Obesity Leads to Tissue, but not Serum Vitamin A Deficiency.

Steven E. Trasino,Xiao-Han Tang,Jose Jessurun,Lorraine J. Gudas

doi:10.1038/srep15893

Abstract

Obesity negatively affects multiple metabolic pathways, but little is known about the impact of obesity on vitamin A (VA)[retinol (ROL)], a nutrient that regulates expression of genes in numerous pathways essential for human development and health. We demonstrate that obese mice, generated from a high fat diet (HFD) or by genetic mutations (i.e., ob/ob; db/db), have greatly reduced ROL levels in multiple organs, including liver, lungs, pancreas, and kidneys, even though their diets have adequate VA. However, obese mice exhibit elevated serum VA. Organs from obese mice show impaired VA transcriptional signaling, including reductions in retinoic acid receptor (RARα, RARβ2 and RARγ) mRNAs and lower intracellular ROL binding protein Crbp1 (RBP1) levels in VA-storing stellate cells. Reductions in organ VA signaling in obese mice correlate with increasing adiposity and fatty liver (steatosis), while with weight loss VA levels and signaling normalize. Consistent with our findings in obese mice, we show that increasing severity of fatty liver disease in humans correlates with reductions in hepatic VA, VA transcriptional signaling, and Crbp1 levels in VA storing stellate cells. Thus, obesity causes a “silent” VA deficiency marked by reductions in VA levels and signaling in multiple organs, but not detected by serum VA.

Highlights

Serum ROL and Retinol Binding Protein-4 (RBP4) in high fat diet (HFD)-wt and in chow-fed ob/ob, and db/db mice were elevated by ~1.5–5 fold compared to levels in chow-fed wt (Fig. 1B, (a,b))
The elevated serum ROL and RBP4 levels in ob/ob and db/db mice were striking and prompted us to ask if the serum ROL profiles of obese mice reflected their hepatic levels of ROL and retinyl-palmitate (RP), the major lipidated storage form of vitamin A (VA)
Crbp[1] and RARβ 2 are essential for normal VA metabolic homeostasis and signaling[31,34], and as our laboratory has previously demonstrated that tissue mRNA levels of these genes are reliable molecular indicators of vitamin A signaling and responsiveness in vivo[12], we investigated the consequences of the obesity-induced reductions in organ ROL levels on VA signaling by measuring the relative mRNA levels of RARβ 2, Crbp[1] and the other RAR isotypes, RARα and RARγ, using real-time PCR

Summary

Results and Discussion

High Fat Diet and Genetically Obese Mice Exhibit Reductions in Vitamin A in Multiple Organs Despite Having Adequate Dietary Vitamin A. The RARα, RARβ2, RARγ , and Crbp[1] transcript levels were not reduced in livers, pancreata, and lungs of HFDR-wt compared to chow-fed wt mice (Fig. 2D(a–d)) These experiments show that: i) reductions in tissue ROL in obese states occur in parallel. We performed immunofluorescence labeling studies to assess SC expression of Crbp[1] and found that, consistent with the hepatic Crbp[1] mRNA levels from 1M and 2M HFD-wt mice, the percentages of Crbp[1] positive SCs were reduced in livers in 1M and 2M HFD-wt mice (Fig. 3D (a–d),E) These data demonstrate that hepatic reductions in VA occur in parallel with increasing obesity and adiposity, but reductions in VA signaling do not occur (Fig. 3C(a,b)) until hepatic levels of both major forms of VA (ROL and RP) are reduced by > ~70% (Fig. 3B(a,b)). We suggest that given the essential functions of VA in humans, “silent” tissue-specific VAD has unappreciated effects on human health in obese individuals, affecting multiple organ systems

Methods

Author Contributions

Additional Information