Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 101 (4): 1045-1050

Copyright © 2004 by the National Academy of Sciences.


MEDICAL SCIENCES

Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41

Yumei Xiong *, Norimasa Miyamoto *, Kenji Shibata *, Mark A. Valasek *, Toshiyuki Motoike * {dagger}, Rafal M. Kedzierski *, and Masashi Yanagisawa * {dagger} {ddagger}

*Howard Hughes Medical Institute and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050; and {dagger}Exploratory Research for Advanced Technology, Yanagisawa Orphan Receptor Project, Japan Science and Technology Agency, Tokyo 135-0064, Japan

Communicated by Joseph L. Goldstein, University of Texas Southwestern Medical Center, Dallas, TX, October 29, 2003

Received for publication March 5, 2003.

Abstract: Leptin is an adipose-derived hormone that regulates a wide variety of physiological processes, including feeding behavior, metabolic rate, sympathetic nerve activity, reproduction, and immune response. Circulating leptin levels are tightly regulated according to energy homeostasis in vivo. Although mechanisms for the regulation of leptin production in adipocytes are not well understood, G protein-coupled receptors may play an important role in this adipocyte function. Here we report that C2–C6 short-chain fatty acids, ligands of an orphan G protein-coupled receptor GPR41, stimulate leptin expression in both a mouse adipocyte cell line and mouse adipose tissue in primary culture. Acute oral administration of propionate increases circulating leptin levels in mice. The concentrations of short-chain fatty acids required to stimulate leptin production are within physiological ranges, suggesting the relevance of this pathway in vivo.


Abbreviations: GPCR, G protein-coupled receptor; SCFA, short-chain fatty acid; siRNA, short interfering RNA.

{ddagger} To whom correspondence should be addressed at: Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Room Y5.210, Dallas, TX 75390-9050. E-mail: masashi.yanagisawa{at}utsouthwestern.edu.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
{beta}-Hydroxybutyrate Modulates N-Type Calcium Channels in Rat Sympathetic Neurons by Acting as an Agonist for the G-Protein-Coupled Receptor FFA3.
Y.-J. Won, V. B. Lu, H. L. Puhl III, and S. R. Ikeda (2013)
J. Neurosci. 33, 19314-19325
   Abstract »    Full Text »    PDF »
Colonic Hydrogen Generated from Fructan Diffuses into the Abdominal Cavity and Reduces Adipose mRNA Abundance of Cytokines in Rats.
N. Nishimura, H. Tanabe, M. Adachi, T. Yamamoto, and M. Fukushima (2013)
J. Nutr. 143, 1943-1949
   Abstract »    Full Text »    PDF »
The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism.
G. den Besten, K. van Eunen, A. K. Groen, K. Venema, D.-J. Reijngoud, and B. M. Bakker (2013)
J. Lipid Res. 54, 2325-2340
   Abstract »    Full Text »    PDF »
The gut microbiome: the role of a virtual organ in the endocrinology of the host.
J. M. Evans, L. S. Morris, and J. R. Marchesi (2013)
J. Endocrinol. 218, R37-R47
   Abstract »    Full Text »    PDF »
Medium-chain Fatty Acid-sensing Receptor, GPR84, Is a Proinflammatory Receptor.
M. Suzuki, S. Takaishi, M. Nagasaki, Y. Onozawa, I. Iino, H. Maeda, T. Komai, and T. Oda (2013)
J. Biol. Chem. 288, 10684-10691
   Abstract »    Full Text »    PDF »
Gustducin couples fatty acid receptors to GLP-1 release in colon.
Y. Li, Z. Kokrashvili, B. Mosinger, and R. F. Margolskee (2013)
Am J Physiol Endocrinol Metab 304, E651-E660
   Abstract »    Full Text »    PDF »
Endogenous metabolites as ligands for G protein-coupled receptors modulating risk factors for metabolic and cardiovascular disease.
S. Tonack, C. Tang, and S. Offermanns (2013)
Am J Physiol Heart Circ Physiol 304, H501-H513
   Abstract »    Full Text »    PDF »
Starch and fiber properties affect their kinetics of digestion and thereby digestive physiology in pigs.
R. T. Zijlstra, R. Jha, A. D. Woodward, J. Fouhse, and T. A. T. G. van Kempen (2012)
J Anim Sci 90, 49-58
   Abstract »    Full Text »    PDF »
GPR41 Gene Expression Is Mediated by Internal Ribosome Entry Site (IRES)-dependent Translation of Bicistronic mRNA Encoding GPR40 and GPR41 Proteins.
K. Bahar Halpern, A. Veprik, N. Rubins, O. Naaman, and M. D. Walker (2012)
J. Biol. Chem. 287, 20154-20163
   Abstract »    Full Text »    PDF »
Effects of Gut Microbes on Nutrient Absorption and Energy Regulation.
R. Krajmalnik-Brown, Z.-E. Ilhan, D.-W. Kang, and J. K. DiBaise (2012)
Nutr Clin Pract 27, 201-214
   Abstract »    Full Text »    PDF »
Mechanisms of Gene Regulation by Fatty Acids.
A. Georgiadi and S. Kersten (2012)
Adv Nutr 3, 127-134
   Abstract »    Full Text »    PDF »
Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein-Coupled Receptor FFAR2.
G. Tolhurst, H. Heffron, Y. S. Lam, H. E. Parker, A. M. Habib, E. Diakogiannaki, J. Cameron, J. Grosse, F. Reimann, and F. M. Gribble (2012)
Diabetes 61, 364-371
   Abstract »    Full Text »    PDF »
Butyrate Activates the cAMP-Protein Kinase A-cAMP Response Element-Binding Protein Signaling Pathway in Caco-2 Cells.
A. Wang, H. Si, D. Liu, and H. Jiang (2012)
J. Nutr. 142, 1-6
   Abstract »    Full Text »    PDF »
TRPM5 is critical for linoleic acid-induced CCK secretion from the enteroendocrine cell line, STC-1.
B. P. Shah, P. Liu, T. Yu, D. R. Hansen, and T. A. Gilbertson (2012)
Am J Physiol Cell Physiol 302, C210-C219
   Abstract »    Full Text »    PDF »
Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).
I. Kimura, D. Inoue, T. Maeda, T. Hara, A. Ichimura, S. Miyauchi, M. Kobayashi, A. Hirasawa, and G. Tsujimoto (2011)
PNAS 108, 8030-8035
   Abstract »    Full Text »    PDF »
G Protein-Coupled Receptors in Child Development, Growth, and Maturation.
A. C. Latronico and Z. Hochberg (2010)
Science Signaling 3, re7
   Abstract »    Full Text »    PDF »
Review: Free fatty acid receptors: emerging targets for treatment of diabetes and its complications.
R. Lee Kennedy, V. Vangaveti, G. Jarrod, V. Shashidhar, V. Shashidhar, and B. T. Baune (2010)
Therapeutic Advances in Endocrinology and Metabolism 1, 165-175
   Abstract »    PDF »
Redundant Control of Adipogenesis by Histone Deacetylases 1 and 2.
M. Haberland, M. Carrer, M. H. Mokalled, R. L. Montgomery, and E. N. Olson (2010)
J. Biol. Chem. 285, 14663-14670
   Abstract »    Full Text »    PDF »
Factors related to colonic fermentation of nondigestible carbohydrates of a previous evening meal increase tissue glucose uptake and moderate glucose-associated inflammation.
M. G Priebe, H. Wang, D. Weening, M. Schepers, T. Preston, and R. J Vonk (2010)
Am J Clin Nutr 91, 90-97
   Abstract »    Full Text »    PDF »
BOARD-INVITED REVIEW: The hepatic oxidation theory of the control of feed intake and its application to ruminants.
M. S. Allen, B. J. Bradford, and M. Oba (2009)
J Anim Sci 87, 3317-3334
   Abstract »    Full Text »    PDF »
Toward a Systems Level Understanding of Organic Anion and Other Multispecific Drug Transporters: A Remote Sensing and Signaling Hypothesis.
S.-Y. Ahn and S. K. Nigam (2009)
Mol. Pharmacol. 76, 481-490
   Abstract »    Full Text »    PDF »
Molecular Pharmacology of Promiscuous Seven Transmembrane Receptors Sensing Organic Nutrients.
P. Wellendorph, L. D. Johansen, and H. Brauner-Osborne (2009)
Mol. Pharmacol. 76, 453-465
   Abstract »    Full Text »    PDF »
Oral Thresholds and Suprathreshold Intensity Ratings for Free Fatty Acids on 3 Tongue Sites in Humans: Implications for Transduction Mechanisms.
R. D. Mattes (2009)
Chem Senses 34, 415-423
   Abstract »    Full Text »    PDF »
Oral Detection of Short-, Medium-, and Long-Chain Free Fatty Acids in Humans.
R. D. Mattes (2009)
Chem Senses 34, 145-150
   Abstract »    Full Text »    PDF »
International Union of Pharmacology. LXXI. Free Fatty Acid Receptors FFA1, -2, and -3: Pharmacology and Pathophysiological Functions.
L. A. Stoddart, N. J. Smith, and G. Milligan (2008)
Pharmacol. Rev. 60, 405-417
   Abstract »    Full Text »    PDF »
Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41.
B. S. Samuel, A. Shaito, T. Motoike, F. E. Rey, F. Backhed, J. K. Manchester, R. E. Hammer, S. C. Williams, J. Crowley, M. Yanagisawa, et al. (2008)
PNAS 105, 16767-16772
   Abstract »    Full Text »    PDF »
Transport of butyryl-L-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB0,+.
S. R. Srinivas, P. D. Prasad, N. S. Umapathy, V. Ganapathy, and P. S. Shekhawat (2007)
Am J Physiol Gastrointest Liver Physiol 293, G1046-G1053
   Abstract »    Full Text »    PDF »
Short-Chain Fatty Acids: Ready for Prime Time?.
C. C. Roy, C. L. Kien, L. Bouthillier, and E. Levy (2006)
Nutr Clin Pract 21, 351-366
   Abstract »    Full Text »    PDF »
Mouse GPR40 heterologously expressed in Xenopus oocytes is activated by short-, medium-, and long-chain fatty acids.
G. Stewart, T. Hira, A. Higgins, C. P. Smith, and J. T. McLaughlin (2006)
Am J Physiol Cell Physiol 290, C785-C792
   Abstract »    Full Text »    PDF »
(D)-{beta}-Hydroxybutyrate Inhibits Adipocyte Lipolysis via the Nicotinic Acid Receptor PUMA-G.
A. K. P. Taggart, J. Kero, X. Gan, T.-Q. Cai, K. Cheng, M. Ippolito, N. Ren, R. Kaplan, K. Wu, T.-J. Wu, et al. (2005)
J. Biol. Chem. 280, 26649-26652
   Abstract »    Full Text »    PDF »
Free Fatty Acids Inhibit Serum Deprivation-induced Apoptosis through GPR120 in a Murine Enteroendocrine Cell Line STC-1.
S. Katsuma, N. Hatae, T. Yano, Y. Ruike, M. Kimura, A. Hirasawa, and G. Tsujimoto (2005)
J. Biol. Chem. 280, 19507-19515
   Abstract »    Full Text »    PDF »
Expression of slc5a8 in Kidney and Its Role in Na+-coupled Transport of Lactate.
E. Gopal, Y.-J. Fei, M. Sugawara, S. Miyauchi, L. Zhuang, P. Martin, S. B. Smith, P. D. Prasad, and V. Ganapathy (2004)
J. Biol. Chem. 279, 44522-44532
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882