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Sympathetic inputs regulate adaptive thermogenesis in brown adipose tissue through cAMP-Salt inducible kinase axis
Open accessAbstract
Various physiological stimuli, such as cold environment, diet, and hormones, trigger brown adipose tissue (BAT) to produce heat through sympathetic nervous system (SNS)- and β-adrenergic receptors (βARs). The βAR stimulation increases intracellular cAMP levels through heterotrimeric G proteins and adenylate cyclases, but the processes by which cAMP modulates brown adipocyte function are not fully understood. Here we described that specific ablation of cAMP production in brown adipocytes led to reduced lipolysis, mitochondrial biogenesis, uncoupling protein 1 (Ucp1) expression, and consequently defective adaptive thermogenesis. Elevated cAMP signaling by sympathetic activation inhibited Salt-inducible kinase 2 (Sik2) through protein kinase A (PKA)-mediated phosphorylation in brown adipose tissue. Inhibition of SIKs enhanced Ucp1 expression in differentiated brown adipocytes and Sik2 knockout mice exhibited enhanced adaptive thermogenesis at thermoneutrality in an Ucp1-dependent manner. Taken together, our data indicate that suppressing Sik2 by PKA-mediated phosphorylation is a requisite for SNS-induced Ucp1 expression and adaptive thermogenesis in BAT, and targeting Sik2 may present a novel therapeutic strategy to ramp up BAT thermogenic activity in humans.
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Under caloric restriction, SNS activity decreases, reducing norepinephrine release and β-adrenergic receptor stimulation, especially in BAT, where UCP1 activity drops.
“Under caloric restriction, SNS activity decreases, reducing norepinephrine release and β-adrenergic receptor stimulation, especially in BAT, where mitochondrial uncoupling protein (UCP1) activity drops.”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [31]
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Metadata
- Authors
- Paulo, E., Wu, D., Wang, Y., Zhang, Y., Wu, Y., Swaney, D. L., Soucheray, M., Jimenez-Morales, D., Chawla, A., Krogan, N. J., & Wang, B.
- Affiliations
- University of California, San Francisco (US)
- City Of Hope National Medical Center (US)
- QB3 (US)
- Corresponding author
- Wang, Biao
- ORCID
- Venue
- Scientific Reports
- Published
- 2018-07-20
- Volume
- 8
- Issue
- 1
- Pages
- 11001-11001
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC6054673
- OpenAlex
- W2884188461
- Cited by
- 59
- References
- 74
- Citations by year
- 2026: 13 · 2025: 8 · 2024: 5 · 2023: 11 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 4
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Larry L. Hillblom Foundation (P30DK063720, U54NS100717, P30DK098722, DK105175, P50GM082250)
- University of Dundee
- National Institutes of Health (UM1OD023221)
- University of California, San Francisco (P30DK098722, P30DK063720)
- National Institute of General Medical Sciences (P50GM082250)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK101064, P30DK098722, R01DK105175, P30DK063720, R01DK094641)
- National Institute of Neurological Disorders and Stroke (U54NS100717)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- brown adipose tissue, adaptive thermogenesis, sympathetic nervous system, cAMP signaling, SIK2, protein kinase A, UCP1, lipolysis, mitochondrial biogenesis, beta-adrenergic receptors, thermoneutrality, brown adipocytes
- MeSH terms
- Uncoupling Protein 1, Cyclic AMP, Animals, Adipose Tissue, Brown, Humans, Phosphorylation, Receptors, Adrenergic, beta, Sympathetic Nervous System, Protein Serine-Threonine Kinases, Cyclic AMP-Dependent Protein Kinases, Thermogenesis, Mice
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