Evaluation of human dermal fibroblasts directly reprogrammed to adipocyte-like cells as a metabolic disease model

Jian-Hua Chen, Kim Jee Goh, Nuno Rocha, Matthijs P Groeneveld, Marina Minic, Timothy G Barrett, David Savage, Robert K Semple

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Adipose tissue is the primary tissue affected in most single gene forms of severe insulin resistance, and growing evidence has implicated it as a site where many risk alleles for insulin resistance identified in population-wide studies may exert their effect. There is thus increasing need for human adipocyte models in which to interrogate the function of known and emerging genetic risk variants, yet primary adipocyte cultures, existing immortalised cell lines, and stem-cell based models all have significant biological or practical limitations. In an attempt to widen the repertoire of human cell models in which to study adipocyte-autonomous effects of relevant human genetic variants, we have undertaken direct reprogramming of skin fibroblasts to adipocyte-like cells by employing an inducible recombinant lentivirus overexpressing the master adipogenic transcription factor PPARγ2. Doxycycline-driven expression of PPARγ2 and adipogenic culture conditions converted dermal fibroblasts into triglyceride-laden cells within days. The resulting cells recapitulated most of the critical aspects of adipocyte biology in vivo, including the expression of mature adipocyte markers, secreted high levels of the adipokine adiponectin, and underwent lipolysis when treated with isoproterenol/IBMX. They did not, however, exhibit insulin-inducible glucose uptake, and withdrawal of doxycycline produced rapid de-lipidation and loss of adipogenic markers. This protocol was applied successfully to a panel of skin cells from individuals with monogenic severe insulin resistance, however, surprisingly, even cell lines harbouring mutations causing severe, generalised lipodystrophy accumulated large lipid droplets and induced adipocyte-specific genes. The direct reprogramming protocol of human dermal fibroblasts to adipocyte-like cells we established is simple, fast and efficient, and has the potential to generate cells which can serve as a tool to address some, though not all, aspects of adipocyte function in the presence of endogenous disease-causing mutations.

Original languageEnglish
JournalDisease Models and Mechanisms
Early online date5 Oct 2017
Publication statusE-pub ahead of print - 5 Oct 2017

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