Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis
Open accessAbstract
All homeotherms use thermogenesis to maintain their core body temperature, ensuring that cellular functions and physiological processes can continue in cold environments. In the prevailing model of thermogenesis, when the hypothalamus senses cold temperatures it triggers sympathetic discharge, resulting in the release of noradrenaline in brown adipose tissue and white adipose tissue. Acting via the β(3)-adrenergic receptors, noradrenaline induces lipolysis in white adipocytes, whereas it stimulates the expression of thermogenic genes, such as PPAR-γ coactivator 1a (Ppargc1a), uncoupling protein 1 (Ucp1) and acyl-CoA synthetase long-chain family member 1 (Acsl1), in brown adipocytes. However, the precise nature of all the cell types involved in this efferent loop is not well established. Here we report in mice an unexpected requirement for the interleukin-4 (IL-4)-stimulated program of alternative macrophage activation in adaptive thermogenesis. Exposure to cold temperature rapidly promoted alternative activation of adipose tissue macrophages, which secrete catecholamines to induce thermogenic gene expression in brown adipose tissue and lipolysis in white adipose tissue. Absence of alternatively activated macrophages impaired metabolic adaptations to cold, whereas administration of IL-4 increased thermogenic gene expression, fatty acid mobilization and energy expenditure, all in a macrophage-dependent manner. Thus, we have discovered a role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold.
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Macrophages and the bone morphogenetic protein BMP8B have the capacity to regulate BAT thermogenesis.
“In addition, recent articles reported that macrophages ([125](#B125)) and the bone morphogenetic protein BMP8B ([172](#B172)) have also the capacity to regulate BAT thermogenesis.”
From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [125]
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- Authors
- Nguyen, K. D., Qiu, Y., Cui, X., Goh, Y. P. S., Mwangi, J., David, T., Mukundan, L., Brombacher, F., Locksley, R. M., & Chawla, A.
- Affiliations
- Stanford University (US)
- University of California, San Francisco (US)
- University of Cape Town (ZA)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Chawla, Ajay
- ORCID
- Venue
- Nature
- Published
- 2011-11-20
- Volume
- 480
- Issue
- 7375
- Pages
- 104-108
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3371761
- OpenAlex
- W2060813891
- Cited by
- 1,038
- References
- 24
- Citations by year
- 2026: 39 · 2025: 32 · 2024: 43 · 2023: 49 · 2022: 64 · 2021: 76 · 2020: 90 · 2019: 79 · 2018: 85 · 2017: 104 · 2016: 95 · 2015: 99 · 2014: 70 · 2013: 63 · 2012: 45
- FWCI
- 39.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (DP1OD006415)
- National Heart, Lung, and Blood Institute (R01HL076746, HL-07674)
- National Institute of Allergy and Infectious Diseases (R01AI026918)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK081405, DK076760, DK-094641, R01DK076760, R01DK094641)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (DP1AR064158)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- M2 macrophages, adaptive thermogenesis, catecholamines, norepinephrine, IL-4, cold exposure, brown adipose tissue, white adipose tissue, lipolysis, thermogenic gene expression, energy expenditure, fatty acid mobilization, non-shivering thermogenesis
- MeSH terms
- Adipose Tissue, Animals, Body Temperature, Catecholamines, Cells, Cultured, Cold Temperature, Energy Metabolism, Gene Expression Regulation, Humans, Macrophage Activation, Macrophages, Male, Mice, Inbred BALB C, Stress, Physiological, Interleukin-4, U937 Cells, Thermogenesis, Mice
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