Lipolysis of bone marrow adipocytes is required to fuel bone and the marrow niche during energy deficits
- University of Michigan-Ann Arbor, United States
- Maine Medical Center Research Institute, United States
Abstract
To investigate roles for bone marrow adipocyte (BMAd) lipolysis in bone homeostasis, we created a BMAd-specific Cre mouse model in which we knocked out adipose triglyceride lipase (ATGL, Pnpla2 gene). BMAd-Pnpla2-/- mice have impaired BMAd lipolysis, and increased size and number of BMAds at baseline. Although energy from BMAd lipid stores is largely dispensable when mice are fed ad libitum, BMAd lipolysis is necessary to maintain myelopoiesis and bone mass under caloric restriction. BMAd-specific Pnpla2 deficiency compounds the effects of caloric restriction on loss of trabecular bone in male mice, likely due to impaired osteoblast expression of collagen genes and reduced osteoid synthesis. RNA sequencing analysis of bone marrow adipose tissue reveals that caloric restriction induces dramatic elevations in extracellular matrix organization and skeletal development genes, and energy from BMAd is required for these adaptations. BMAd-derived energy supply is also required for bone regeneration upon injury, and maintenance of bone mass with cold exposure.
Data availability
The accession number for the BMAT bulk RNA seq data reported in this paper is GEO: GSE183784.
Article and author information
Author details
Kanakadurga Singer
Funding
National Institutes of Health (R01 DK62876)
- Ormond MacDougald
National Institutes of Health (T32 DK071212)
- Kenneth T Lewis
National Institutes of Health (F32 DK122654)
- Kenneth T Lewis
National Institutes of Health (T32 DK101357)
- Rebecca L Schill
National Institutes of Health (F32 DK123887)
- Rebecca L Schill
National Institutes of Health (R01AR066028)
- Kurt D Hankenson
National Institutes of Health (R24DK092759)
- Clifford J Rosen
American Diabetes Association (1-18-PDF-087)
- Ziru Li
American Heart Association (20-PAF00361)
- Emily Bowers
National Institutes of Health (R24 DK092759)
- Ormond MacDougald
National Institutes of Health (R01 DK126230)
- Ormond MacDougald
National Institutes of Health (R01 AG069795)
- Ormond MacDougald
National Institutes of Health (T32 GM835326)
- Steven M Romanelli
National Institutes of Health (F31 DK12272301)
- Steven M Romanelli
National Institutes of Health (T32 HD007505)
- Devika P Bagchi
National Institutes of Health (T32 GM007863)
- Devika P Bagchi
National Institutes of Health (R01DK115583)
- Kanakadurga Singer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Mone Zaidi, Icahn School of Medicine at Mount Sinai, United States
Ethics
Animal experimentation: All procedures were approved by the University of Michigan Committee on the Use and Care of Animals with the protocol number as PRO00009687.
Version history
- Received: March 9, 2022
- Preprint posted: March 21, 2022 (view preprint)
- Accepted: June 21, 2022
- Accepted Manuscript published: June 22, 2022 (version 1)
- Version of Record published: July 11, 2022 (version 2)
Copyright
© 2022, Li et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,370
- views
-
- 948
- downloads
-
- 40
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Lipolysis of bone marrow adipocytes is required to fuel bone and the marrow niche during energy deficits
eLife 11:e78496.
https://doi.org/10.7554/eLife.78496
Further reading
-
- Cancer Biology
- Cell Biology
Pancreatic ductal adenocarcinoma carries a dismal prognosis, with high rates of metastasis and few treatment options. Hyperactivation of KRAS in almost all tumours drives RAC1 activation, conferring enhanced migratory and proliferative capacity as well as macropinocytosis. Macropinocytosis is well understood as a nutrient scavenging mechanism, but little is known about its functions in trafficking of signalling receptors. We find that CYRI-B is highly expressed in pancreatic tumours in a mouse model of KRAS and p53-driven pancreatic cancer. Deletion of Cyrib (the gene encoding CYRI-B protein) accelerates tumourigenesis, leading to enhanced ERK and JNK-induced proliferation in precancerous lesions, indicating a potential role as a buffer of RAC1 hyperactivation in early stages. However, as disease progresses, loss of CYRI-B inhibits metastasis. CYRI-B depleted tumour cells show reduced chemotactic responses to lysophosphatidic acid, a major driver of tumour spread, due to impaired macropinocytic uptake of the lysophosphatidic acid receptor 1. Overall, we implicate CYRI-B as a mediator of growth and signalling in pancreatic cancer, providing new insights into pathways controlling metastasis.
-
- Cell Biology
- Physics of Living Systems
An influx of water molecules can help immune cells called neutrophils to move to where they are needed in the body.
