TY - JOUR
T1 - Conditional loss of IKKα in Osterix + cells has no effect on bone but leads to age-related loss of peripheral fat
AU - Davis, Jennifer L.
AU - Pokhrel, Nitin Kumar
AU - Cox, Linda
AU - Rohatgi, Nidhi
AU - Faccio, Roberta
AU - Veis, Deborah J.
N1 - Funding Information:
This work was supported by National Institutes of Health Grants R01 AR052705 and P01 CA100730 (to DJV), R01 AR070030 (to DJV and RF), R01 AR066551 (to RF), and F31 AR068853 and T32 CA113275 (to JLD). MicroCT and histology services were provided by the Washington University Musculoskeletal Research Center’s Structure and Strength and Histology and Morphometry Cores, supported by P30 AR074992. EchoMRI analysis was performed in the Washington University Nutrition Obesity Research Center, supported by P30 DK056341 via a just-in-time grant. Additional support was provided by the Siteman Cancer Center Investment Program, St. Louis, MO to RF. Funding from Shriners Hospitals for Children was provided to DJV and RF. We wish to thank Crystal Idleburg for histological expertise, Dr. Giulia Furesi for flow cytometry, and Dr. Sangeeta Adak and Dr. Erica Scheller for assistance with fat and metabolism experiments.
Funding Information:
This work was supported by National Institutes of Health Grants R01 AR052705 and P01 CA100730 (to DJV), R01 AR070030 (to DJV and RF), R01 AR066551 (to RF), and F31 AR068853 and T32 CA113275 (to JLD). MicroCT and histology services were provided by the Washington University Musculoskeletal Research Center’s Structure and Strength and Histology and Morphometry Cores, supported by P30 AR074992. EchoMRI analysis was performed in the Washington University Nutrition Obesity Research Center, supported by P30 DK056341 via a just-in-time grant. Additional support was provided by the Siteman Cancer Center Investment Program, St. Louis, MO to RF. Funding from Shriners Hospitals for Children was provided to DJV and RF. We wish to thank Crystal Idleburg for histological expertise, Dr. Giulia Furesi for flow cytometry, and Dr. Sangeeta Adak and Dr. Erica Scheller for assistance with fat and metabolism experiments.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - NF-κB has been reported to both promote and inhibit bone formation. To explore its role in osteolineage cells, we conditionally deleted IKKα, an upstream kinase required for non-canonical NF-κB activation, using Osterix (Osx)-Cre. Surprisingly, we found no effect on either cancellous or cortical bone, even following mechanical loading. However, we noted that IKKα conditional knockout (cKO) mice began to lose body weight after 6 months of age with severe reductions in fat mass and lower adipocyte size in geriatric animals. qPCR analysis of adipogenic markers in fat pads of cKO mice indicated no difference in early differentiation, but instead markedly lower leptin with age. We challenged young mice with a high fat diet finding that cKO mice gained less weight and showed improved glucose metabolism. Low levels of recombination at the IKKα locus were detected in fat pads isolated from old cKO mice. To determine whether recombination occurs in adipocytes, we examined fat pads in Osx-Cre;TdT reporter mice; these showed increasing Osx-Cre-mediated expression in peripheral adipocytes from 6 weeks to 18 months. Since Osx-Cre drives recombination in peripheral adipocytes with age, we conclude that fat loss in cKO mice is most likely caused by progressive deficits of IKKα in adipocytes.
AB - NF-κB has been reported to both promote and inhibit bone formation. To explore its role in osteolineage cells, we conditionally deleted IKKα, an upstream kinase required for non-canonical NF-κB activation, using Osterix (Osx)-Cre. Surprisingly, we found no effect on either cancellous or cortical bone, even following mechanical loading. However, we noted that IKKα conditional knockout (cKO) mice began to lose body weight after 6 months of age with severe reductions in fat mass and lower adipocyte size in geriatric animals. qPCR analysis of adipogenic markers in fat pads of cKO mice indicated no difference in early differentiation, but instead markedly lower leptin with age. We challenged young mice with a high fat diet finding that cKO mice gained less weight and showed improved glucose metabolism. Low levels of recombination at the IKKα locus were detected in fat pads isolated from old cKO mice. To determine whether recombination occurs in adipocytes, we examined fat pads in Osx-Cre;TdT reporter mice; these showed increasing Osx-Cre-mediated expression in peripheral adipocytes from 6 weeks to 18 months. Since Osx-Cre drives recombination in peripheral adipocytes with age, we conclude that fat loss in cKO mice is most likely caused by progressive deficits of IKKα in adipocytes.
UR - http://www.scopus.com/inward/record.url?scp=85126872099&partnerID=8YFLogxK
U2 - 10.1038/s41598-022-08914-6
DO - 10.1038/s41598-022-08914-6
M3 - Article
C2 - 35318397
AN - SCOPUS:85126872099
VL - 12
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 4915
ER -