Pharmacological inhibition of ALDH1A enzymes suppresses weight gain in a mouse model of diet-induced obesity

Abstract

Background: Retinoic acid (RA) is known to play a role in weight regulation. Because mice without ALDH1A1, a major RA synthesizing enzyme, are resistant to diet-induced obesity, we tested a hypothesis that pharmacological inhibition of RA synthesis can suppress weight gain in a murine model of diet-induced obesity.

Methods: C57BL/6J male mice were fed a high fat diet (HFD) for 8 weeks to induce obesity and then randomized to a HFD with or without WIN 18,446, an RA synthesis inhibitor, for an additional 9 weeks. Body weight, body composition, energy expenditure, activity, and food intake were measured. Levels of retinoids, lipids, and genes involved in the metabolism of retinoid and lipids were also determined.

Result: s Mice treated with WIN 18,446 gained significantly less weight and had decreased adipose tissue weight, adipocyte size, and macrophage infiltration in adipose tissue. In addition, we observed higher UCP1 expression in adipose tissues and decreased expression of RA responsive genes and genes involved in fatty acid synthesis in the livers and lungs of mice treated with WIN 18,446.

Conclusions: Pharmacological suppression of RA synthesis via inhibition of ALDH1A1 may be a potential target for treatment of obesity.

Keywords: Animal model; Drug development; Energy expenditure; Enzymes; Retinoids.

Figure 1

Production of retinoic acid in H1299 cells expressing (A) ALDH1A1 and (B) ALDH1A2. Cells were treated with WIN 18,446 and retinal for the first 24 hrs and then washed and replenished with new media containing only retinal (indicated with arrows) for additional 48 hrs. Data are expressed as mean ± SEM.

Figure 2

(A) Body weight curve, (B) glucose tolerance test, (C) energy expenditure, and (D) activity in mice fed a high fat diet with or without WIN 18,446. HFD, high fat diet (n=6), HFD + WIN 18,446 (n=6). Data are expressed as mean ±SEM or individual data points with bars representing mean ±SEM. *, p<0.05, **, p<0.01, ***, p<0.001; unpaired Student’s t-test

Figure 3

(A) H&E stained adipose tissues, (B) adipocyte size and (C) degree of inflammation in four adipose depots, (D) immunohistochemistry staining of UCP1 in mesenteric adipose tissues, and (E) UCP-1 expression levels in mesenteric fat. Mes, mesenteric; Epi, epididymal; Ing, inguinal; Retro, retroperitoneal fat. Original magnification for A and D, 10X. Individual data points are shown with bars representing mean ± SEM. **, p<0.01; unpaired Student’s t-test.

Figure 4

mRNA expression of genes involved in retinoid metabolism in liver (A-D) and lung (E-H) of mice fed a high fat diet with and without WIN 18,446. Expression levels are shown as relative to those found in mice fed a HFD after normalization by ß-actin or HPRT. HFD, high fat diet; WIN, WIN 18,446. Individual data points are shown with bars representing mean ± SEM. *, p<0.05; **, p<0.01; unpaired Student’s t-test.