title: Elevated autophagy gene expression in adipose tissue of obese humans: A potential non-cell-cycle-dependent function of E2F1.
abstract: 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.
authors.affiliation: a Department of Clinical Biochemistry and Pharmacology ; Faculty of Health Sciences; Ben-Gurion University of the Negev ; Beer-Sheva , Israel.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Haim
authors.affiliation: b Department of Medicine ; University of Leipzig ; Leipzig , Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.affiliation: a Department of Clinical Biochemistry and Pharmacology ; Faculty of Health Sciences; Ben-Gurion University of the Negev ; Beer-Sheva , Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Slutsky
authors.affiliation: a Department of Clinical Biochemistry and Pharmacology ; Faculty of Health Sciences; Ben-Gurion University of the Negev ; Beer-Sheva , Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Goldstein
authors.affiliation: b Department of Medicine ; University of Leipzig ; Leipzig , Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Klöting
authors.affiliation: c Soroka Academic Medical Center and Faculty of Health Sciences; Ben-Gurion University of the Negev ; Beer-Sheva , Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Harman-Boehm
authors.affiliation: c Soroka Academic Medical Center and Faculty of Health Sciences; Ben-Gurion University of the Negev ; Beer-Sheva , Israel.
authors.forename: Boris
authors.initials: B
authors.lastname: Kirshtein
authors.affiliation: d The Mina and Everard Goodman Faculty of Life Science; Bar-Ilan University ; Ramat Gan , Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Ginsberg
authors.affiliation: e Institute of Anatomy; University of Leipzig ; Leipzig , Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Gericke
authors.affiliation: b Department of Medicine ; University of Leipzig ; Leipzig , Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Guiu Jurado
authors.affiliation: a Department of Clinical Biochemistry and Pharmacology ; Faculty of Health Sciences; Ben-Gurion University of the Negev ; Beer-Sheva , Israel.
authors.forename: Julia
authors.initials: J
authors.lastname: Kovsan
authors.affiliation: a Department of Clinical Biochemistry and Pharmacology ; Faculty of Health Sciences; Ben-Gurion University of the Negev ; Beer-Sheva , Israel.
authors.forename: Tanya
authors.initials: T
authors.lastname: Tarnovscki
authors.affiliation: c Soroka Academic Medical Center and Faculty of Health Sciences; Ben-Gurion University of the Negev ; Beer-Sheva , Israel.
authors.forename: Leonid
authors.initials: L
authors.lastname: Kachko
authors.affiliation: a Department of Clinical Biochemistry and Pharmacology ; Faculty of Health Sciences; Ben-Gurion University of the Negev ; Beer-Sheva , Israel.
authors.forename: Nava
authors.initials: N
authors.lastname: Bashan
authors.affiliation: f Department of Epidemiology ; Ben-Gurion University of the Negev ; Beer-Sheva , Israel.
authors.forename: Yiftach
authors.initials: Y
authors.lastname: Gepner
authors.affiliation: f Department of Epidemiology ; Ben-Gurion University of the Negev ; Beer-Sheva , Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Shai
authors.affiliation: a Department of Clinical Biochemistry and Pharmacology ; Faculty of Health Sciences; Ben-Gurion University of the Negev ; Beer-Sheva , Israel.|g National Institute of Biotechnology in the Negev; Ben-Gurion University of the Negev ; Beer-Sheva , Israel.
authors.forename: Assaf
authors.initials: A
authors.lastname: Rudich
keywords: E2F1; adipose tissue; autophagy; obesity; stress response; transcriptional regulation