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 EndoGökhan S. Hotamisligil, Masahiko Kurabayashi

研究成果: Article査読

31 被引用数 (Scopus)

抄録

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.

本文言語English
論文番号e79386
ジャーナルPloS one
8
11
DOI
出版ステータスPublished - 2013 11 14

ASJC Scopus subject areas

  • 一般

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