The nuclear receptor PPARγ, encoded by the PPARG gene, plays a central role in adipocyte differentiation but also exerts essential functions in the placenta. Pathogenic variants of this gene cause a form of familial partial lipodystrophy (FPLD3), a rare disease characterized by abnormal adipose tissue distribution and severe metabolic complications. The authors assessed the metabolic, reproductive, and perinatal features of patients carrying such variants, drawing on current and retrospective data collected at a national reference center for rare diseases.
The cohort comprised 26 patients from 15 unrelated families (18 women, median age 43 years) carrying monoallelic PPARG variants, with the exception of one homozygous patient presenting with congenital generalized lipodystrophy—the first reported case with this status. Among heterozygous patients aged at least 16 years (n = 24), 92% had diabetes, 96% partial lipodystrophy, 78% hypertriglyceridemia, 71% hepatic steatosis, and 58% hypertension, with a mean body mass index of 26 kg/m². Women were frequently affected by acute pancreatitis (6 cases) and/or polycystic ovary syndrome (12 cases). The authors emphasize that diabetes often arises before the clinical recognition of lipodystrophy, which, in patients who are commonly overweight, contributes to underdiagnosis of the disease.
Analysis of perinatal data from 17 patients distinguished the presence (n = 8) or absence (n = 9) of an unfavorable maternal metabolic environment. The median gestational age at birth was low in both groups (37 and 36 weeks of gestation), and prematurity was high (52.9% of heterozygous variant carriers). As expected, birth weight was higher in cases of exposure to a dysmetabolic environment of maternal origin. Conversely, 85.7% of unexposed patients, in whom the variant was—or was very likely—of paternal origin, were small for gestational age.
The authors conclude that lipodystrophy-related PPARG variants induce early metabolic complications and suggest that placental expression of fetal-borne variants could impair prenatal growth and parturition. These observations are consistent with in vitro work showing that a lipodystrophy-associated variant, expressed in human trophoblast cells, inhibits the differentiation of villous cytotrophoblasts into syncytiotrophoblasts. Accordingly, close metabolic and obstetric monitoring is warranted in women with FPLD3, as is fetal growth monitoring in the offspring of any individual, male or female, carrying a pathogenic PPARG variant.