Human congenital perilipin deficiency and insulin resistance

Lipid droplets (LDs) can form in all eukaryotic cells, but white adipocytes are uniquely adapted to store energy as neutral lipid within a large unilocular LD. Non-esterified fatty acids can then be released from the LD store by lipases for use in oxidative tissues. Perilipin was the first mammalian LD protein to be identified in adipocytes where it plays a key role in co-ordinating access of lipases to the core triacylglycerol. We recently identified the first human loss-of-function mutations in PLIN1 in patients with a novel form of familial partial lipodystrophy, severe insulin resistance, diabetes, dyslipidaemia and fatty liver. Adipose tissue samples from affected patients revealed remarkably similar features to those previously observed in samples from obese insulin resistant patients, namely macrophage infiltration and fibrosis. Cellular mechanistic studies suggest that the mutations lead to increased basal lipolysis, which is likely to be a major factor in the subsequent inflammatory response. Perilipin is almost exclusively expressed in white adipocytes, so the serious metabolic sequelae observed in these patients suggest that primary defects in adipose tissue can lead to all the typical features seen in patients with the metabolic syndrome. They also suggest that lipolytic inhibitors may be therapeutically useful in these patients.