Table 1. PPARβ/δ mutant phenotypes.

Mutation	Method	Phenotype	References/Link
Overexpression	Transgenesis (Adipose Tissue) VP16-PPARβ/δ cDNA was placed downstream of the 5.4 kb promoter/enhancer of the mouse aP2 gene	Constitutively active PPARβ/δ/VP16 fusion protein in white adipose tissue triggers fatty acid mobilization and oxidation leading to mass reduction (Mm).	[Wang et al., 2003]
Overexpression	Transgenesis (Skeletal Muscle) CAG promoter driving PPARβ/δ-IRES-Hygromycin chimeric mRNA. Expression under CRE-mediated recombination of transcriptional Stop fragment	PPARβ/δ overexpression in skeletal muscle provokes a shift toward more oxidative fibers and general decrease of body fat content (Mm).	[Luquet et al., 2003]
Overexpression	Transgenesis (Skeletal Muscle) The VP16-PPARβ/δ fusion cDNA was placed downstream of the human α-skeletal actin promoter, and upstream of the SV40 intron/poly(A) sequence	Transgenic mice with targeted expression and activation of PPARβ/δ in skeletal muscle showed an increase in oxidative mitochondria-rich skeletal muscle fibers resulting in increased physical endurance as compared to wild type.	[Wang et al., 2004]
Overexpression	Transgenesis (Skeletal Muscle) Microinjection of the skeletal muscle promoter MCK-PPARβ/δ construct into fertilized one-cell C57BL/6 × CBA/J F1 embryos	PPARβ/δ, but not PPARα, was shown to be capable of increasing capacity for muscle glucose oxidation by activating transcription of the Ldhb gene through cooperation with AMPK and the transcription factor MEF2.	[Gan et al., 2011], [Gan et al., 2013]
Inducible/ Overexpression	Transgenesis (Cardiac Muscle) VP16-PPARβ/δ (VPD) was cloned in CAG-LoxP-CAT-LoxP vector. VPD transgenic mice were then crossed with the αMyHC-Mer-Cre-Mer (TMCM) mice to obtain cardiomyocytes-specific Tamoxifen inducible PPARβ/δ overexpression.	VP16-PPARβ/δ cardiomiocytes overexpressed PPARβ/δ mRNA and protein upon Tamoxifen treatment. Materials and Methods to obtain the transgenic mice are listed. No description of mice phenotype is here reported.	[Kim et al., 2013]
Inducible activation	Transgenesis (Epidermis) Mice were generated by microinjection of the expression unit, containing PPARβ/δ under control of human CYP1A1 promoter, into pro-nuclei of C57BL/J6 x CBA F1 fertilized eggs	Upon activation of PPARβ/δ, transgenic mice sustain an inflammatory skin disease strikingly similar to psoriasis, featuring hyperproliferation of keratinocytes, dendritic cell accumulation, and endothelial activation.	[Romanowska et al., 2010]
Deletion	Tissue specific knockout (Adipose Tissue) Homozygous floxed PPARβ/δ mice were bred with mice carrying an adipose-specific CRE-recombinase transgene, driven by the promoter of the aP2 gene	PPARβ/δ adipocyte specific deletion does not cause a decrease fat mass (white and brown).	[Barak et al., 2002]
Deletion	Tissue specific knockout (Cardiac Muscle) Homozygous floxed-PPARβ/δ mice were bred with -MyHC-Cre mice to produce a cardiomyocyte- restricted deletion of PPARβ/δ (CR-PPARβ/δ-/-) mice	Cardiomyocyte-restricted deletion of PPARβ/δ in mice down-regulated expression of key fatty acid oxidation genes and decreased basal myocardial FAO leading to lipid accumulation.	[Cheng et al., 2004]
Deletion	Tissue specific knockout (Skeletal Muscle) Homozygous floxed-PPARβ/δ mice were bred with HSA-Cretg/0 mice that express the Cre recombinase under the control of the human α-skeletal actin promote	Specifically deletion PPARβ/δ in skeletal muscles results lower oxidative activity of the muscle fibers and an increased body fat mass leading to insulin resistance (Mm).	[Schuler et al., 2006]
Deletion	Tissue specific knockout (Myeloid cells) Homozygous floxed-PPARβ/δ mice were bred with mice that express the Cre recombinase under the control of the lysozyme promoter.	Myeloid-specific PPARβ/δ KO mice render macrophages incapable of transition to the M2 phenotype, which in turns causes inflammation and metabolic derangement in adipocytes. These mice develop insulin resistance and show increased adipocyte lipolysis and severe hepatosteatosis.	[Kang et al., 2008]
Deletion	Tissue specific knockout (Myeloid cells) Homozygous floxed-PPARβ/δ mice were bred with mice that express the Cre recombinase under the control of the lysozyme promoter.	PPARβ/δ has a pivotal role in orchestrating the timely disposal of apoptotic cells by macrophages, ensuring that tolerance to self is maintained.	[Mukundan et al., 2009]
Deletion	Tissue specific knockout (Liver) Liver-specific PPARβ/δ KO mice (in C57BL/6 background) were generated by crossing PPARδ flox/flox mice to albumin-Cre transgenic mice.	No specific phenotype affecting the liver is described. Used as negative control for mice expressing in the liver an adenovirus allowing the overexpression of PPARβ/δ. Liver specific deletion shows that PPARβ/δ controls the temporal expression of hepatic lipogenic genes (ACC1 abolished, ACC2, FAS and SCD1shifted during dark cycle in PPARβ/δ KO mice). Liver-specific PPARβ/δ KO mice present also alteration in the pattern of serum lipids and reduced muscle fatty acid uptake in the dark cycle in vivo.	[Liu et al., 2011], [Liu, 2012]
Deletion	Tissue specific knockout (Hematopoietic cells) To delete PPARβ/δ, MSCV-puro-IRES-GFP or MSCV-puro-Cre-IRES-GFP retroviral vectors were used in purified KSL cells from Ppardflox/flox mice	The lack of PPARβ/δ in Hematopoietic stem cells markedly affects their long-term repopulating capacity due to the PML–PPARβ/δ –FAO metabolic pathway that regulates this process.	[Ito et al., 2012]
Deletion	Tissue specific knockout (Pancreas) Homozygous floxed PPARβ/δ were bred with mice expressing the Cre transgene under control of the promoter of transcription factor pancreatic and duodenal homeobox factor 1 (PDX1; Pdx1Cre)	Mutant animals presented increased numbers of islets and, more importantly, enhanced insulin secretion that caused hyperinsulinemia.	[Iglesias et al., 2012]
Deletion	Total body knockout The homologous recombination of the targeting vector leads to the disruption of the last coding exon of the PPARβ/δ gene.	Homozygous PPARβ/δ-null term fetuses were smaller than controls, they present smaller gonadal adipose stores. Myelination of the corpus callosum was altered in the brain of PPARβ/δ null mice.	[Peters et al., 2000]
Deletion	Total body knockout The homologous recombination of the targeting vector leads to the replacement of the 4th exon of the PPARβ/δ gene, encoding the first half of the DNA-binding domain.	This deletion results in placental defects and very frequent (>90%) mid-gestation lethality. Surviving PPARβ/δ null mice exhibit a striking reduction in adiposity relative to wild-type levels (Mm).	[Barak et al., 2002]
Deletion	Total body knockout The homologous recombination of the targeting vector leads to the replacement of the 4th and part of the 5th exon of the PPARβ/δ gene, encoding the DNA-binding domain.	Deletion of PPARβ/δ provokes severe alteration of placenta development, leading to embryonic death at embryonic day 9.5 (E9.5) to E10.5 of most, but not all, PPARβ/δ -null mutant embryos (Mm).	[Nadra et al., 2006]
Models	Commercially available PPARβ/δ mice models	http://www.findmice.org/summary?query=ppard&states=Any&_states=1&types=Any&_types=1&repositories=Any&_repositories=1&_mutations=on	International Mouse Strain Resource (IMSR)

The main PPARβ/δ-based mouse models are herein listed according to the type of mutation and tissue/cell specificity. The main observations reported from the mutant are also briefly commented.