A Strategy for Discovery of Endocrine Interactions with Application to Whole-Body Metabolism
Open accessAbstract
Inter-tissue communication via secreted proteins has been established as a vital mechanism for proper physiologic homeostasis. Here, we report a bioinformatics framework using a mouse reference population, the Hybrid Mouse Diversity Panel (HMDP), which integrates global multi-tissue expression data and publicly available resources to identify and functionally annotate novel circuits of tissue-tissue communication. We validate this method by showing that we can identify known as well as novel endocrine factors responsible for communication between tissues. We further show the utility of this approach by identification and mechanistic characterization of two new endocrine factors. Adipose-derived Lipocalin-5 is shown to enhance skeletal muscle mitochondrial function, and liver-secreted Notum promotes browning of white adipose tissue, also known as "beiging." We demonstrate the general applicability of the method by providing in vivo evidence for three additional novel molecules mediating tissue-tissue interactions.
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Lcn5 (LCN6 in humans) promotes insulin sensitivity by enhancing muscle mitochondrial function.
“An example of the use of novel strategies for the discovery of endocrine interactions with physiological relevance for whole‐body metabolism is the recent discovery of a novel adipokine, mouse lipocalin 5 (Lcn5; LCN6 in humans), that has the ability to promote insulin sensitivity by enhancing muscle mitochondrial function 135.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [135]
The effects of Lcn5 in promoting glucose and insulin sensitivity in vivo were more pronounced in a high‐fat high‐sucrose (HF‐HS) model.
“Of note, despite showing significant effects in promoting muscle mitochondrial function in cellular models, the effects of the novel adipokine Lcn5 in promoting glucose and insulin sensitivity in vivo were more pronounced in a high‐fat high‐sucrose (HF‐HS) model.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [135]
Lcn5 overexpression had positive effects on the metabolic status whether at the beginning or after several weeks of HF‐HS diet.
“However, it is worth noting that Lcn5 overexpression had positive effects on the metabolic status whether at the beginning or after several weeks of HF‐HS diet 135.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [135]
Population‐based methods taking advantage of natural variations between transcript levels within strains of a mouse reference population have been used to identify new inter‐organ communication networks in metabolism.
“More recently, population‐based methods taking advantage of the natural variations between transcript levels within strains of a mouse reference population have been used to identify new inter‐organ communication networks in metabolism 135.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [135]
A bioinformatic‐based approach allowed for the identification of Lcn5 and Notum.
“This bioinformatic‐based approach allowed for the identification of Lcn5, an adipokine that promotes muscle mitochondrial function, and of Notum, a hepatokine that promotes WAT browning and BAT thermogenesis 135.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [135]
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“…test the hypothesis, we treated 3T3L1 adipocytes for the first 3 days of brown differentiation with vehicle or 200 ng/mL NOTUM, a protocol that has been previously used to test whether various pharmacologic agents could promote beiging of 3T3L1 adipocytes (Asano et al., 2014; Zhang et al., 2014).”
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- Authors
- Seldin, M. M., Koplev, S., Rajbhandari, P., Vergnes, L., Rosenberg, G. M., Meng, Y., Pan, C., Phuong, T. M. N., Gharakhanian, R., Che, N., Mäkinen, S., Shih, D. M., Civelek, M., Parks, B. W., Kim, E. D., Norheim, F., Chella Krishnan, K., Hasin-Brumshtein, Y., Mehrabian, M., Laakso, M., Drevon, C. A., Koistinen, H. A., Tontonoz, P., Reue, K., Cantor, R. M., Björkegren, J. L. M., & Lusis, A. J.
- Affiliations
- University of California, Los Angeles (US)
- Karolinska University Hospital (SE)
- University of Helsinki (FI)
- University of Virginia (US)
- University of Wisconsin–Madison (US)
- University of Oslo (NO)
- University of Eastern Finland (FI)
- Corresponding author
- Lusis, Aldons J.
- ORCID
- Seldin, Marcus M.
- Koplev, Simon
- Rajbhandari, Prashant
- Vergnes, Laurent
- Rosenberg, Gregory M.
- Meng, Yonghong
- Pan, Calvin
- Gharakhanian, Raffi
- Mäkinen, Selina
- Shih, Diana M.
- Civelek, Mete
- Parks, Brian W.
- Norheim, Frode
- Hasin-Brumshtein, Yehudit
- Mehrabian, Margarete
- Laakso, Markku
- Drevon, Christian A.
- Koistinen, Heikki A.
- Tontonoz, Peter
- Reue, Karen
- Cantor, Rita M.
- Björkegren, Johan L.M.
- Lusis, Aldons J.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 27
- Issue
- 5
- Pages
- 1138-1155.e6
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5935137
- OpenAlex
- W2800349415
- Cited by
- 84
- References
- 122
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 9 · 2023: 19 · 2022: 11 · 2021: 8 · 2020: 6 · 2019: 9 · 2018: 1
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nd)
- Funders
- NIH (T32HL007895, T32HL69766, HL28481, HL30568, R00HL121172)
- Fondation Leducq (12CVD02)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- inter-tissue communication, hormone signaling, secreted proteins, Hybrid Mouse Diversity Panel, multi-tissue gene expression, notum, skeletal muscle mitochondrial function, white adipose tissue browning, whole-body metabolism
- MeSH terms
- Adipose Tissue, Animals, Cells, Cultured, Endocrine System, Homeostasis, Mice, Inbred C57BL, Mitochondria, Muscle, Skeletal, Mitochondrial Proteins, Proteomics, Mice, Lipocalins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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