Researchers from the German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), the German Center for Diabetes Research (DZD), ETH Zurich and the University of Cambridge have now for the first time studied the role of phosphatidylinositol-binding clathrin assembly protein (PICALM) in white adipose tissue and its importance for metabolic health. They demonstrated that a reduced expression of PICALM improves insulin sensitivity and glucose transport in fat cells. These findings could contribute to the development of new therapeutic approaches for treating type 2 diabetes and obesity.
White adipose tissue, once considered merely a fat storage depot, is now recognised as an endocrine organ that plays a central role in metabolism. Obesity-driven white adipose tissue dysfunction is one of the main causes of type 2 diabetes (T2D).
Although adipose tissue only takes up around 5% of postprandial glucose and is therefore not directly responsible for reducing blood sugar levels, the insulin-stimulated uptake of glucose into fat cells (adipocytes) plays a crucial role. It is a key component in the finely tuned energy homeostasis of adipocytes and disturbances to this process can cause adipocytes to release more fatty acids into the bloodstream, which can lead to fat deposits in organs such as the liver and muscles.
In recent years, it has been appreciated that insulin resistance and associated metabolic disorders are presumably mainly attributed to impaired insulin-stimulated glucose uptake via GLUT4, rather than to defects in proximal insulin signalling. Consequently, elucidating the metabolic pathways associated with the GLUT4 transporter represents a promising avenue for discovering new therapeutic targets.
In preliminary studies, the DIfE team headed by Dr Heike Vogel used transcriptome analyses to identify phosphatidylinositol binding PICALM as one of the genes with the strongest expression differences in the adipose tissue of diabetes-prone and diabetes-resistant mice. PICALM is a well-known susceptibility gene for Alzheimer's disease and encodes an adapter protein that is ubiquitously expressed, i.e. in every cell. However, its role in adipose tissue and metabolic health had not been studied until now.
The research team investigated whether there is a link between reduced expression of PICALM in white adipose tissue and improved glucose homeostasis.
In order to better understand the role of PICALM in metabolic regulation and its potential as a therapeutic target for obesity and T2D, the DIfE scientists combined a variety of methods. For example, they compared the expression of PICALM in the white adipose tissue of diabetes-prone and diabetes-resistant mice as well as people with different body mass indexes.
In addition, the team also examined the extent to which PICALM expression can be influenced by dietary interventions, such as intermittent fasting in mice and bariatric surgery in people with obesity. In a cell culture model, they manipulated PICALM levels in premature (preadipocytes) and mature fat cells in order to investigate the effects on the translocation of the glucose transporter GLUT4 from an intracellular reservoir to the cell surface, insulin signalling and adipogenesis.
The results show for the first time that PICALM regulates both GLUT4 translocation and insulin signalling in adipocytes. Interestingly, a reduced expression of PICALM results in amplified insulin-stimulated GLUT4 translocation and insulin signalling. The researchers demonstrated that PICALM also affects the maturation of fat cells, which suggests distinct roles in preadipocytes and mature adipocytes.
"Here, we are describing a new role of the adapter protein PICALM in the regulation of glucose homeostasis and insulin signalling. Particularly noteworthy is the finding that the expression of PICALM is both influenced by genetic predisposition to type 2 diabetes and can also be reduced by dietary interventions,” explained Dr Jasmin Gaugel, first author of the study. “Unlike other well-known regulators of insulin signaling, PICALM does not only influence signal transmission, but also has a direct impact on the cellular processes that are necessary for glucose uptake.”
In the future, besides the effects of PICALM in adipose tissue, the DIfE researchers also intend to study its significance in the skeletal muscles, where they have already observed a strong influence on muscle cell differentiation.
"In principle, PICALM represents a very exciting therapeutic target. In order to further clarify our initial results regarding the metabolic role of PICALM, we want to study transgenic animals with, for example, a muscle-specific deletion of PICALM," added Vogel, explaining the future research objectives.
In the long term, the development of medication that specifically modulates the role of PICALM in order to improve glucose homeostasis and lower the risk of T2D is a conceivable goal.
The findings were reported in the paper, ‘Picalm, a novel regulator of GLUT4-trafficking in adipose tissue’, published in Molecular Metabolism. To access this paper, please click here
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