Document Detail

Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).
MedLine Citation:
PMID:  21518883     Owner:  NLM     Status:  MEDLINE    
The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gβγ-PLCβ-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis.
Ikuo Kimura; Daisuke Inoue; Takeshi Maeda; Takafumi Hara; Atsuhiko Ichimura; Satoshi Miyauchi; Makio Kobayashi; Akira Hirasawa; Gozoh Tsujimoto
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-04-25
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  108     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-05-11     Completed Date:  2011-07-15     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8030-5     Citation Subset:  IM    
Department of Genomic Drug Discovery Science, Kyoto University Graduate School of Pharmaceutical Sciences, Sakyo-ku, Kyoto 606-8501, Japan.
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MeSH Terms
3-Hydroxybutyric Acid / administration & dosage
Action Potentials / drug effects
Base Sequence
Energy Metabolism / drug effects
Fatty Acids, Volatile / administration & dosage,  physiology*
Gene Knockdown Techniques
HEK293 Cells
Ketone Bodies / administration & dosage,  physiology*
Mice, Inbred C57BL
Mice, Knockout
Propionates / administration & dosage
RNA, Small Interfering / genetics
Receptors, G-Protein-Coupled / antagonists & inhibitors,  deficiency,  genetics,  physiology*
Signal Transduction
Sympathetic Nervous System / drug effects,  physiology*
Reg. No./Substance:
0/Fatty Acids, Volatile; 0/Gpr41 protein, mouse; 0/Ketone Bodies; 0/Propionates; 0/RNA, Small Interfering; 0/Receptors, G-Protein-Coupled; 300-85-6/3-Hydroxybutyric Acid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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