Erythropoietin and high fat diet-induced hypothalamic inflammation

Josu Cabn1, Soumyadeep Dey1 and Constance T. Noguchi1*

1

Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, MD

PROJECT DESCRIPTION
Erythropoietin (Epo) is a 165 amino acid cytokine produced in the fetal liver and adult
kidney and is responsive to low blood oxygen levels. It interacts with hematopoietic
stem cells in the bone marrow to stimulate the production of red blood cells (RBCs), and
it also plays a role in peripheral tissues to produce a myriad of extra-hematopoietic
effects. Epo produced in the brain by astrocytes and neuronal cells has been proven to
stimulate the differentiation and maturation of neural progenitor cells in culture and
prevents ischemia-induced cell death after middle-cerebral artery occlusion in animal
models. Erythropoietin receptor (EpoR) in the brain is expressed in microglial cells
which can sense the presence of saturated fatty acids and release pro-inflammatory
mediators in response.

OBJECTIVE/PURPOSE
To assess Epos signaling in the hypothalamus and its involvement in the recruitment
and activation of microglial cells and how this process consequently helps in the
regulation of body energy homeostasis and metabolic response to a high fat-diet (HFD).

METHODOLOGY
A two-week HFD regimen was administered to wild-type (WT) mice controls, transgenic
mice with chronic human Epo overexpression in the brain (Tg21 mouse model), and
transgenic mice with EpoR knockout localized to neuronal cells in the brain (EpoR NestinKO
mouse model). Hypothalamic sections were prepared with antibodies both against the
inflammatory cytokine TNF- and Iba-1 (microglial marker).

PRESENTERS ROLE IN RESEARCH PROJECT

Medical student working along with a post-doctoral fellow at the National Institutes of
Health main campus. Worked with study design, protocols, literature review,
experimental procedures, discussion of results and statistical analysis of these.

RESULTS
Tg21 mice had significantly lower fasting blood glucose levels both at baseline and after
the two-week HFD challenge, supporting our hypothesis of Epos energy-regulating
effects. To add to this effect, Tg21 mice had significantly lower weight gain, attributed to
a lesser fat mass gain throughout the experiment. All of this without a significantly
different hematocrit level, indicating Epos signaling in the brain is independent of
peripheral RBC numbers. In contrast, EpoRNestinKO mice had significantly higher fat mass
gain throughout the two-week experiment and showed an increased trend in fasting
blood glucose levels. WT mouse brain sections had significantly higher microglial cells
present in hypothalamic sections compared with Tg21 mice

DISCUSSION/CONCLUSION
Epo signaling in the arcuate nucleus of the hypothalamus acts to decrease microglial
cell activation and reduce the inflammatory impact mediated by a HFD regimen
independently of peripheral RBC numbers.