BADERC-Zhijun Luo

Jodie Babitt, M.D.

My research interest is in the area of iron homeostasis and the bone
morphogenetic protein (BMP) signaling pathway. As you know, diabetes mellitus is
a common complication of iron overload disorders such as hemochromatosis. Even
in apparently healthy populations, increased dietary iron, especially heme iron,
and high body iron stores, as measured by serum ferritin, are associated with an
increased risk of type II diabetes and other insulin resistance states. A
causative role for iron in the development of diabetes mellitus is supported by
the fact that body iron reduction by phlebotomy or iron chelators improves
glycemic control in these patients. Although the mechanisms by which iron
contributes to the pathogenesis of diabetes and diabetic complications are not
fully understood, oxidative stress induced by iron excess is thought to play a
role.

We have discovered that the BMP signaling pathway plays a crucial role in
regulating systemic iron homeostasis. Indeed, we have determined that HJV
(encoding hemojuvelin), the gene most commonly mutated in the severe juvenile
onset form of hereditary hemochromatosis, is a BMP co-receptor, and that
hemojuvelin-mediated BMP signals control expression of the key iron regulatory
hormone hepcidin (Babitt et al., Nat. Genet. 2006). We have also shown that BMP
signaling pathway activators and inhibitors modulate hepcidin expression and
systemic iron balance in vivo (Babitt et al. J. Clin. Invest. 2007). More
recently, we have discovered that BMP6 is the main BMP ligand involved in
hepcidin regulation and iron homeostasis, and that Bmp6 KO mice develop a
similar iron overload phenotype as Hjv KO mice (Andriopoulos. . .Babitt, Nat.
Genet. 2009).

Notably, the Bmp6 KO mice develop impaired glucose tolerance. We are currently
investigating whether the impaired glucose tolerance in Bmp6 KO mice is due to
iron overload per se, or whether there is a separate role for BMP6 in glucose
homeostasis. Indeed, emerging evidence suggests that the BMP signaling pathway
itself may play a role in glucose metabolism. For example, BMP9 has been
proposed to play a role as a hepatic insulin sensitizing substance. Inhibition
of endogenous BMP9 expression induces glucose intolerance and insulin resistance
in rats, while BMP9 administration improves glucose homeostasis in diabetic
rodents. Additionally, BMP ligands and the BMP type I receptor ALK3 are
expressed in pancreatic beta cells, and mice heterozygous for mutations in ALK3
develop abnormal glucose metabolism with impaired insulin secretion.

Other current work focuses on determining the molecular and cellular mechanisms
by which body iron levels sensed to regulate BMP6 expression, hepcidin
expression and systemic iron balance. We are dissecting the specific
protein-interaction domains that allow BMP6 and its co-receptor HJV to interact
to enhance SMAD signaling and hepcidin expression, and we are investigating
whether this BM6-HJV-SMAD signaling pathway interacts with other proteins known
to be involved in hepcidin regulation and iron homeostasis, including the
hemochromatosis protein HFE and transferrin receptor 2. Additionally, we are
developing BMP pathway modulators as potential new therapies for anemia and iron
overload disorders. Given the pathogenic role for iron in diabetes mellitus, and
the emerging link between the BMP signaling pathway and glucose homeostasis, our
work may provide new insights into the pathogenesis of diabetes and may
ultimately lead to new treatment strategies.






			Jodie Babitt, M.D. My research interest is in the area of iron homeostasis and the bone morphogenetic protein (BMP) signaling pathway. As you know, diabetes mellitus is a common complication of iron overload disorders such as hemochromatosis. Even in apparently healthy populations, increased dietary iron, especially heme iron, and high body iron stores, as measured by serum ferritin, are associated with an increased risk of type II diabetes and other insulin resistance states. A causative role for iron in the development of diabetes mellitus is supported by the fact that body iron reduction by phlebotomy or iron chelators improves glycemic control in these patients. Although the mechanisms by which iron contributes to the pathogenesis of diabetes and diabetic complications are not fully understood, oxidative stress induced by iron excess is thought to play a role. We have discovered that the BMP signaling pathway plays a crucial role in regulating systemic iron homeostasis. Indeed, we have determined that HJV (encoding hemojuvelin), the gene most commonly mutated in the severe juvenile onset form of hereditary hemochromatosis, is a BMP co-receptor, and that hemojuvelin-mediated BMP signals control expression of the key iron regulatory hormone hepcidin (Babitt et al., Nat. Genet. 2006). We have also shown that BMP signaling pathway activators and inhibitors modulate hepcidin expression and systemic iron balance in vivo (Babitt et al. J. Clin. Invest. 2007). More recently, we have discovered that BMP6 is the main BMP ligand involved in hepcidin regulation and iron homeostasis, and that Bmp6 KO mice develop a similar iron overload phenotype as Hjv KO mice (Andriopoulos. . .Babitt, Nat. Genet. 2009). Notably, the Bmp6 KO mice develop impaired glucose tolerance. We are currently investigating whether the impaired glucose tolerance in Bmp6 KO mice is due to iron overload per se, or whether there is a separate role for BMP6 in glucose homeostasis. Indeed, emerging evidence suggests that the BMP signaling pathway itself may play a role in glucose metabolism. For example, BMP9 has been proposed to play a role as a hepatic insulin sensitizing substance. Inhibition of endogenous BMP9 expression induces glucose intolerance and insulin resistance in rats, while BMP9 administration improves glucose homeostasis in diabetic rodents. Additionally, BMP ligands and the BMP type I receptor ALK3 are expressed in pancreatic beta cells, and mice heterozygous for mutations in ALK3 develop abnormal glucose metabolism with impaired insulin secretion. Other current work focuses on determining the molecular and cellular mechanisms by which body iron levels sensed to regulate BMP6 expression, hepcidin expression and systemic iron balance. We are dissecting the specific protein-interaction domains that allow BMP6 and its co-receptor HJV to interact to enhance SMAD signaling and hepcidin expression, and we are investigating whether this BM6-HJV-SMAD signaling pathway interacts with other proteins known to be involved in hepcidin regulation and iron homeostasis, including the hemochromatosis protein HFE and transferrin receptor 2. Additionally, we are developing BMP pathway modulators as potential new therapies for anemia and iron overload disorders. Given the pathogenic role for iron in diabetes mellitus, and the emerging link between the BMP signaling pathway and glucose homeostasis, our work may provide new insights into the pathogenesis of diabetes and may ultimately lead to new treatment strategies.