title: Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).
abstract: 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.
authors.affiliation: Department of Genomic Drug Discovery Science, Kyoto University Graduate School of Pharmaceutical Sciences, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kimura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Inoue
authors.forename: Takeshi
authors.initials: T
authors.lastname: Maeda
authors.forename: Takafumi
authors.initials: T
authors.lastname: Hara
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Ichimura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyauchi
authors.forename: Makio
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Akira
authors.initials: A
authors.lastname: Hirasawa
authors.forename: Gozoh
authors.initials: G
authors.lastname: Tsujimoto
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000008:administration & dosage; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D004734:Energy Metabolism / Q000187:drug effects; D005232:Fatty Acids, Volatile / Q000008:administration & dosage / Q000502:physiology*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007657:Ketone Bodies / Q000008:administration & dosage / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011422:Propionates / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*
chemical_list: D005232:Fatty Acids, Volatile; C506482:Gpcr41 protein, mouse; D007657:Ketone Bodies; D011422:Propionates; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D020155:3-Hydroxybutyric Acid