PPARγ signaling and metabolism: the good, the bad and the future

Abstract

Thiazolidinediones (TZDs) are potent insulin sensitizers that act through the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) and are highly effective oral medications for type 2 diabetes. However, their unique benefits are shadowed by the risk for fluid retention, weight gain, bone loss and congestive heart failure. This raises the question as to whether it is possible to build a safer generation of PPARγ-specific drugs that evoke fewer side effects while preserving insulin-sensitizing potential. Recent studies that have supported the continuing physiologic and therapeutic relevance of the PPARγ pathway also provide opportunities to develop newer classes of molecules that reduce or eliminate adverse effects. This review highlights key advances in understanding PPARγ signaling in energy homeostasis and metabolic disease and also provides new explanations for adverse events linked to TZD-based therapy.

Effects on metabolic markers are modified by PPARG2 and COX2 polymorphisms in infants randomized to fish oil

“…PPARG2 is also involved in controlling genes regulating glucose homeostasis (Ahmadian et al 2013), and the variant of the PPARG2 Pro12Ala polymorphism has been associated with a reduced risk of diabetes (Stumvoll and Haring 2002). This is in line with the findings of a study in 571 adults where postprandial plasma glucose was lower among female variant allele carriers of PPARG2 Pro12Ala (Ylonen et al 2008).…”

“…Based on the interaction with PPARG2, this effect appears to be mediated via PPARc2, which is primarily found in adipose tissue where it regulates adipocyte differentiation and metabolism (Ahmadian et al 2013;Tontonoz and Spiegelman 2008). Both n-3 LCPUFA and eicosanoids can activate PPARc, which then promotes lipid uptake and storage in adipose tissue (Tontonoz and Spiegelman 2008).…”

The LIM protein Ajuba promotes adipogenesis by enhancing PPARγ and p300/CBP interaction

“…PPARγ is highly expressed in adipose tissue and functions as a master regulator of the adipocyte differentiation. 5,6 This is firmly supported by the PPARγ-null mice that are completely devoid of adipose tissue. 7 As a result of utilizing different promoter and alternative splicing, PPARγ gene produces two protein isoforms, named PPARγ1 and PPARγ2, with the latter containing additional 30 amino acids at the extreme N-terminus.…”

“…Like other nuclear receptors, PPARγ contains four domains from the N-terminus to C-terminus: A/B domain (AF1 domain), C domain (DNA-binding domain), D domain (Hinge domain), E/F domain (AF2 domain/ligand-binding domain). 5,6 The A/B domain possesses ligand-independent transactivity by directly recruiting co-activators, such as PGC2 and histone acetyltransferase p300/CBP. 9,10 The DNA-binding domain encompasses two C4-type zinc-fingers mediating the interaction with PPRE.…”

“…Co-regulators bind this site through their conservative NR boxes (LXXLL), and this binding is strictly regulated by ligand: in the absence of ligand, co-repressors like NcoR/SMRT are docked at this domain, whereas in the presence of ligand, those co-repressors are replaced by co-activators such as SRC and p300/CBP. 5,6,13 Ajuba is a member of the LIM protein family characterized by containing tandem LIM domains at the C termini. The LIM domain is a double zinc-fingers in structure and was initially identified in Caenorhabditis elegans Lin-11, rat Isl-1 and C. elegans Mec-3, from which the acronym LIM was derived.…”