Functions of Prdm16 in thermogenic fat cells

Abstract

The PR-domain containing 16 (Prdm16) protein is a powerful inducer of the thermogenic phenotype in fat cells. In both developmental (brown) and induced (beige) thermogenic adipose tissue, Prdm16 has a critical role in maintaining proper tissue structure and function. It has roles throughout the course of differentiation, beginning with lineage determination activity in precursor cells, and continuing with coactivator functions that enable and maintain thermogenic gene expression. These abilities are primarily mediated by interactions with other adipogenic factors, suggesting that Prdm16 acts to coordinate the overall brown adipose phenotype. Mouse models have confirmed that thermogenic adipose depends upon Prdm16, and that this type of fat tissue provides substantial metabolic protection against the harmful effects of a high fat/high energy diet. Activation of Prdm16, therefore, holds promise for stimulating thermogenesis in fat cells to reduce human obesity and its complications.

Keywords: BAT; Prdm16; WAT; adipogenesis; beige/brown/white adipose tissue; obesity; thermogenesis.

Figure 1.

Prdm16 in BAT determination. Prdm16 is essential for maintaining BAT in adult mice. However, redundancy exists for BAT determination at earlier stages of development, although not for suppression of WAT-selective genes. The redundant factor during juvenile and early adult periods is Prdm3. The basis for compensation neonatally remains unknown. In contrast, the Prdm16-interacting protein Ehmt1 is required at all stages, suggesting that it may act as a common partner to several Prdm family members to allow for BATogenesis. Ectopic expression of Ap2-Prdm16 in WAT results in results in a beige fat pad.

Figure 2.

Prdm16 domain structure. Prdm16 can be partitioned into six major regions, including a PR/SET domain (PR); two zinc-finger domain containing seven or three C2H2 zinc finger motifs (ZF1/ZF2); a proximal regulatory region (PRR); a repression domain (RD); a second zinc-finger domain containing three C2H2 zinc finger motifs (ZF2); and an acidic activation domain (AD). (A) The PR domain has Histone-H3 lysine-4 (H3K4) monomethylase activity. (B) ZF1 and ZF2 have protein-protein interactions with a variety of factors. (C–E) Specific sequence motifs regulate Prdm16-mediated gene repression. (C) Sumoylation enhances interactions with CtBP. (D) By homology to MECOM, Prdm16 is potentially phosphorylated at Ser758. (E) Of two consensus CtBP motifs, the second is functional and required for interaction with CtBP1 and CtBP2.

Figure 3.

Model of gene regulation by Prdm16. Questions remain to be answered regarding the specific mechanisms by which Prdm16 selects between target gene (A and B) activation or (C and D) repression; recognizes target gene regulatory elements; and interacts with co-regulatory proteins. (A) Prdm16 and C/ebpβ cooperate to activate adipogenic gene expression. (B) In differentiation, some (or all) of Prdm16, C/ebp, Pparγ, and Pgc1α assemble a transactivating complex at thermogenic genes. How either complex (A) or (B) interacts with RNA polymerase II (PolII) to stimulate transcription remains to be described. (C) Myogenic genes are repressed by Prdm16 and Ehmt1. (D) WAT genes are repressed by Prdm16+Ehmt1 and Prdm16+CtBP; it is unclear if the complex involves Prdm16+Ehmt1+CtBP. It is unclear how sequence-specific DNA binding of the Prdm16 complex occurs at repressive gene elements (C and D).