Concerted action of aldehyde dehydrogenases influences depot-specific fat formation

Mol Endocrinol. 2011 May;25(5):799-809. doi: 10.1210/me.2010-0465. Epub 2011 Mar 24.

Abstract

Vitamin A metabolite retinoic acid (RA) regulates life-sustaining differentiation processes and metabolic homeostasis. The aldehyde dehydrogenase-1 (Aldh1) family of enzymes (Aldh1a1, a2, and a3) catalyzes RA production from retinaldehyde and thereby controls concentrations of this transcriptionally active metabolite. The hierarchy of Aldh1 functions in adipose tissue has not been elucidated. We hypothesized that Aldh1 enzymes produce endogenous RA and regulate adipogenesis and fat formation in a fat depot-specific manner. We demonstrate that adipogenesis in vitro is accompanied by RA production generated primarily by Aldh1a1. In Aldh1a1-deficient adipocytes, adipogenesis is impaired compared with wild-type adipocytes due to markedly reduced expression of PPARγ regulated through zinc-finger protein 423 (ZFP423)-dependent mechanisms. These effects were recovered to some extent either by RA stimulation or overexpression of any of the Aldh1 enzymes in Aldh1a1(-/-) cells arguing that Aldh1a1 plays a dominant role in autocrine RA production. In vivo studies in C57/BL6 and Aldh1a1(-/-) mice on a regular diet revealed that multiple Aldh1 enzymes regulate differences in the formation of sc and visceral fat. In Aldh1a1(-/-) mice, visceral fat essentially lacked all Aldh1 expression. This loss of RA-producing enzymes was accompanied by 70% decreased expression of ZFP423, PPARγ, and Fabp4 in visceral fat of Aldh1a1(-/-) vs. wild-type mice and by the predominant loss of visceral fat. Subcutaneous fat of Aldh1a1(-/-) mice expressed Aldh1a3 for RA production that was sufficient to maintain expression of ZFP423 and PPARγ and sc fat mass. Our data suggest a paradigm for regulation of fat depots through the concerted action of Aldh1 enzymes that establish RA-dependent tandem regulation of transcription factors ZFP423 and PPARγ in a depot-specific manner.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / cytology
  • Adipocytes / enzymology
  • Adipogenesis*
  • Adult
  • Aldehyde Dehydrogenase 1
  • Animals
  • Body Fat Distribution
  • CCAAT-Binding Factor / metabolism
  • Calcium-Binding Proteins
  • Cell Differentiation
  • Cytokines / metabolism
  • DNA-Binding Proteins / metabolism
  • Female
  • Genes, Reporter
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Intra-Abdominal Fat / metabolism
  • Isoenzymes / metabolism*
  • Luciferases / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Nicotinamide Phosphoribosyltransferase / metabolism
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Response Elements
  • Retinal Dehydrogenase / metabolism*
  • Subcutaneous Fat / metabolism
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Tretinoin / metabolism

Substances

  • Aldehyde Dehydrogenase 1
  • CCAAT-Binding Factor
  • Calcium-Binding Proteins
  • Cytokines
  • DNA-Binding Proteins
  • Dlk1 protein, mouse
  • Ebfaz protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Isoenzymes
  • PPAR gamma
  • Transcription Factors
  • Tretinoin
  • Luciferases
  • ALDH1A1 protein, human
  • Aldh1 protein, mouse
  • Retinal Dehydrogenase
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, mouse