Erythropoietin (Epo), known for its hematopoietic role, is produced in the brain by

astrocytes and neuronal cells. Erythropoietin receptor (EpoR) in the brain is expressed
on microglial cells which can sense the presence of saturated fatty acids and release
pro-inflammatory mediators in response. We hypothesized that Epo signaling in the
hypothalamus acts to reduce microglial cell activation and consequently helps in the
regulation of body energy homeostasis and metabolic response to a high fat-diet (HFD).

A two-week HFD regimen was administered to three transgenic mouse strains.

Hypothalamic sections were prepared with antibodies both against the inflammatory
cytokine TNF- and Iba-1 (microglial marker).

The three mouse strains differed significantly in lower fasting blood glucose (FBG)
levels and weight gain, both at baseline and after the HFD challenge. This without a
significantly different hematocrit level, indicating Epos signaling in the brain is
independent of peripheral RBC numbers. They also significantly differed in the number
of activated microglial cells present in hypothalamic sections.

In summary, these studies suggest an important extrahematopoietic and homeostatic

function of Epo in brain inflammation and metabolism.