2026-06-01 | Case Report: Twenty years of metreleptin therapy in congenital generalized lipodystrophy type 1: the longest reported follow-up to date.
Congenital generalized lipodystrophy (CGL) is a rare disorder marked by near-total loss of adipose tissue and severe metabolic disturbances due to leptin deficiency and the inability to store nutrients in adipose tissue effectively. Metreleptin is the only approved leptin replacement therapy for this condition. Here we present the >20-year follow-up of two sisters with CGL type 1 (AGPAT2 deficiency, OMIM# 608594), enrolled in early metreleptin trials. Clinical outcomes, adherence, immunogenicity, and pregnancies were assessed. Both cases showed rapid and sustained metabolic improvement after metreleptin initiation, allowing insulin discontinuation and triglyceride normalization. Menstrual cycles resumed within six months; allowing both to carry successful pregnancies while continuing metreleptin. Both cases experienced reduced treatment adherence over time, linked to psychological distress. One case developed both anti-drug antibodies and neutralizing activity through immune based assay after 14 years, but without significant clinical impact. In conclusion, these cases highlight both the sustained metabolic benefits of therapy and the complex challenges that may arise over time, such as antibody formation and difficulties in maintaining long-term adherence. Documentation of unmet medical needs can provide guidance and impetus for improved therapeutic approaches to achieve optimum quality of life.
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2026-04-07 | AAV-mediated delivery of leptin but not adiponectin improves metabolic health in a mouse model of congenital generalised lipodystrophy
Lipodystrophies are a group of disorders featuring reduced adipose tissue mass or function, which often leads to significant metabolic disease, reduced lifespan and impaired quality of life. Individuals with congenital generalised lipodystrophy (CGL) have severely reduced adipose tissue mass. The loss of healthy systemic lipid storage typically causes hepatic steatosis and lipoatrophic diabetes. In addition, adipocyte-secreted hormones including leptin and adiponectin are dramatically reduced. Leptin has critical roles regulating appetite and broader effects on lipid and glucose metabolism. Daily injection with recombinant leptin is currently the only specific, approved treatment for CGL. The consequences of adiponectin loss in these patients are not fully understood. Likewise, the potential therapeutic benefit of adiponectin delivery is unclear. Here we examine the effect of delivering leptin or adiponectin by adeno-associated virus (AAV) as potential gene therapy treatment for metabolic disease in CGL using a well-characterised murine model of the condition. AAV mediated leptin delivery significantly improved hepatic steatosis and hyperinsulinemia. However, adiponectin delivery did not lead to any observed beneficial effects. This demonstrates the potential of gene therapy approaches for long-term delivery of leptin in individuals with lipodystrophy, without the need for continuous supply of perishable therapeutics and painful daily injections.
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2026-03-26 | Gpat3 Knockout Attenuates Adipose Loss and Steatohepatitis in Agpat2-Deficient Mice.
Congenital generalized lipodystrophy (CGL) type 1, caused by mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2), is characterized by near-total absence of adipose tissue and severe metabolic disturbances, including hepatic steatosis, insulin resistance, and hypertriglyceridemia. Although AGPAT2's enzymatic function in lysophosphatidic acid acylation during glycerolipid biosynthesis is well characterized, the molecular mechanisms driving disease pathogenesis remain incompletely understood. In this study, significant up-regulation of glycerol-3-phosphate acyltransferase 3 (GPAT3), in both embryonic fibroblasts and liver tissue from AGPAT2-deficient mice, was identified. Through generation of Agpat2/Gpat3 double-knockout mice, it was demonstrated that GPAT3 ablation leads to multiple metabolic improvements: enhanced survival rates, partial preservation of adipose tissue (with more pronounced effects in brown than white adipose depots), marked attenuation of hepatic steatosis accompanied by reduced inflammation and fibrosis, and amelioration of hyperglycemia and hyperinsulinemia. Neonatal analyses demonstrated that GPAT3 deletion delayed adipose tissue degeneration while markedly decreasing macrophage infiltration (F4/80+ cells) and apoptotic signaling (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells). Ultrastructural examination revealed improved adipocyte morphology with normalized organelle architecture. These results identify GPAT3 as a key metabolic regulator in AGPAT2 deficiency, demonstrating that its inhibition partially restores adipose tissue and liver function. The conserved benefits of GPAT3 deficiency in both CGL1/AGPAT2 and CGL2/Seipin models highlight GPAT3 as a promising therapeutic target for congenital lipodystrophies.
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