Congenital generalised lipodystrophy is a heterogeneous group of rare disorders defined by a severe reduction or complete absence of adipose tissue. The most severe form studied here, congenital generalised lipodystrophy type 2 (CGL2), is caused by mutations in the BSCL2 gene, which disable the encoded protein seipin and lead to a near-complete loss of fat tissue. Because adipocytes are the body’s safe reservoir for storing lipids, their absence forces fat to accumulate in inappropriate places, particularly the liver. Patients typically develop profound insulin resistance, early-onset diabetes, hypertriglyceridemia and hepatic steatosis, which frequently progresses to metabolic dysfunction-associated steatotic liver disease. Beyond the metabolic burden, the condition markedly reduces both quality of life and life expectancy, and therapeutic options remain limited, partly because the disorder is so rare and its pathophysiology incompletely understood.

A defining feature of CGL2 and related lipodystrophies is the loss of hormones secreted by adipocytes, above all leptin and adiponectin. Leptin regulates appetite and exerts broader effects on lipid and glucose metabolism, and its near-total absence leaves patients with persistent, ravenous hunger. Replacement therapy with metreleptin, a recombinant form of the hormone, has demonstrated substantial clinical benefit, improving glycaemic control, hypertriglyceridemia and hepatic steatosis. But the treatment demands lifelong daily injections, which are especially painful in people who lack the subcutaneous fat that normally cushions such injections. Recombinant leptin is also costly, availability can be limited, and some patients develop neutralising antibodies that blunt responsiveness. The consequences of adiponectin loss, by contrast, are not fully understood, and whether delivering adiponectin therapeutically could help these patients has remained largely unexplored.

Gene therapy offered the research team a way to sidestep the limitations of conventional hormone replacement. Among available delivery platforms, AAV vectors have become a leading choice for in vivo applications because of their favourable safety profile and their ability to sustain long-term transgene expression in non-dividing tissues, and several AAV-based therapies have now been approved for inherited disorders. The team selected AAV serotype 8, driven by the strong, widely active CMV promoter, based on its broad tissue targeting, high hepatic transduction efficiency and the group’s previous success expressing transgenes in their CGL2 mouse model. Nine-week-old seipin knockout (SKO) mice, which model CGL2 on a C57BL/6J background, received a single intraperitoneal injection of one trillion genome copies of AAV8 encoding either human leptin, human adiponectin, or the reporter protein eGFP as a control, with wild-type littermates providing healthy reference values.

The vectors worked as designed. Seven weeks after injection, serum analysis revealed robust circulating levels of human leptin in the leptin-treated mice and human adiponectin in the adiponectin-treated mice, confirming that the delivered transgenes were being expressed and secreted. Body composition, measured by EchoMRI, showed that all SKO groups had significantly reduced fat mass and increased lean mass compared with wild-type controls, as expected given the absence of adipose tissue. Over the seven-week assessment period, control SKO mice gained weight to a similar degree as wild-type littermates, a pattern the authors attribute to liver expansion from accumulating lipid roughly matching the white fat gain seen in healthy mice. The leptin-treated mice, however, did not significantly increase their body weight over the study period, while adiponectin-treated mice gained weight similarly to controls.

Metabolic testing revealed a clear divergence between the two hormone treatments. Oral glucose tolerance, impaired in control SKO mice relative to wild-type littermates, was not restored by leptin gene therapy. Yet insulin sensitivity improved moderately, ad libitum fed blood glucose levels fell, and, most strikingly, fasting serum insulin, which was markedly elevated in control SKO mice in line with observations in CGL2 patients, was fully normalised in the leptin-treated group. A quantitative insulin-sensitivity check index analysis confirmed that the decreased insulin sensitivity of control SKO mice was rescued to values similar to wild-type controls. Adiponectin delivery, in contrast, failed to change any of these metabolic parameters, in both the male mice of the main cohort and a separate cohort of female SKO mice examined specifically to capture any sex-specific effects.

The effects of leptin extended to appetite and thirst. Because of their near-absent leptin, CGL2 patients and SKO mice exhibit persistent hunger and overeating, along with polydipsia, a hallmark of metabolic dysregulation common in diabetic states. The researchers measured food and water intake over four-day periods before and six weeks after the AAV injection. Following leptin gene therapy, food intake was significantly reduced and water intake was lowered, indicating that a single injection could provide sustained relief from the increased appetite that so burdens patients with this condition. The authors suggest that, by extension, the approach could alleviate hyperphagia in people with CGL2, though this remains to be demonstrated clinically.

The most dramatic effects appeared in the liver. Control SKO mice showed the expected hepatomegaly, with liver weight significantly higher than in wild-type controls, and a significant increase in hepatic triglyceride content. In leptin-treated mice, the enlarged liver size was reduced and the hepatic triglyceride accumulation was entirely normalised, a result corroborated by histological examination showing a substantial reduction of steatosis. Serum alanine aminotransferase, a marker of hepatic dysfunction, appeared reduced by leptin therapy, although neither the elevation in controls nor the reduction with treatment reached statistical significance. Picrosirius red staining showed only modest fibrosis in these 16-week-old mice, contrasting with the more robust fibrosis the team previously observed in 28-week-old SKO mice, implying progressive development of fibrosis with age in this model. Adiponectin treatment produced no reduction in liver weight, triglycerides or steatosis.

Molecular analysis offered clues to how leptin exerts its hepatic benefit, while also revealing the limits of the intervention. Western blotting showed that the lipid droplet protein PLIN2, elevated in control SKO mice, was substantially reduced by leptin therapy, consistent with the drop in intracellular lipid. Among the many lipogenic and metabolic genes examined, only the transcription factor Pparγ and its downstream target Cd36, a fatty acid translocase upregulated in fatty liver disease that facilitates fatty acid uptake, were significantly increased in control SKO mice and normalised by leptin. Genes encoding collagen markers of fibrosis were elevated in control SKO mice but not normalised by leptin, and lipogenic genes such as Fasn and Scd1, though increased, were not restored. Expression of the metabolic regulator FGF-21, elevated in control SKO mice, was reversed by leptin, likely reflecting reduced cellular stress. The authors note that leptin gene therapy does not completely reverse the effects of seipin loss on hepatic lipid metabolism gene expression.

Why adiponectin failed remains uncertain, and the authors outline several possibilities. Serum adiponectin levels achieved by the AAV vector were substantially lower than endogenous murine adiponectin levels previously measured in control mice, which may have limited any effect. The transgene-derived adiponectin likely came mostly from the liver, given the near-absence of adipose tissue, whereas adiponectin secreted from adipocytes may be more effective owing to secondary modifications and oligomerisation; the team did not determine whether the circulating human adiponectin formed the high molecular weight oligomers known to be biologically important. It is also possible that adiponectin’s benefits in other models require functional adipose tissue, which is effectively absent in both SKO mice and CGL patients. The study has further limitations: only male mice were used in the main cohort, investigators were not blinded to genotype or treatment, and the longevity of leptin expression specifically must still be assessed, although the team’s previous work with the same vector showed liver expression persisting for at least five months. AAV therapies can also cause serious adverse effects, including inflammatory responses and hepatotoxicity, and it remains unknown whether leptin delivered as a gene therapy might provoke antibodies similar to those seen with daily metreleptin injections. Translating the approach to humans will require more appropriate serotypes, vectors and dosing regimens. Still, the authors suggest that combining leptin delivery with their previously demonstrated adipose-selective re-expression of seipin, which partially restored adipose tissue but left leptin levels low and steatosis incompletely reversed, might yield enhanced therapeutic effects. For now, the study establishes the first evidence of significant potential for leptin gene therapy in a recognised preclinical model of congenital generalised lipodystrophy, pointing toward a long-lasting, effective and less painful future therapy for people living with the disorder.

Subject of Research: AAV-mediated leptin versus adiponectin gene therapy in a mouse model of congenital generalised lipodystrophy

Article Title: AAV-mediated delivery of leptin but not adiponectin improves metabolic health in a pre-clinical mouse model of congenital generalised lipodystrophy

Article References: Sommer, N., Roumane, A., Tiwari, M., Han, W., Heisler, L. K., Mcilroy, G. D., & Rochford, J. J. (2026). AAV-mediated delivery of leptin but not adiponectin improves metabolic health in a pre-clinical mouse model of congenital generalised lipodystrophy. Gene Therapy. https://doi.org/10.1038/s41434-026-00646-w

Image Credits: AI Generated

DOI: 10.1038/s41434-026-00646-w

Keywords: lipodystrophy, leptin, adiponectin, gene therapy, AAV8, seipin, hepatic steatosis, insulin resistance, metreleptin, SKO mice, adipokines, rare disease