Alström syndrome as a model of metabolic syndrome of putative central nervous

System Origin

R. Vettor, P. Maffei, G. Milan, M. Granzotto, C. Pagano and G. Federspil

Internal Medicine, Department of Medical and Surgical Sciences, University of Padova, Italy

Alström syndrome is a rare recessive inherited syndrome of the young causing progressively severe conditions such as blindness, hearing loss, kidney disease, scoliosis, heart disease, obesity and type 2 diabetes. The Alström gene which maps on chromosome 2p13 could therefore provide clues to the normal pathways that regulate weight and normal blood glucose levels. The infantile obesity observed in individuals with Alström syndrome is probably caused by mutation of ALMS1, as it constitutes a relatively early phenotype observed in all affected children. We recorded the anthropometric parameters of 14 patients with Alström syndrome (10 M, 4 F). A group of healthy subjects matched for sex and age was also studied. Whole-body BIA was used to calculate impedance indices of the whole body specific resistivities; total body water (TBW), fat-free mass (FFM) and body fat were assessed using the 4-CM. Patients with Alström syndrome exhibited a clear increase in BMI and a preferential abdominal distribution of fat in both sexes with an increased WHR. Besides at the central nervous system ALMS1 is widely expressed in many other organs and tissues including muscle and adipose tissue and a defective function of ALMS1 in the target organs of insulin action tissue and in the pancreas, might lead to the development of type 2 diabetes. We investigated the expression of ALMS1 during 3T3-L1 preadipocyte differentiation. Levels of ALMS1 mRNA is present in both mature adipocytes and in cells before the initiation of differentiation. ALMS1 mRNA levels did not change during differentiation while aP2 RNA mRNA was shown to be higher in mature adipocytes compared to preadipocytes. Therefore ALMS1 seems to be unrelated to adipocyte growth and differentiation. Hypoadiponectinemia has been documented in subjects with obesity and diabetes mellitus. Plasma adiponectin levels are considerably low among Alström syndrome subjects and negatively correlated with BMI and the indexes of insulin resistance. Whether the plasma adiponectin level could be a suitable biomarker for following the clinical progress of metabolic syndrome in Alström warrants further investigation.

The early onset of obesity and the sensory deficits observed in individuals with Alström syndrome seem to reveal the presence of a neuronal dysfunction at the hypothalamic level leading to hyperphagia followed by obesity and subsequently type 2 diabetes. This resembles what happens in genetically or central nervous system lesioned animal model of obesity. The similarity with other monogenic form of obesity such as Prader-Willi and Lawrence-Moon-Bardet-Biedl syndromes both characterized by hyperfagia, rapid weight gain and very early appearance of type 2 diabetes has to be taken into consideration. The time course of appearance of obesity and insulin resistance in animal model and some evidence for functional damage at the CNS in PWS as potential trigger of the obesity development will be discussed.