Familial partial lipodystrophy resulting from loss-of-function PPARγ pathogenic variants: phenotypic, clinical, and genetic features

Abstract

The PPARG gene encodes a member of a nuclear receptor superfamily known as peroxisome proliferator-activated gamma (PPARγ). PPARγ plays an essential role in adipogenesis, stimulating the differentiation of preadipocytes into adipocytes. Loss-of-function pathogenic variants in PPARG reduce the activity of the PPARγ receptor and can lead to severe metabolic consequences associated with familial partial lipodystrophy type 3 (FPLD3). This review focuses on recent scientific data related to FPLD3, including the role of PPARγ in adipose tissue metabolism and the phenotypic and clinical consequences of loss-of-function variants in the PPARG gene. The clinical features of 41 PPARG pathogenic variants associated with FPLD3 patients were reviewed, highlighting the genetic and clinical heterogeneity observed among 91 patients. Most of them were female, and the average age at the onset and diagnosis of lipoatrophy was 21 years and 33 years, respectively. Considering the metabolic profile, hypertriglyceridemia (91.9% of cases), diabetes (77%), hypertension (59.5%), polycystic ovary syndrome (58.2% of women), and metabolic-dysfunction-associated fatty liver disease (87,5%). We also discuss the current treatment for FPLD3. This review provides new data concerning the genetic and clinical heterogeneity in FPLD3 and highlights the importance of further understanding the genetics of this rare disease.

Keywords: PPAR gamma; adipose tissue; diabetes mellitus; genetic lipodystrophy; insulin resistance.

Figure 1

Schematic representation of the main human PPARG transcripts and its PPARγ protein isoforms. (A) The structure of the PPARG1, 2, and 3 transcripts is highlighted, showing exons 1 to 6, common to all PPARγ transcripts, while PPARG2 has the additional exon B and encodes the canonical and dominant PPARγ2 isoform. PPARG1 also presents exons A1 and A2, while PPARG3 also presents the A2 exon. (B) PPARγ1 has 475 amino acids and is expressed at low levels in adipose tissue, skeletal muscle, macrophages, and epithelium from the colon. PPARγ2 presents 30 additional amino acids (magenta) and is mainly found in WAT, BAT, and the liver. PPARγ3 has 248 aa and has higher expression levels in macrophages, adipose tissue, and large intestine epithelium. The main PPARγ isoforms 1, 2, and 3 are composed of 4 functional domains: N-terminus domain AF-1 (orange), DNA Binding Domain – DBD (blue), Hinge (yellow), and Ligand Binding Domain – LBD (green) in the C-terminus. The AF-1 domain and the Hinge region are poorly conserved, while the DBD, LBD, and AF-2 domains are highly conserved. The image was made using IBS 2.0 software. (C) Protein sequence alignment of the PPARγ1, 2, and 3 isoforms. PPARγ isoform sequences were aligned via T-Coffee. Pink represents identical alignments; yellow corresponds to similar alignments; and green regions show different alignments. ∗ corresponds to an equal match. Cons: consensus sequence. The PPARγ sequences used were: PPARγ1 (NM_001354666; NP_001341595.2), PPARγ2 (NM_015869.5; NP_056953.2), and PPARγ3 (NM_001330615.4; NP_001317544.2).

Figure 2

Representation of adipocyte differentiation control performed by PPARγ, C/EBP, and RXR. The figure emphasizes the process of differentiation of white adipocytes from pre-adipocytes, highlighting the transcriptional roles of PPARγ (red), C/EBP (orange), and RXR (yellow) in the nucleus of preadipocytes under differentiation to complete maturation. Own authorship using resources from SMART – Servier Medical Art.

Figure 3

PPARγ actions and insulin sensibility. Activation of PPARγ in adipose tissue promotes the differentiation of pre-adipocytes into insulin-sensitive adipocytes, favoring the uptake of more lipids and influencing the production of adipokines, resulting in higher levels of adiponectin and reduced levels of TNF-α. These mechanisms benefit glucose metabolism, including less hepatic glucose production and more skeletal muscle glucose uptake, improving insulin sensibility. PPARγ activation also stimulates the transformation of macrophages into less inflammatory cells, thereby reducing macrophage infiltration into adipose tissue. Own authorship using resources from SMART – Servier Medical Art.