Abstract
Dysregulation of signaling pathways in adipose tissue leading to insulin resistance can contribute to the development of obesity-related metabolic disorders. Alström Syndrome, a recessive ciliopathy, caused by mutations in ALMS1, is characterized by progressive metabolic alterations such as childhood obesity, hyperinsulinemia, and type 2 diabetes. Here we investigated the role of Alms1 disruption in AT expansion and insulin responsiveness in a murine model for Alström Syndrome. A gene trap insertion in Alms1 on the insulin sensitive C57BL6/Ei genetic background leads to early hyperinsulinemia and a progressive increase in body weight. At 6 weeks of age, before the onset of the metabolic disease, the mutant mice had enlarged fat depots with hypertrophic adipocytes, but without signs of inflammation. Expression of lipogenic enzymes was increased. Pre-adipocytes isolated from mutant animals demonstrated normal adipogenic differentiation but gave rise to mature adipocytes with reduced insulin-stimulated glucose uptake. Assessment of whole body glucose homeostasis revealed glucose intolerance. Insulin stimulation resulted in proper AKT phosphorylation in adipose tissue. However, the total amount of glucose transporter 4 (SLC4A2) and its translocation to the plasma membrane were reduced in mutant adipose depots compared to wildtype littermates. Alterations in insulin stimulated trafficking of glucose transporter 4 are an early sign of metabolic dysfunction in Alström mutant mice, providing a possible explanation for the reduced glucose uptake and the compensatory hyperinsulinemia. The metabolic signaling deficits either reside downstream or are independent of AKT activation and suggest a role for ALMS1 in GLUT4 trafficking. Alström mutant mice represent an interesting model for the development of metabolic disease in which adipose tissue with a reduced glucose uptake can expand by de novo lipogenesis to an obese state.
Highlights
Increased prevalence of obesity and diabetes, often associated with reduced lifespan, is a worldwide problem in the human population
Adipose tissue is a dynamic organ that regulates fat mass and glucose homeostasis often involving the crosstalk with multiple systems
The metabolic impairments are partially manageable by therapeutic interventions [30,31], but the missing link between ALMS1 disruption and metabolic alterations hampers the identification of a specific treatment
Summary
Increased prevalence of obesity and diabetes, often associated with reduced lifespan, is a worldwide problem in the human population. Obesity is characterized by AT expansion through hyperplasia and/or hypertrophy [1] and by the presence of dysfunctional AT with fibrosis, altered angiogenesis and inflammation, and often associated with local and systemic insulin resistance (IR) [2]. It is generally thought [3,4,5] that hyperinsulinemia triggers the expansion of AT in the early phase of obesity and IR of muscle and adipose tissues appears later, suggesting that adipogenesis requires insulin-sensitive fat cells. Our findings suggest a direct role of ALMS1 in glucose homeostasis via the GLUT4 trafficking pathway
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