Switch from Stress Response to Homeobox Transcription Factors in Adipose Tissue After Profound Fat Loss

Abstract

BackgroundIn obesity, impaired adipose tissue function may promote secondary disease through ectopic lipid accumulation and excess release of adipokines, resulting in systemic low-grade inflammation, insulin resistance and organ dysfunction. However, several of the genes regulating adipose tissue function in obesity are yet to be identified.Methodology/Principal FindingsIn order to identify novel candidate genes that may regulate adipose tissue function, we analyzed global gene expression in abdominal subcutaneous adipose tissue before and one year after bariatric surgery (biliopancreatic diversion with duodenal switch, BPD/DS) (n = 16). Adipose tissue from lean healthy individuals was also analyzed (n = 13). Two different microarray platforms (AB 1700 and Illumina) were used to measure the differential gene expression, and the results were further validated by qPCR. Surgery reduced BMI from 53.3 to 33.1 kg/m2. The majority of differentially expressed genes were down-regulated after profound fat loss, including transcription factors involved in stress response, inflammation, and immune cell function (e.g., FOS, JUN, ETS, C/EBPB, C/EBPD). Interestingly, a distinct set of genes was up-regulated after fat loss, including homeobox transcription factors (IRX3, IRX5, HOXA5, HOXA9, HOXB5, HOXC6, EMX2, PRRX1) and extracellular matrix structural proteins (COL1A1, COL1A2, COL3A1, COL5A1, COL6A3).Conclusions/SignificanceThe data demonstrate a marked switch of transcription factors in adipose tissue after profound fat loss, providing new molecular insight into a dichotomy between stress response and metabolically favorable tissue development. Our findings implicate homeobox transcription factors as important regulators of adipose tissue function.

The Transcription Factor Paired-Related Homeobox 1 (Prrx1) Inhibits Adipogenesis by Activating Transforming Growth Factor-β (TGFβ) Signaling

“…6). Prrx1 expression also increases in subcutaneous WAT after fat loss during bariatric surgery (62). Together, these data suggest that altered metabolic states impact WAT Prrx1 expression in both mice and humans.…”

Pathways commonly dysregulated in mouse and human obese adipose tissue: FAT/CD36 modulates differentiation and lipogenesis

“…Extracellular matrix remodelling plays a crucial role in adipose tissue expandability. 33 Collagen protein COL1A1 is a major ECM gene in adipose tissue which expression level is increased after weight loss 34 or reduced in obese adipose tissue. 35 Collagen COL3A1 expression is higher after weight loss 34 and its turnover is regulated by the metalloprotease MMP9 in human adipose tissue.…”

“…33 Collagen protein COL1A1 is a major ECM gene in adipose tissue which expression level is increased after weight loss 34 or reduced in obese adipose tissue. 35 Collagen COL3A1 expression is higher after weight loss 34 and its turnover is regulated by the metalloprotease MMP9 in human adipose tissue. 35 MMP9 itself is involved in ECM remodeling, with increased expression during adipogenesis, 36 its expression is reduced after weight loss 37 and increased in obese stroma-vascular fraction 38 and in adipose tissue with obesity-associated insulin resistance.…”

Differentiation and characterization of human facial subcutaneous adipocytes

“…found that the profound fat loss via bariatric surgery significantly upregulated the HOX gene expression in the abdominal subcutaneous adipose from the obese patient. 29 The mechanistic understanding of how the HOX network controls adipogenesis needs to be investigated in depth.…”