A critical role of fatty acid binding protein 4 and 5 (FABP4/5) in the systemic response to fasting

Mas Rizky A A Syamsunarno, Tatsuya Iso, Hirofumi Hanaoka, Aiko Yamaguchi, Masaru Obokata, Norimichi Koitabashi, Kosaku Goto, Takako Hishiki, Yoshiko Nagahata, Hiroki Matsui, Motoaki Sano, Masaki Kobayashi, Osamu Kikuchi, Tsutomu Sasaki, Kazuhisa Maeda, Masami Murakami, Tadahiro Kitamura, Makoto Suematsu, Yoshito Tsushima, Keigo Endo & 2 others Gökhan S. Hotamisligil, Masahiko Kurabayashi

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

During prolonged fasting, fatty acid (FA) released from adipose tissue is a major energy source for peripheral tissues, including the heart, skeletal muscle and liver. We recently showed that FA binding protein 4 (FABP4) and FABP5, which are abundantly expressed in adipocytes and macrophages, are prominently expressed in capillary endothelial cells in the heart and skeletal muscle. In addition, mice deficient for both FABP4 and FABP5 (FABP4/5 DKO mice) exhibited defective uptake of FA with compensatory up-regulation of glucose consumption in these tissues during fasting. Here we showed that deletion of FABP4/5 resulted in a marked perturbation of metabolism in response to prolonged fasting, including hyperketotic hypoglycemia and hepatic steatosis. Blood glucose levels were reduced, whereas the levels of non-esterified FA (NEFA) and ketone bodies were markedly increased during fasting. In addition, the uptake of the 125I-BMIPP FA analogue in the DKO livers was markedly increased after fasting. Consistent with an increased influx of NEFA into the liver, DKO mice showed marked hepatic steatosis after a 48-hr fast. Although gluconeogenesis was observed shortly after fasting, the substrates for gluconeogenesis were reduced during prolonged fasting, resulting in insufficient gluconeogenesis and enhanced hypoglycemia. These metabolic responses to prolonged fasting in DKO mice were readily reversed by re-feeding. Taken together, these data strongly suggested that a maladaptive response to fasting in DKO mice occurred as a result of an increased influx of NEFA into the liver and pronounced hypoglycemia. Together with our previous study, the metabolic consequence found in the present study is likely to be attributed to an impairment of FA uptake in the heart and skeletal muscle. Thus, our data provided evidence that peripheral uptake of FA via capillary endothelial FABP4/5 is crucial for systemic metabolism and may establish FABP4/5 as potentially novel targets for the modulation of energy homeostasis.

Original languageEnglish
Article numbere79386
JournalPLoS One
Volume8
Issue number11
DOIs
Publication statusPublished - 2013 Nov 14

Fingerprint

fatty acid-binding proteins
Fatty Acid-Binding Proteins
fasting
Fasting
Fatty Acids
Liver
Muscle
Gluconeogenesis
gluconeogenesis
hypoglycemia
fatty acids
Tissue
Hypoglycemia
Metabolism
mice
uptake mechanisms
skeletal muscle
Myocardium
liver
Skeletal Muscle

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Syamsunarno, M. R. A. A., Iso, T., Hanaoka, H., Yamaguchi, A., Obokata, M., Koitabashi, N., ... Kurabayashi, M. (2013). A critical role of fatty acid binding protein 4 and 5 (FABP4/5) in the systemic response to fasting. PLoS One, 8(11), [e79386]. https://doi.org/10.1371/journal.pone.0079386

A critical role of fatty acid binding protein 4 and 5 (FABP4/5) in the systemic response to fasting. / Syamsunarno, Mas Rizky A A; Iso, Tatsuya; Hanaoka, Hirofumi; Yamaguchi, Aiko; Obokata, Masaru; Koitabashi, Norimichi; Goto, Kosaku; Hishiki, Takako; Nagahata, Yoshiko; Matsui, Hiroki; Sano, Motoaki; Kobayashi, Masaki; Kikuchi, Osamu; Sasaki, Tsutomu; Maeda, Kazuhisa; Murakami, Masami; Kitamura, Tadahiro; Suematsu, Makoto; Tsushima, Yoshito; Endo, Keigo; Hotamisligil, Gökhan S.; Kurabayashi, Masahiko.

In: PLoS One, Vol. 8, No. 11, e79386, 14.11.2013.

Research output: Contribution to journalArticle

Syamsunarno, MRAA, Iso, T, Hanaoka, H, Yamaguchi, A, Obokata, M, Koitabashi, N, Goto, K, Hishiki, T, Nagahata, Y, Matsui, H, Sano, M, Kobayashi, M, Kikuchi, O, Sasaki, T, Maeda, K, Murakami, M, Kitamura, T, Suematsu, M, Tsushima, Y, Endo, K, Hotamisligil, GS & Kurabayashi, M 2013, 'A critical role of fatty acid binding protein 4 and 5 (FABP4/5) in the systemic response to fasting', PLoS One, vol. 8, no. 11, e79386. https://doi.org/10.1371/journal.pone.0079386
Syamsunarno MRAA, Iso T, Hanaoka H, Yamaguchi A, Obokata M, Koitabashi N et al. A critical role of fatty acid binding protein 4 and 5 (FABP4/5) in the systemic response to fasting. PLoS One. 2013 Nov 14;8(11). e79386. https://doi.org/10.1371/journal.pone.0079386
Syamsunarno, Mas Rizky A A ; Iso, Tatsuya ; Hanaoka, Hirofumi ; Yamaguchi, Aiko ; Obokata, Masaru ; Koitabashi, Norimichi ; Goto, Kosaku ; Hishiki, Takako ; Nagahata, Yoshiko ; Matsui, Hiroki ; Sano, Motoaki ; Kobayashi, Masaki ; Kikuchi, Osamu ; Sasaki, Tsutomu ; Maeda, Kazuhisa ; Murakami, Masami ; Kitamura, Tadahiro ; Suematsu, Makoto ; Tsushima, Yoshito ; Endo, Keigo ; Hotamisligil, Gökhan S. ; Kurabayashi, Masahiko. / A critical role of fatty acid binding protein 4 and 5 (FABP4/5) in the systemic response to fasting. In: PLoS One. 2013 ; Vol. 8, No. 11.
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abstract = "During prolonged fasting, fatty acid (FA) released from adipose tissue is a major energy source for peripheral tissues, including the heart, skeletal muscle and liver. We recently showed that FA binding protein 4 (FABP4) and FABP5, which are abundantly expressed in adipocytes and macrophages, are prominently expressed in capillary endothelial cells in the heart and skeletal muscle. In addition, mice deficient for both FABP4 and FABP5 (FABP4/5 DKO mice) exhibited defective uptake of FA with compensatory up-regulation of glucose consumption in these tissues during fasting. Here we showed that deletion of FABP4/5 resulted in a marked perturbation of metabolism in response to prolonged fasting, including hyperketotic hypoglycemia and hepatic steatosis. Blood glucose levels were reduced, whereas the levels of non-esterified FA (NEFA) and ketone bodies were markedly increased during fasting. In addition, the uptake of the 125I-BMIPP FA analogue in the DKO livers was markedly increased after fasting. Consistent with an increased influx of NEFA into the liver, DKO mice showed marked hepatic steatosis after a 48-hr fast. Although gluconeogenesis was observed shortly after fasting, the substrates for gluconeogenesis were reduced during prolonged fasting, resulting in insufficient gluconeogenesis and enhanced hypoglycemia. These metabolic responses to prolonged fasting in DKO mice were readily reversed by re-feeding. Taken together, these data strongly suggested that a maladaptive response to fasting in DKO mice occurred as a result of an increased influx of NEFA into the liver and pronounced hypoglycemia. Together with our previous study, the metabolic consequence found in the present study is likely to be attributed to an impairment of FA uptake in the heart and skeletal muscle. Thus, our data provided evidence that peripheral uptake of FA via capillary endothelial FABP4/5 is crucial for systemic metabolism and may establish FABP4/5 as potentially novel targets for the modulation of energy homeostasis.",
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AU - Syamsunarno, Mas Rizky A A

AU - Iso, Tatsuya

AU - Hanaoka, Hirofumi

AU - Yamaguchi, Aiko

AU - Obokata, Masaru

AU - Koitabashi, Norimichi

AU - Goto, Kosaku

AU - Hishiki, Takako

AU - Nagahata, Yoshiko

AU - Matsui, Hiroki

AU - Sano, Motoaki

AU - Kobayashi, Masaki

AU - Kikuchi, Osamu

AU - Sasaki, Tsutomu

AU - Maeda, Kazuhisa

AU - Murakami, Masami

AU - Kitamura, Tadahiro

AU - Suematsu, Makoto

AU - Tsushima, Yoshito

AU - Endo, Keigo

AU - Hotamisligil, Gökhan S.

AU - Kurabayashi, Masahiko

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