Endocrine Abstracts

Genetic defects in PCNT, encoding the centrosomal protein pericentrin, cause a rare syndrome of primordial dwarfism, skeletal dysplasia and facial dysmorphism, known as Majewski Osteodysplastic Primordial Dwarfism Type II (MOPDII). We now report that 11 out of 15 patients with PCNT defects had clinical and/or biochemical evidence of severe insulin resistance (IR), many also with severe dyslipidaemia; the remaining four were under 4 years-old. The metabolic profile of MOPDII therefore resembles an extreme, early-onset (but not congenital) form of the prevalent metabolic syndrome. Such an exaggerated metabolic phenotype is also seen in Alström syndrome (AS), caused by genetic defects in ALMS1, which encodes another large centrosomal protein. These findings suggest that the centrosome may play a general role in maintaining metabolic homeostasis in humans. The centrosomal localisation of both pericentrin and ALMS1 implicates them circumstantially in mitotic and/or interphase microtubule organization. However, specific roles in canonical insulin action have not been sought. We have therefore tested two hypotheses regarding the basis of severe IR in MOPDII and/or AS: first, that it is associated with cell autonomous defects in insulin action; and second, that it is explained by a relative failure of adipose tissue differentiation, and thus ‘fat failure’. Stable knockdown of either pericentrin or ALMS1 in murine 3T₃-L1 preadipocytes impaired induction of adipocyte gene expression and lipid accumulation. Furthermore, pericentrin knockdown was associated with a slower rate of cell proliferation. Proximal insulin signalling events were unaffected in the presence of either knockdown, and although insulin-stimulated deoxyglucose uptake was decreased, this was commensurate with the adipogenic defect. Our findings suggest that partial failure of adipocyte differentiation and thus adipose tissue expandability may contribute to the severe metabolic syndrome of MOPDII and AS, but provide no evidence for a role of either pericentrin or ALMS1 in cell autonomous insulin action.