TY - DATA T1 - Elevated autophagy gene expression in adipose tissue of obese humans: A potential non-cell-cycle-dependent function of E2F1 PY - 2015/11/02 AU - Yulia Haim AU - Matthias Blüher AU - Nora Klöting AU - Ilana Harman-Boehm AU - Boris Kirshtein AU - Doron Ginsberg AU - Martin Gericke AU - Julia Kovsan AU - Tanya Tarnovscki AU - Nava Bashan AU - Assaf Rudich AU - Noa Slutsky AU - Nir Goldstein AU - Esther Guiu Jurado AU - Leonid Kachko AU - Yiftach Gepner AU - Iris Shai UR - https://tandf.figshare.com/articles/journal_contribution/Elevated_autophagy_gene_expression_in_adipose_tissue_of_obese_humans_A_potential_non_cell_cycle_dependent_function_of_E2F1/1621905 DO - 10.6084/m9.figshare.1621905.v1 L4 - https://ndownloader.figshare.com/files/2604655 KW - adipoq KW - body mass index KW - CCND KW - ffa KW - adipocyte KW - bmi KW - E 2F expression KW - HEK 293 cells KW - E 2F protein KW - atg KW - E 2F binding KW - 1LC KW - mef KW - autophagy genes KW - MKI KW - Adipose tissue KW - tnf KW - E 2F KW - Elevated autophagy gene expression KW - Elevated E 2F KW - cell cycle E 2F target KW - e 2f knockout mice KW - E 2F Autophagy genes KW - autophagy gene expression KW - upregulated E 2F sensitizes adipose tissue autophagy KW - Atg 7 siRNA N2 - Autophagy genes' expression is upregulated in visceral fat in human obesity, associating with obesity-related cardio-metabolic risk. E2F1 (E2F transcription factor 1) was shown in cancer cells to transcriptionally regulate autophagy. We hypothesize that E2F1 regulates adipocyte autophagy in obesity, associating with endocrine/metabolic dysfunction, thereby, representing non-cell-cycle function of this transcription factor. E2F1 protein (N=69) and mRNA (N=437) were elevated in visceral fat of obese humans, correlating with increased expression of ATG5 (autophagy-related 5), MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β), but not with proliferation/cell-cycle markers. Elevated E2F1 mainly characterized the adipocyte fraction, whereas MKI67 (marker of proliferation Ki-67) was elevated in the stromal-vascular fraction of adipose tissue. In human visceral fat explants, chromatin-immunoprecipitation revealed body mass index (BMI)-correlated increase in E2F1 binding to the promoter of MAP1LC3B, but not to the classical cell cycle E2F1 target, CCND1 (cyclin D1). Clinically, omental fat E2F1 expression correlated with insulin resistance, circulating free-fatty-acids (FFA), and with decreased circulating ADIPOQ/adiponectin, associations attenuated by adjustment for autophagy genes. Overexpression of E2F1 in HEK293 cells enhanced promoter activity of several autophagy genes and autophagic flux, and sensitized to further activation of autophagy by TNF. Conversely, mouse embryonic fibroblast (MEF)-derived adipocytes from e2f1 knockout mice (e2f1−/−) exhibited lower autophagy gene expression and flux, were more insulin sensitive, and secreted more ADIPOQ. Furthermore, e2f1−/− MEF-derived adipocytes, and autophagy-deficient (by Atg7 siRNA) adipocytes were resistant to cytokines-induced decrease in ADIPOQ secretion. Jointly, upregulated E2F1 sensitizes adipose tissue autophagy to inflammatory stimuli, linking visceral obesity to adipose and systemic metabolic-endocrine dysfunction. ER -