A fatty acid-dependent hypothalamic–DVC neurocircuitry that regulates hepatic secretion of triglyceride-rich lipoproteins
Open accessAbstract
The brain emerges as a regulator of hepatic triglyceride-rich very-low-density lipoproteins (VLDL-TG). The neurocircuitry involved as well as the ability of fatty acids to trigger a neuronal network to regulate VLDL-TG remain unknown. Here we demonstrate that infusion of oleic acid into the mediobasal hypothalamus (MBH) activates a MBH PKC-δ→KATP-channel signalling axis to suppress VLDL-TG secretion in rats. Both NMDA receptor-mediated transmissions in the dorsal vagal complex (DVC) and hepatic innervation are required for lowering VLDL-TG, illustrating a MBH-DVC-hepatic vagal neurocircuitry that mediates MBH fatty acid sensing. High-fat diet (HFD)-feeding elevates plasma TG and VLDL-TG secretion and abolishes MBH oleic acid sensing to lower VLDL-TG. Importantly, HFD-induced dysregulation is restored with direct activation of either MBH PKC-δ or KATP-channels via the hepatic vagus. Thus, targeting a fatty acid sensing-dependent hypothalamic–DVC neurocircuitry may have therapeutic potential to lower hepatic VLDL-TG and restore lipid homeostasis in obesity and diabetes. The brain has a central role in the regulation of organismal energy homeostasis. Here the authors show that neurons in the mediobasal hypothalamus respond to fatty acids by generating neuronal signals, relayed to the liver viavagal nerves that mediate secretion of very-low-density lipoproteins.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Free fatty acid sensing by the hypothalamus is a well-established modulator of neuronal activity, affecting peripheral metabolism.
“Free fatty acid sensing by the hypothalamus is a well-established modulator of neuronal activity57, affecting peripheral metabolism58–60”
From IDOL regulates systemic energy balance through control of neuronal VLDLR expression (2019) · cites this paper as [60]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Central Administration of Oleic Acid Inhibits Glucose Production and Food Intake
Obici, S., Feng, Z., Morgan, K., Stein, D., Karkanias, G., & Rossetti, L. (2002) · Diabetes · doi:10.2337/diabetes.51.2.271 · Cited by 654 · see citing works
Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity
Unger, R. H., & Scherer, P. E. (2010) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2010.01.009 · Cited by 436 · see citing works
The central melanocortin system directly controls peripheral lipid metabolism
Nogueiras, R., Wiedmer, P., Perez-Tilve, D., Veyrat-Durebex, C., Keogh, J. M., Sutton, G. M., Pfluger, P. T., Castaneda, T. R., Neschen, S., Hofmann, S. M., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31743 · Cited by 396 · see citing works
New Perspectives on Atherogenesis: Role of Abnormal Triglyceride-Rich Lipoprotein Metabolism
Ginsberg, H. N. (2002) · Circulation · doi:10.1161/01.cir.0000035280.64322.31 · Cited by 255 · see citing works
Molecular disruption of hypothalamic nutrient sensing induces obesity
He, W., Lam, T. K. T., Obici, S., & Rossetti, L. (2006) · Nature Neuroscience · doi:10.1038/nn1626 · Cited by 233 · see citing works
Self-citationGoff, D. C., Gerstein, H. C., Ginsberg, H. N., Cushman, W. C., Margolis, K. L., Byington, R. P., Buse, J. B., Genuth, S., Probstfield, J. L., & Simons-Morton, D. G. (2007) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2007.03.002 · Cited by 229 · see citing works
Site and mechanism of leptin action in a rodent form of congenital lipodystrophy
Asilmaz, E., Cohen, P., Miyazaki, M., Dobrzyn, P., Ueki, K., Fayzikhodjaeva, G., Soukas, A. A., Kahn, C. R., Ntambi, J. M., Socci, N. D., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200419511 · Cited by 210 · see citing works
Hypothalamic AMP-Activated Protein Kinase Regulates Glucose Production
Yang, C. S., Lam, C. K. L., Chari, M., Cheung, G. W. C., Kokorovic, A., Gao, S., Leclerc, I., Rutter, G. A., & Lam, T. K. T. (2010) · Diabetes · doi:10.2337/db10-0221 · Cited by 86 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 3
- Kakuma, T. et al. Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets. Proc. Natl Acad. Sci. USA 97, 8536-8541 (2000).
- Iizuka, K., Bruick, R. K., Liang, G., Horton, J. D. & Uyeda, K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc. Natl Acad. Sci. USA 101, 7281-7286 (2004).
- Jumpertz, R. et al. Associations of fatty acids in cerebrospinal fluid with peripheral glucose concentrations and energy metabolism. PLoS ONE 7, e41503 (2012).
Cited by
Sorted by citations
Brain insulin signalling in metabolic homeostasis and disease
Scherer, T., Sakamoto, K., & Buettner, C. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00498-x · Cited by 205 · see citing works
IDOL regulates systemic energy balance through control of neuronal VLDLR expression
Lee, S. D., Priest, C., Bjursell, M., Gao, J., Arneson, D. V., Ahn, I. S., Diamante, G., van Veen, J. E., Massa, M. G., Calkin, A. C., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0127-7 · Cited by 26 · see citing works
- Authors
- Yue, J. T. Y., Abraham, M. A., LaPierre, M. P., Mighiu, P. I., Light, P. E., Filippi, B. M., & Lam, T. K. T.
- Affiliations
- University Health Network (CA)
- University of Alberta (CA)
- Corresponding author
- Lam, Tony K. T.
- Venue
- Nature Communications
- Published
- 2015-01-12
- Volume
- 6
- Issue
- 1
- Pages
- 5970-5970
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2024353014
- Cited by
- 46
- References
- 8
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 6 · 2023: 2 · 2021: 4 · 2020: 5 · 2019: 6 · 2018: 2 · 2017: 9 · 2016: 7 · 2015: 2
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Canadian Diabetes Association
- University of Toronto
- Canadian Institutes of Health Research (67170_1, MOP-86554)
- Banting and Best Diabetes Centre, University of Toronto
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- mediobasal hypothalamus, dorsal vagal complex, very low density lipoprotein secretion, triglyceride-rich lipoproteins, oleic acid, fatty acid sensing, PKCδ, ATP-sensitive potassium channels, NMDA receptor, high-fat diet, lipid homeostasis, obesity, diabetes mellitus, neurocircuitry
- MeSH terms
- Adenoviridae, Animals, Apolipoproteins B, Brain, Fatty Acids, Homeostasis, Hypothalamus, Lipoproteins, Lipoproteins, VLDL, Liver, Male, Neurons, Protein Kinase C, Triglycerides, Vagus Nerve, Potassium Channels, Rats, Sprague-Dawley, Oleic Acid, Green Fluorescent Proteins, Rats
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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
