Autocrine Function of Aldehyde Dehydrogenase 1 as a Determinant of Diet- and Sex-Specific Differences in Visceral Adiposity

  1. Ouliana Ziouzenkova1
  1. 1Department of Human Nutrition, The Ohio State University, Columbus, Ohio
  2. 2Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio
  3. 3Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, California
  4. 4Department of Animal Sciences, The Ohio State University, Columbus, Ohio
  5. 5Mass Spectrometry and Proteomics Facility, The Ohio State University, Columbus, Ohio
  6. 6Nucleic Acid Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  7. 7Development and Aging Program, Sanford-Burnham Medical Research Institute, La Jolla, California
  8. 8Institute of Molecular Biosciences, Karl Franzens University, Graz, Austria
  1. Corresponding author: Ouliana Ziouzenkova, ziouzenkova.1{at}osu.edu.
  1. R.Y. and B.R. contributed equally to this work.

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 Ucp1-positive cells in female Aldh1a1−/− 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.

  • Received December 20, 2011.
  • Accepted June 30, 2012.

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