PPAR Research

Review Article

PPAR Gamma: Coordinating Metabolic and Immune Contributions to Female Fertility

Table 1

Phenotypes and reproductive effects associated with PPARG mutations in mice and humans. Abbreviations used: ART: artificial reproductive technology; BAT: brown adipose tissue; BMI: body mass index; HbA(1C): haemoglobin A1C; KO: knock-out; PCOS: polycystic ovary syndrome; T2DM: Type 2 Diabetes Mellitus; TG: Triglycerides; WAT: white adipose tissue.


Species	Genetic Abberation	Outcome	Effect on female fertility	Reference

Mouse	Global PPARG^-/-	Neonatal death	—	[23]
	Global PPARG^-/+	Improved insulin sensitivity	Fertile	[39]
	Mammary, epithelium, ovary, B- and T-cell null	Ovarian dysfunction and abrogated mammary development	30% of animals completely infertile, remainder had delayed conception, reduced litter size	[7]
	PPARG^hyp/hyp: WAT BAT, liver, and muscle null.	Normal birthweight but subsequent growth retardation, lipodystrophy, hyperlipideamia, and mild glucose intolerance	Heterozygote matings produce normal sized litters, but homozygote matings result in reduced litter size.	[40]

Human	Pro12Ala (34C > G), PPARG2 only.	Ala allele PPREs affinity, PPARG transactivation. Insulin sensitivity in some studies, conflicting reports on association with BMI.	Possible relationship with PCOS. In wider, non-PCOS population Ala allele associated with testosterone production	[41–43]
	Pro115Gln (344G > T), PPARG2 only.	Constitutively activated PPARG, adipocyte differentiation. Severe obesity, subjects T2DM.	Fertility not assessed.	[44]
	His447His (1431C > T)	T allele may increase adipocyte differentiation. Presence of T allele associated with BMI, and insulin sensitivity.	T allele more common in PCOS compared to BMI-matched controls. T allele associated with testosterone.	[43, 45]
	Pro467Leu (1647C > T)	Mutation in LBD, coactivator recruitment and downstream transactivation. Basal gene activity. Lipodystrophy but normal BMI, severe insulin resistance and hypertension. One carrier (from 4) responsive to rosiglitazone therapy.	Oligomenorrhoea and hirtsutism, required ART for 1st pregnancy, complicated by pre-eclampsia and induced labour. 2nd pregnancy spontaneously conceived, with pre-eclampia, preterm emergency caesarean, and neonatal infant death.	[46, 47]
	Val290Met (1115G > A)	Mutation affects LBD, profound blockage of transcriptional activation. Similar phenotype to P467L. Unresponive to rosiglitazone therapy.	Primary amenorrhoea, hirsutism, acanthosis nigricans, and hypertension.	[46, 47]
	Phe388Leu (1164T > A)	PPARG-ligand binding, basal transcriptional activity. Lipodystrophic and hypertensive with TG. Hyperinsulinemic, later T2DM.	Irregular menses, and bilateral polycystic ovaries treated with salpingo-oopherectomy. Prior to this carried two pregnancies.	[48]
	Arg397Cys (1273C > T)	Mutation in LBD, unknown effect on PPARG function. Lipodystrophic, TG and T2DM.	Hirsutism but no other indications of hyperandrogenism. Delayed menarche, but regular menses.	[49]