According to an article published in Nature Metabolism on June 27, 2022, researchers from the University of Cologne reported that they have discovered an increased rate of type 2 diabetes (T2D) and obesity in individuals with impaired synaptic signaling of lysophospholipids (LPA), controlled by agouti-related peptide neurons (AgRP). These LPAs, in turn, control the excitability potential of nerve cells in the cerebral cortex, resulting in regulation of food intake and appetite, and the researchers suggest that administration of inhibitors can modulate excessive food intake.
The research was led by Professor Johannes Vogt, faculty of Medicine, University of Munster, and colleagues, including scientists from the Yale School of Medicine in New Haven, Connecticut. They used mouse models to demonstrate that an increase in lysophosphatidylcholine (LPC) in the blood after a prolonged fast increased the LPA in the brain, which has been recognized as an important discovery.
The researchers discovered that LPAs control the excitability of neurons in the cerebral cortex and how essential they are in the control of eating behaviors. Because AgRP regulates the levels of LPC in the blood—which ultimately is converted into LPA by the enzyme autotaxin (ATX)—the use of ATX inhibitors to curb appetite proved to be a promising pharmacologic hypothesis.
The researchers hypothesized that a mutation was to blame, and mice expressing this human mutation (Prg-1R346T) were more likely to exhibit higher synaptic lipid—mediated cortical excitability and had an increased fasting-induced hyperphagia, which is known to be an abnormally strong and insatiable hunger that results in overeating. Human subjects with this mutation were more likely to have a higher BMI, be diagnosed with obesity, have a greater prevalence of T2D, and have other associated metabolic adversities.
"We saw a significant reduction in excessive food intake and obesity through gene mutation and pharmacological inhibition of ATX. Our fundamental findings on the LPA-controlled excitability of the brain, which we have worked on for years, therefore also play a central role for eating behaviour," stated Dr. Vogt. According to another research colleague at the University of Munster, Professor Robert Nitsch, "The data show that people with disturbed synaptic LPA signaling pathway are more likely to be overweight and suffer from type II diabetes. This is a strong indication of a possible therapeutic success of ATX inhibitors, which we are currently developing together with the Hans Knoll Institute in Jena for use in humans."
The authors concluded, "These findings reveal a direct influence of circulating LPAs under the control of hypothalamic AgRP neurons on cortical excitability, unmasking an alternative non-neuronal route by which the hypothalamus can exert a robust impact on the cortex and thereby affect food intake."
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