A critical role of fatty acid binding protein 4 and 5 (FABP4/5) in the systemic response to fasting.
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 (125)I-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.
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Mas Rizky A A
MR
Syamsunarno
Tatsuya
T
Iso
Hirofumi
H
Hanaoka
Aiko
A
Yamaguchi
Masaru
M
Obokata
Norimichi
N
Koitabashi
Kosaku
K
Goto
Takako
T
Hishiki
Yoshiko
Y
Nagahata
Hiroki
H
Matsui
Motoaki
M
Sano
Masaki
M
Kobayashi
Osamu
O
Kikuchi
Tsutomu
T
Sasaki
Kazuhisa
K
Maeda
Masami
M
Murakami
Tadahiro
T
Kitamura
Makoto
M
Suematsu
Yoshito
Y
Tsushima
Keigo
K
Endo
Gökhan S
GS
Hotamisligil
Masahiko
M
Kurabayashi
D000818:Animals; D001786:Blood Glucose; D015243:Cholesterol, VLDL / Q000097:blood; D005215:Fasting / Q000502:physiology*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000235:genetics; D007657:Ketone Bodies / Q000096:biosynthesis / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D015243:Cholesterol, VLDL; C493411:Fabp4 protein, mouse; C082667:Fabp5 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005230:Fatty Acids, Nonesterified; D007657:Ketone Bodies; D009363:Neoplasm Proteins; D014280:Triglycerides