vitro simulating ischemia/reperfusion (I/R) neuronal injury. Different from previous reports on stroke, we tested ferroptosis by measuring the levels of core proteins, such as ACSL4, 15-LOX2, Ferritin and GPX4. In addition, I/R injury induces excessive degradation of ferritin via the autophagy pathway and subsequent increase of free iron in neurons. This phenomenon has recently been termed ferritinophagy and reported to be regulated by nuclear receptor coactivator 4 (NCOA4) in some cell lines. Increased NCOA4 in cytoplasm was detected in our study and then silenced by shRNA to investigate its function. Both in vivo and in vitro , NCOA4 deletion notably abrogated ferritinophagy caused by I/R injury and thus inhibited ferroptosis. Furthermore, we found that NCOA4 was upregulated by ubiquitin specific peptidase 14 (USP14) via a deubiquitination process in damaged neurons, and we found evidence of pharmacological inhibition of USP14 effectively reducing NCOA4 levels to protect neurons from ferritinophagy-mediated ferroptosis. These findings suggest a novel and effective target for treating ischemic stroke. [Display omitted] [ABSTRACT FROM AUTHOR]