title: Autocrine function of aldehyde dehydrogenase 1 as a determinant of diet- and sex-specific differences in visceral adiposity.
abstract: Mechanisms for sex- and depot-specific fat formation are unclear. We investigated the role of retinoic acid (RA) production by aldehyde dehydrogenase 1 (Aldh1a1, -a2, and -a3), the major RA-producing enzymes, on sex-specific fat depot formation. Female Aldh1a1(-/-) mice, but not males, were resistant to high-fat (HF) diet-induced visceral adipose formation, whereas subcutaneous fat was reduced similarly in both groups. Sexual dimorphism in visceral fat (VF) was attributable to elevated adipose triglyceride lipase (Atgl) protein expression localized in clusters of multilocular uncoupling protein 1 (Ucp1)-positive cells in female Aldh1a1(-/-) mice compared with males. Estrogen decreased Aldh1a3 expression, limiting conversion of retinaldehyde (Rald) to RA. Rald effectively induced Atgl levels via nongenomic mechanisms, demonstrating indirect regulation by estrogen. Experiments in transgenic mice expressing an RA receptor response element (RARE-lacZ) revealed HF diet-induced RARE activation in VF of females but not males. In humans, stromal cells isolated from VF of obese subjects also expressed higher levels of Aldh1 enzymes compared with lean subjects. Our data suggest that an HF diet mediates VF formation through a sex-specific autocrine Aldh1 switch, in which Rald-mediated lipolysis in Ucp1-positive visceral adipocytes is replaced by RA-mediated lipid accumulation. Our data suggest that Aldh1 is a potential target for sex-specific antiobesity therapy.
authors.affiliation: Department of Human Nutrition, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Rumana
authors.initials: R
authors.lastname: Yasmeen
authors.forename: Barbara
authors.initials: B
authors.lastname: Reichert
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Deiuliis
authors.forename: Fangping
authors.initials: F
authors.lastname: Yang
authors.forename: Alisha
authors.initials: A
authors.lastname: Lynch
authors.forename: Joseph
authors.initials: J
authors.lastname: Meyers
authors.forename: Molly
authors.initials: M
authors.lastname: Sharlach
authors.forename: Sangsu
authors.initials: S
authors.lastname: Shin
authors.forename: Katharina S
authors.initials: KS
authors.lastname: Volz
authors.forename: Kari B
authors.initials: KB
authors.lastname: Green
authors.forename: Kichoon
authors.initials: K
authors.lastname: Lee
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Gregg
authors.initials: G
authors.lastname: Duester
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.forename: Sanjay
authors.initials: S
authors.lastname: Rajagopalan
authors.forename: Ouliana
authors.initials: O
authors.lastname: Ziouzenkova
mesh_terms: D041721:3T3-L1 Cells; D050154:Adiposity; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D059305:Diet, High-Fat; D005260:Female; D006801:Humans; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D007527:Isoenzymes / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050697:Retinal Dehydrogenase / Q000502:physiology*; D012727:Sex Characteristics
chemical_list: D007527:Isoenzymes; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase