Reversing adipocyte differentiation: implications for treatment of obesity - PubMed (original) (raw)

Reversing adipocyte differentiation: implications for treatment of obesity

Y T Zhou et al. Proc Natl Acad Sci U S A. 1999.

Abstract

Conventional treatment of obesity reduces fat in mature adipocytes but leaves them with lipogenic enzymes capable of rapid resynthesis of fat, a likely factor in treatment failure. Adenovirus-induced hyperleptinemia in normal rats results in rapid nonketotic fat loss that persists after hyperleptinemia disappears, whereas pair-fed controls regain their weight in 2 weeks. We report here that the hyperleptinemia depletes adipocyte fat while profoundly down-regulating lipogenic enzymes and their transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma in epididymal fat; enzymes of fatty acid oxidation and their transcription factor, PPARalpha, normally low in adipocytes, are up-regulated, as are uncoupling proteins 1 and 2. This transformation of adipocytes from cells that store triglycerides to fatty acid-oxidizing cells is accompanied by loss of the adipocyte markers, adipocyte fatty acid-binding protein 2, tumor necrosis factor alpha, and leptin, and by the appearance of the preadipocyte marker Pref-1. These findings suggest a strategy for the treatment of obesity by alteration of the adipocyte phenotype.

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Figures

Figure 1

Figure 1

(A) The appearance of epididymal fat pads of a control rat infused with AdCMV-β-gal and a hyperleptinemic rat infused with AdCMV-leptin. Grossly visible fat is absent from the latter; arrow points to the stromal-vascular remnant. (B) Wet weight, DNA, and TG content of epididymal fat pads of rats before and 6 days after hyperleptinemia and expressed as percent of the prehyperleptinemic value. ∗∗, P < 0.01 versus day 6 of hyperleptinemia.

Figure 2

Figure 2

Expression of genes involved in fatty acid metabolism in epididymal fat pads of normal rats before and after 4 or 6 days of hyperleptinemia. (A) mRNAs encoding enzymes of fatty acid oxidation, ACO and CPT-1. (B) mRNA of UCP-1 and UCP-2. (C) Enzymes of lipogenesis, ACC, FAS, and GPAT. S-V, stromal-vascular tissue from which adipocytes have been mechanically removed. ∗, Immunoblot.

Figure 3

Figure 3

(A) Expression of PPARα and PPARγ protein in epididymal fat pad of normal rats before and 4 and 6 days after induction of hyperleptinemia. (B) Expression of markers of mature adipocytes, aP2, TNF-α, leptin, and LPL, and a preadipocyte marker, Pref-1, in epididymal tissue of normal rats before and 4 and 6 days after induction of hyperleptinemia. S-V, stromal-vascular tissue from normal untreated rats. ∗, Immunoblot.

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