Metabolic Reprogramming of Macrophages: GLUCOSE TRANSPORTER 1 (GLUT1)-MEDIATED GLUCOSE METABOLISM DRIVES A PROINFLAMMATORY PHENOTYPE

Glucose is a critical component in the proinflammatory response of macrophages (MΦs). However, the contribution of glucose transporters (GLUTs) and the mechanisms regulating subsequent glucose metabolism in the inflammatory response are not well understood. Because MΦs contribute to obesity-induced inflammation, it is important to understand how substrate metabolism may alter inflammatory function. We report that GLUT1 (SLC2A1) is the primary rate-limiting glucose transporter on proinflammatory-polarized MΦs. Furthermore, in high fat diet-fed rodents, MΦs in crown-like structures and inflammatory loci in adipose and liver, respectively, stain positively for GLUT1. We hypothesized that metabolic reprogramming via increased glucose availability could modulate the MΦ inflammatory response. To increase glucose uptake, we stably overexpressed the GLUT1 transporter in RAW264.7 MΦs (GLUT1-OE MΦs). Cellular bioenergetics analysis, metabolomics, and radiotracer studies demonstrated that GLUT1 overexpression resulted in elevated glucose uptake and metabolism, increased pentose phosphate pathway intermediates, with a complimentary reduction in cellular oxygen consumption rates. Gene expression and proteome profiling analysis revealed that GLUT1-OE MΦs demonstrated a hyperinflammatory state characterized by elevated secretion of inflammatory mediators and that this effect could be blunted by pharmacologic inhibition of glycolysis. Finally, reactive oxygen species production and evidence of oxidative stress were significantly enhanced in GLUT1-OE MΦs; antioxidant treatment blunted the expression of inflammatory mediators such as PAI-1 (plasminogen activator inhibitor 1), suggesting that glucose-mediated oxidative stress was driving the proinflammatory response. Our results indicate that increased utilization of glucose induced a ROS-driven proinflammatory phenotype in MΦs, which may play an integral role in the promotion of obesity-associated insulin resistance

The Impact of Ethnicity on Craniosynostosis in the United States.

While many studies have examined potential risk factors for nonsyndromic craniosynostosis, there have been no publications to date investigating the role of ethnicity in the United States. The current study was undertaken as the first multi-center investigation to examine the relationship between ethnicity and nonsyndromic craniosynostosis, looking at both overall prevalence as well as potential correlation between ethnicity and pattern of affected suture site. A chart review of patients diagnosed with nonsyndromic craniosynostosis treated at four major children\u27s hospitals was performed to obtain ethnicity data. Analysis was preformed based on ethnic group as well as suture site affected. To account for potentialOne regional selection bias, the KID database (1997-2012) was utilized to identify all cases of craniosynostosis on a national level. This data was analyzed against birth rates by ethnicity obtained from CDC WONDER natality database.Amongst the 2112 cases of nonsyndromic craniosynostosis at all institutions, Caucasians and African Americans were consistently the predominant ethnic groups. There was a statistically significant difference in the distribution of affected suture type with African Americans more likely to present with unicoronal synostosis and Caucasians more likely to present with metopic synostosis (P = 0.005). The national data revealed that there were more cases of craniosynostosis in Caucasians and fewer in African Americans than expected when compared to population birth rates. Our findings demonstrate that the Caucasian race is associated with increased rates of synostosis