Natural human genetic variation determines basal and inducible expression of PM20D1 , an obesity-associated gene

Abstract

PM20D1 is a candidate thermogenic enzyme in mouse fat, with its expression cold-induced and enriched in brown versus white adipocytes. Thiazolidinedione (TZD) antidiabetic drugs, which activate the peroxisome proliferator-activated receptor-γ (PPARγ) nuclear receptor, are potent stimuli for adipocyte browning yet fail to induce Pm20d1 expression in mouse adipocytes. In contrast, PM20D1 is one of the most strongly TZD-induced transcripts in human adipocytes, although not in cells from all individuals. Two putative PPARγ binding sites exist near the gene’s transcription start site (TSS) in human but not mouse adipocytes. The −4 kb upstream site falls in a segmental duplication of a nearly identical intronic region +2.5 kb downstream of the TSS, and this duplication occurred in the primate lineage and not in other mammals, like mice. PPARγ binding and gene activation occur via this upstream duplicated site, thus explaining the species difference. Furthermore, this functional upstream PPARγ site exhibits genetic variation among people, with 1 SNP allele disrupting a PPAR response element and giving less activation by PPARγ and TZDs. In addition to this upstream variant that determines PPARγ regulation of PM20D1 in adipocytes, distinct variants downstream of the TSS have strong effects on PM20D1 expression in human fat as well as other tissues. A haplotype of 7 tightly linked downstream SNP alleles is associated with very low PMD201 expression and correspondingly high DNA methylation at the TSS. These PM20D1 low-expression variants may account for human genetic associations in this region with obesity as well as neurodegenerative diseases.

FTO intronic SNP strongly influences human neck adipocyte browning determined by tissue and PPARγ specific regulation: a transcriptome analysis

“…PM20D1 encodes an enzyme that catalyzes the synthesis of Nlipidated/N-fatty-acyl amino acids which function as endogenous uncouplers of mitochondrial respiration in a UCP1-independent manner [6]; it was expressed higher in DN brown adipocytes and rosiglitazone increased its the expression in both SC and DN adipocytes without influence of the FTO allele status. This specific effect of the PPARγ-agonist was observed in other studies as well [9,41].…”

“…Among the upregulated browning genes outside of the PPAR pathway, CIDEA was listed by ProFAT and also found in the Group 1 genes above, similarly to PM20D1 which was strongly influenced by natural genetic variations in humans [41] and CPT1B which was essential for beta-oxydation of fatty acids. Gamma-butyrobetaine dioxygenase (BBOX1) catalyzes the formation of L-carnitine from gamma-butyrobetaine and has been reported to play a role in adipocyte browning [42].…”

FTO Intronic SNP Strongly Influences Human Neck Adipocyte Browning Determined by Tissue and PPARγ Specific Regulation: A Transcriptome Analysis

“…PM20D1 encodes an enzyme that catalyzes the synthesis of N-lipidated/N-fatty-acyl amino acids, which function as endogenous uncouplers of mitochondrial respiration in a UCP1-independent manner [6]; it was expressed higher in DN brown adipocytes and rosiglitazone increased its expression in both SC and DN adipocytes regardless of the FTO allele status. This specific effect of the PPARγ-agonist was observed in other studies as well [9,41].…”

“…We found that KLF11 was among the rosiglitazone upregulated genes ( Figure 5D) in either SC or DN adipocytes suggesting that it may be involved in the regulation of browning of neck area adipocytes. Among the upregulated browning genes outside of the PPAR pathway, CIDEA was listed by ProFAT and also found in the Group 1 genes above, similar to PM20D1, which was strongly influenced by natural genetic variations in humans [41] and CPT1B which was essential for beta-oxidation of fatty acids. Gamma-butyrobetaine dioxygenase (BBOX1) catalyzes the formation of L-carnitine from gamma-butyrobetaine and has been reported to play a role in adipocyte browning [42].…”

Genetic background and diet affect brown adipose gene co-expression – metabolic associations

“…Thus it is critical to understand how gene-by-environment interactions are contributing to metabolic dysfunction. Such interactions have been shown to underlie variation in obesity and diabetes risk [3–8], and many individual genes have been identified with natural variants in human populations affecting metabolic response to environmental perturbations [9–14]. Research in animal models, in particular mouse models, has been used to manipulate dietary intake and environment in order to better understand the gene-by-environment interactions most relevant to human metabolism [15–19].…”