Mechanisms Linking Lipodystrophy to Metabolic Syndrome

The study of human monogenic lipodystrophy and insulin resistance is not only of relevance to those with these rare conditions, but also widens general understanding of adipose tissue physiology and insulin signalling.

Ineke Luijten and research images

Previous studies have identified mutations in two genes that cause lipodystrophy, but with differing metabolic effects: one is the Mitofusin 2 gene, MFN2, which codes for an outer mitochondrial membrane protein that plays an important role in mitochondrial network formation, and mitochondrial tethering to various organelles (Rocha et al, eLife 2017), and the other is the PIK3R1 gene, encoding the phosphoinositide 3-kinase (PI3K) catalytic subunits p85alpha, p55alpha and p50alpha (Huang-Doran et al, JCI Insight 2017).  Mutations in these genes cause a form of Multiple Symmetric Lipomatosis (MSL) and SHORT Syndrome, respectively, but whereas MSL is associated with fatty liver and dyslipidaemia, this is not a feature of SHORT syndrome. Using a combination of disease modelling approaches using genome editing, coupled to in vivo and in vitro functional analyses, we aim to unravel the mechanisms whereby these mutations perturb adipose tissue function with divergent downstream consequences, to gain insights into mechanisms linking adipose dysfunction and metabolic syndrome.

Related Researchers

This work is led by Dr Ineke Luijten, a postdoctoral researcher from The Netherlands. She completed her BSc and MSc degrees in Molecular Nutrition and Toxicology at the University of Wageningen. Her PhD studies focused on adipose tissue physiology and were performed in the lab of Jan Nedergaard and Barbara Cannon at Stockholm University, as well as in the lab of Shingo Kajimura at UCSF. Ineke joined the Semple lab in 2019.


Wellcome Trust and Swedish Research Council