Cover Story Current Issue

White adipose tissue (WAT) is a complex organ that plays a central role in systemic energy balance through its interrelated metabolic, endocrine, and immune functions. Adipocytes, the parenchymal cells of adipose tissue, have diverse functions that include storage and mobilization of lipids. They also release endocrine signals that report energy status to the brain, regulating metabolic functions in peripheral organs. Importantly, the metabolic character of white adipocytes is flexible, with cells capable of assuming distinct anabolic and catabolic/thermogenic phenotypes, often within the same adipose tissue depot

Elizabeth A. Rondini, Vanesa D. Ramseyer, Rayanne B. Burl, Roger Pique-Regi, James G. Granneman

Full text

 

Current Issue

Hepatocyte-specific glucose-6-phosphatase deficiency disturbs platelet aggregation and decreases blood monocytes upon fasting-induced hypoglycemia

Anouk M. La Rose, Venetia Bazioti, Joanne A. Hoogerland, Arthur F. Svendsen, ... Marit Westerterp

Objective

Glycogen storage disease type 1a (GSD Ia) is a rare inherited metabolic disordercaused by mutations in the glucose-6-phosphatase (G6PC1) gene. When untreated, GSD Ia leads to severe fasting-induced hypoglycemia. Although current intensive dietary management aims to prevent hypoglycemia, patients still experience hypoglycemic events. Poor glycemic control in GSD Ia is associated with hypertriglyceridemiahepatocellular adenoma and carcinoma, and also with an increased bleeding tendency of unknown origin.

Methods

To evaluate the effect of glycemic control on leukocyte levels and coagulation in GSD Ia, we employed hepatocyte-specific G6pc1 deficient (L-G6pc−/−) mice under fed or fasted conditions, to match good or poor glycemic control in GSD Ia, respectively.

Results

We found that fasting-induced hypoglycemia in L-G6pc−/− mice decreased blood leukocytes, specifically proinflammatory Ly6Chi monocytes, compared to controls. Refeeding reversed this decrease. The decrease in Ly6Chi monocytes was accompanied by an increase in plasma corticosterone levels and was prevented by the glucocorticoid receptor antagonist mifepristone. Further, fasting-induced hypoglycemia in L-G6pc−/− mice prolonged bleeding time in the tail vein bleeding assay, with reversal by refeeding. This could not be explained by changes in coagulation factors V, VII, or VIII, or von Willebrand factor. While the prothrombinand activated partial thromboplastin time as well as total platelet counts were not affected by fasting-induced hypoglycemia in L-G6pc−/− mice, ADP-induced platelet aggregation was disturbed.

Conclusions

These studies reveal a relationship between fasting-induced hypoglycemia, decreased blood monocytes, and disturbed platelet aggregation in L-G6pc−/− mice. While disturbed platelet aggregation likely accounts for the bleeding phenotype in GSD Ia, elevated plasma corticosterone decreases the levels of proinflammatory monocytes. These studies highlight the necessity of maintaining good glycemic control in GSD Ia.

Hepatocyte-specific glucose-6-phosphatase deficiency disturbs platelet aggregation and decreases blood monocytes upon fasting-induced hypoglycemia

Anouk M. La Rose, Venetia Bazioti, Joanne A. Hoogerland, Arthur F. Svendsen, ... Marit Westerterp

Objective

Glycogen storage disease type 1a (GSD Ia) is a rare inherited metabolic disordercaused by mutations in the glucose-6-phosphatase (G6PC1) gene. When untreated, GSD Ia leads to severe fasting-induced hypoglycemia. Although current intensive dietary management aims to prevent hypoglycemia, patients still experience hypoglycemic events. Poor glycemic control in GSD Ia is associated with hypertriglyceridemiahepatocellular adenoma and carcinoma, and also with an increased bleeding tendency of unknown origin.

Methods

To evaluate the effect of glycemic control on leukocyte levels and coagulation in GSD Ia, we employed hepatocyte-specific G6pc1 deficient (L-G6pc−/−) mice under fed or fasted conditions, to match good or poor glycemic control in GSD Ia, respectively.

Results

We found that fasting-induced hypoglycemia in L-G6pc−/− mice decreased blood leukocytes, specifically proinflammatory Ly6Chi monocytes, compared to controls. Refeeding reversed this decrease. The decrease in Ly6Chi monocytes was accompanied by an increase in plasma corticosterone levels and was prevented by the glucocorticoid receptor antagonist mifepristone. Further, fasting-induced hypoglycemia in L-G6pc−/− mice prolonged bleeding time in the tail vein bleeding assay, with reversal by refeeding. This could not be explained by changes in coagulation factors V, VII, or VIII, or von Willebrand factor. While the prothrombinand activated partial thromboplastin time as well as total platelet counts were not affected by fasting-induced hypoglycemia in L-G6pc−/− mice, ADP-induced platelet aggregation was disturbed.

Conclusions

These studies reveal a relationship between fasting-induced hypoglycemia, decreased blood monocytes, and disturbed platelet aggregation in L-G6pc−/− mice. While disturbed platelet aggregation likely accounts for the bleeding phenotype in GSD Ia, elevated plasma corticosterone decreases the levels of proinflammatory monocytes. These studies highlight the necessity of maintaining good glycemic control in GSD Ia.

2020 impact factor: 7.4

The 60 Second Metabolist

In this section authors briefly report on their work recently published in Molecular Metabolism.

Watch the most recent interviews by clicking the video still. 

Here is a video of Vimeo. When the iframes is activated, a connection to Vimeo is established and, if necessary, cookies from Vimeo are also used. For further information on cookies policy click here.

Here is a video of Vimeo. When the iframes is activated, a connection to Vimeo is established and, if necessary, cookies from Vimeo are also used. For further information on cookies policy click here.