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Arcuate NPY Controls Sympathetic Output and BAT Function via a Relay of Tyrosine Hydroxylase Neurons in the PVN
Open accessAbstract
Neuropepetide Y (NPY) is best known for its powerful stimulation of food intake and its effects on reducing energy expenditure. However, the pathways involved and the regulatory mechanisms behind this are not well understood. Here we demonstrate that NPY derived from the arcuate nucleus (Arc) is critical for the control of sympathetic outflow and brown adipose tissue (BAT) function. Mechanistically, a key change induced by Arc NPY signaling is a marked Y1 receptor-mediated reduction in tyrosine hydroxylase (TH) expression in the hypothalamic paraventricular nucleus (PVN), which is also associated with a reduction in TH expression in the locus coeruleus (LC) and other regions in the brainstem. Consistent with this, Arc NPY signaling decreased sympathetically innervated BAT thermogenesis, involving the downregulation of uncoupling protein 1 (UCP1) expression in BAT. Taken together, these data reveal a powerful Arc-NPY-regulated neuronal circuit that controls BAT thermogenesis and sympathetic output via TH neurons.
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“Obesity is also accompanied by an increased NPY expression in the ARC.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [129]
In the citing paper
“This increase triggers a reduction in the expression of tyrosine hydroxylase neurons in the paraventricular nucleus (PVN) of the hypothalamus and consequently, diminishes the thermogenic activation of BAT and overall energy expenditure 129.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [129]
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Self-citationO-GlcNAc Transferase Enables AgRP Neurons to Suppress Browning of White Fat
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Self-citationThe regulation of food intake by insulin in the central nervous system
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“Increased NPY expression in the ARC under fasting, stress, or chronic-overfeeding conditions, acting via PVN Y1 receptors, results in the inhibition of TH tonus and sympathetically innervated BAT thermogenesis by downregulating uncoupling protein 1(UCP1) expression in BAT (Shi et al., 2013).”
BackgroundInfluentialSelf-citationA novel thermoregulatory role for PDE10A in mouse and human adipocytes
Hankir, M. K., Kranz, M., Gnad, T., Weiner, J., Wagner, S., Deuther‐Conrad, W., Bronisch, F., Steinhoff, K. G., Luthardt, J., Klöting, N., et al. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201506085 · Cited by 60
“Importantly, we demonstrated that acute administration of MP-10 has no effect on the expression of hypothalamic neuropeptides, which are known to recruit BAT via the sympathetic nervous system (Brito et al, 2007; Shi et al, 2013), in accordance with a lack of PDE10A expression in this brain region.”
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“hypothalamus and brainstem Expressions of TH mRNA at the hypothalamic paraventricular nucleus and the locus coerulus at the brainstem have been suggested to be responsible for the sympathetic innervation and thermogenic activity of the IBAT (Shi et al. , 2013).”
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“Discussion It is well established that activation of ArcN NPY/AgRP neurons can trigger positive energy balance, largely by stimulating food intake, but also by reducing energy expenditure (6, 14, 15, 35, 36).”
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“NPY derived from ARC AgRP/NPY neurons inhibits BAT SNA via activation of Y1 receptor in unknown target neurons (Shi et al. 2013).”
Lau, J., Farzi, A., Qi, Y., Heilbronn, R., Mietzsch, M., Shi, Y., & Herzog, H. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.10.015 · Cited by 53
Self-citationArima, Y., Ohki, T., Nishikawa, N., Higuchi, K., Ota, M., Tanaka, Y., Nio‐Kobayashi, J., Elfeky, M., Sakai, R., Mori, Y., et al. (2017) · eLife · doi:10.7554/elife.25517 · Cited by 54
“It is reported that PVN neurons include TH+ neurons are activated by several stresses, especially chronic ones ( Herman and Cullinan, 1997 ; Ramot et al., 2017 ; Shi et al., 2013 ; Ulrich-Lai and Herman, 2009 ).”
BackgroundThe role of dietary salt in metabolism and energy balance: Insights beyond cardiovascular disease
Wu, Q., Burley, G., Li, L., Lin, S., & Shi, Y. (2023) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14980 · Cited by 59
Self-citationHypothalamic endoplasmic reticulum stress as a key mediator of obesity‐induced leptin resistance
Ye, Z., Liu, G., Guo, J., & Su, Z. (2018) · Obesity Reviews · doi:10.1111/obr.12673 · Cited by 54
“Orexigenic neuropeptide AgRP and NPY, which are derived from the ARC, reduced sympathetically innervated BAT thermogenesis, and the downregulation of these neuropeptides led to a lean phenotype by decreasing food intake and activating BAT function (186,187).”
BackgroundIntermittent Moderate Energy Restriction Improves Weight Loss Efficiency in Diet-Induced Obese Mice
Seimon, R. V., Shi, Y., Slack, K., Lee, K., Fernando, H. A., Nguyen, A., Zhang, L., Lin, S., Enriquez, R. F., Lau, J., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0145157 · Cited by 51
“previously observed effects of dietary obesity in rodents [38,39], and whereas hypothalamic NPY expression was reduced relative to values in CAF mice in both groups of energy-restricted mice, there was no significant difference in this parameter for mice on the continuous or intermittent diet.”
Self-citationDnmt3a in Sim1 Neurons Is Necessary for Normal Energy Homeostasis
Kohno, D., Lee, S., Harper, M. J., Kim, K. W., Sone, H., Sasaki, T., Kitamura, T., Fan, G., & Elmquist, J. K. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.1316-14.2014 · Cited by 52
“It has been shown that TH levels regulate BAT thermogenesis and sympathetic outflow (Shi et al., 2013).”
BackgroundSilva‐Cutini, M. A., de Almeida, S. A., do Nascimento, A. M., Abreu, G. R., Bissoli, N. S., Lenz, D., Endringer, D. C., Brasil, G. A., de Lima, E. M., Biancardi, V. C., et al. (2019) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2019.01.006 · Cited by 50
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“TH + neurons are highly prevalent in the PVN and are key regulators of sympathetic activity 54 .”
BackgroundSkeleton interoception regulates bone and fat metabolism through hypothalamic neuroendocrine NPY
Lv, X., Gao, F., Li, T. P., Xue, P., Wang, X., Wan, M., Hu, B., Chen, H., Jain, A., Shao, Z., et al. (2021) · eLife · doi:10.7554/elife.70324 · Cited by 45
Stress- and diet-induced fat gain is controlled by NPY in catecholaminergic neurons
Zhang, L., Lee, I.-C. J., Enriquez, R. F., Lau, J., Vähätalo, L. H., Baldock, P. A. J., Savontaus, E., & Herzog, H. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2014.05.001 · Cited by 49
“In situ hybridization In situ hybridization was performed on brain sections from wild type and catNPY mice to examine NPY expression following procedures described previously [4].”
BackgroundMethodResultInfluentialSelf-citationNeuronal Control of Adaptive Thermogenesis
Yang, X., & Ruan, H. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00149 · Cited by 47
“Orexigenic neuropeptides AgRP and NPY inhibit BAT function, while anorexigenic α-MSH increases SNS activity and BAT function (60, 61).”
BackgroundIwagaki, N., Ganley, R. P., Dickie, A. C., Polgár, E., Hughes, D. I., del Río, P., Revina, Y., Watanabe, M., Todd, A. J., & Riddell, J. S. (2015) · Pain · doi:10.1097/j.pain.0000000000000407 · Cited by 43
The role of neuropeptide Y in the pathophysiology of atherosclerotic cardiovascular disease
Zhu, P., Sun, W., Zhang, C.-L., Song, Z.-Y., & Lin, S. (2016) · International Journal of Cardiology · doi:10.1016/j.ijcard.2016.06.138 · Cited by 44
Self-citationMelanocortin neurons: Multiple routes to regulation of metabolism
Shen, W.-J., Yao, T. S., Kong, X., Williams, K. W., & Liu, T. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.05.007 · Cited by 45
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Hypothalamic control of hepatic lipid metabolism via the autonomic nervous system
Bruinstroop, E., Fliers, E., & Kalsbeek, A. (2014) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2014.05.001 · Cited by 41
Thiamine deficiency induces anorexia by inhibiting hypothalamic AMPK
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Ablation of glucokinase-expressing tanycytes impacts energy balance and increases adiposity in mice
Rohrbach, A., Caron, É., Dali, R., Brunner, M., Pasquettaz, R., Kolotuev, I., Santoni, F. A., Thorens, B., & Langlet, F. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101311 · Cited by 38
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“For example, TH and NPY/AgRP neurons exhibit a bidirectional synaptic mechanism during which TH neurons stimulate food intake via direct excitatory dopamine action on NPY/ AgRP neurons, and NPY/AgRP neurons regulate thermogenesis via Y1 receptors on TH neurons [21,36,52].”
BackgroundInfluentialSympathetic NPY controls glucose homeostasis, cold tolerance, and cardiovascular functions in mice
Kumari, R., Paşcalău, R., Wang, H., Bajpayi, S., Yurgel, M. E., Quansah, K. K., Hattar, S. S., Tampakakis, E., & Kuruvilla, R. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.113674 · Cited by 37
“Previous studies have documented that central NPY signaling suppresses sympathetic tone, 46–48 while NPY, derived from peripheral sources, exerts post-and presynaptic effects in potentiating NE-induced responses and inhibiting NE release, respectively.”
BackgroundIp, C. K., Rezitis, J., Qi, Y., Bajaj, N., Koller, J., Farzi, A., Shi, Y., Tasan, R. O., Zhang, L., & Herzog, H. (2023) · Neuron · doi:10.1016/j.neuron.2023.05.010 · Cited by 36
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Self-citationBrowning of white adipose tissue: role of hypothalamic signaling
Bi, S., & Li, L. (2013) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12258 · Cited by 35
Regulation of thermogenic adipocytes during fasting and cold
Reinisch, I., Schreiber, R., & Prokesch, A. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.110869 · Cited by 36
Neuropeptide Y in the noradrenergic neurones induces obesity and inhibits sympathetic tone in mice
Vähätalo, L. H., Ruohonen, S. T., Mäkelä, S., Kovalainen, M., Huotari, A., Mäkelä, K. A., Määttä, J. A., Miinalainen, I., Gilsbach, R., Hein, L., et al. (2014) · Acta Physiologica · doi:10.1111/apha.12436 · Cited by 35
mTORC1 in energy expenditure: consequences for obesity
Allard, C., Miralpeix, C., López-Gambero, A. J., & Cota, D. (2024) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00934-0 · Cited by 39
“These two neuronal populations respectively decrease and increase energy expenditure through effects on SNS activity 41,51 .”
Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice
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“It was also demonstrated that the ability of neuropeptide Y-expressing neurons in the ARC to regulate BAT thermogenesis coincideswith an altered sympathetic output via TH neurons in the PVN and LC (Shi et al., 2013).”
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“173,174 This suppression of UCP1 expression attenuates lipolysis and thermogenesis in brown fat.”
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“The arcuate AgRP/NPY neurons are reported to control sympathetic output and UCP-1 expression in BAT (30), and central administration of AgRP reportedly decreased UCP-1 expression without affecting food intake (31).”
Background
Metadata
- Authors
- Shi, Y.-C., Lau, J., Lin, Z., Zhang, H., Zhai, L., Sperk, G., Heilbronn, R., Mietzsch, M., Weger, S., Huang, X.-F., Enriquez, R. F., Castillo, L., Baldock, P. A., Zhang, L., Sainsbury, A., Herzog, H., & Lin, S.
- Affiliations
- Garvan Institute of Medical Research (AU)
- Charité – Universitätsmedizin Berlin (DE)
- University of Wollongong (AU)
- The University of Sydney (AU)
- Corresponding author
- Herzog, Herbert
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 17
- Issue
- 2
- Pages
- 236-248
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2002941555
- Cited by
- 266
- References
- 49
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 19 · 2023: 19 · 2022: 13 · 2021: 22 · 2020: 20 · 2019: 16 · 2018: 23 · 2017: 25 · 2016: 21 · 2015: 28 · 2014: 27 · 2013: 8
- FWCI
- 19.45
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-07-02)
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 369 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research Online (University of Wollongong) (submittedVersion)
- The Sydney eScholarship Repository (The University of Sydney) (submittedVersion)
- Funders
- National Health and Medical Research Council (427661)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- neuropeptide Y, arcuate nucleus, paraventricular nucleus, tyrosine hydroxylase, sympathetic nervous system, brown adipose tissue, thermogenesis, UCP1, Y1 receptor, hypothalamus, locus coeruleus, energy expenditure
- MeSH terms
- Uncoupling Protein 1, Animals, Arcuate Nucleus of Hypothalamus, Adipose Tissue, Brown, Energy Metabolism, Feeding Behavior, Gene Expression Regulation, Glutamate Decarboxylase, Ion Channels, Male, Mice, Inbred C57BL, Neurons, Neuropeptide Y, Oxygen Consumption, Paraventricular Hypothalamic Nucleus, Pro-Opiomelanocortin, RNA, Messenger, Sympathetic Nervous System, Temperature, Tyrosine 3-Monooxygenase, Signal Transduction, Receptors, Neuropeptide Y, Thermogenesis, Models, Animal, Mitochondrial Proteins, Mice, Agouti-Related Protein, Diet, High-Fat
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