TY - JOUR
T1 - A critical role of fatty acid binding protein 4 and 5 (FABP4/5) in the systemic response to fasting
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
N1 - Funding Information:
The authors study was supported by Astra Zeneca Research Grant. The authors acquired this fund by competition of research proposal. The fund does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
PY - 2013/11/14
Y1 - 2013/11/14
N2 - 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.
AB - 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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U2 - 10.1371/journal.pone.0079386
DO - 10.1371/journal.pone.0079386
M3 - Article
C2 - 24244493
AN - SCOPUS:84896710962
SN - 1932-6203
VL - 8
JO - PLoS One
JF - PLoS One
IS - 11
M1 - e79386
ER -