Journal
NATURE MEDICINE
Volume 18, Issue 6, Pages 943-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2756
Keywords
-
Funding
- US National Institutes of Health (NIH) [DK 065122, DK073601]
- American Diabetes Association [1-09-RA-156]
- Michigan Diabetes Research and Training Center
- NIH [5P60 DK20572, 5 P30 CA46592, P30AG013283, DK34933]
- University of Michigan's Cancer Center
- University of Michigan Nathan Shock Center
- University of Michigan Gut Peptide Research Center
Ask authors/readers for more resources
The canonical inhibitor of nuclear factor kappa B kinase subunit beta (IKK-beta)-nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (NF-kappa B1) pathway has been well documented to promote insulin resistance; however, the noncanonical NF-kappa B-inducing kinase (NIK)-NF-kappa B2 pathway is not well understood in obesity. Additionally, the contribution of counter-regulatory hormones, particularly glucagon, to hyperglycemia in obesity is unclear. Here we show that NIK promotes glucagon responses in obesity. Hepatic NIK was abnormally activated in mice with dietary or genetic obesity. Systemic deletion of Map3k14, encoding NIK, resulted in reduced glucagon responses and hepatic glucose production (HGP). Obesity is associated with high glucagon responses, and liver-specific inhibition of NIK led to lower glucagon responses and HGP and protected against hyperglycemia and glucose intolerance in obese mice. Conversely, hepatocyte-specific overexpression of NIK resulted in higher glucagon responses and HGP. In isolated mouse livers and primary hepatocytes, NIK also promoted glucagon action and glucose production, at least in part by increasing cAMP response element-binding (CREB) stability. Therefore, overactivation of liver NIK in obesity promotes hyperglycemia and glucose intolerance by increasing the hyperglycemic response to glucagon and other factors that activate CREB.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available