A Critical Role of Fatty Acid Binding Protein 4 and 5 (FABP4/5) in the Systemic Response to Fasting

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.

Identification of fatty acid binding protein 4 as an adipokine that regulates insulin secretion during obesity

“…Despite the array of metabolic effects attributed to FABP4, its mode of action remains to be determined. One feature that may consolidate many of these observations is the lipid binding property of FABP4: nuclear localisation and transcriptional activity in adipocytes are regulated by lipid binding [41,42]; liver steatosis in Fabp4 / Fabp5 KO mice is attributed to a role for dysregulated NEFA uptake into heart and skeletal muscle [38]; and we show here in the case of the β-cell, that the most prominent effects of rFABP4 on potentiating GSIS occur in the presence of linoleate. Moreover, neither rFABP4 nor linoleate supplied alone at physiological concentrations significantly altered GSIS.…”

Serum Adropin and Adipose Fatty-Acid Binding Protein at 6th Week of Pregnancy Are Significant Predictors for Development of Insulin Resistance at the 24th Week.

“…2. ELISA estimation of serum insulin levels using ELYSA kit (Enzymuntest Insulin, ES 600, Boehringer Mannheim) (22) , ADR using ELYSA kit (MyBioSource Inc., San Diego, California, USA) (23) and FABP4 using ELYSA kit (MyBioSource Inc., San Diego, California, USA) (24) .…”

The control of insulin secretion by adipokines: current evidence for adipocyte-beta cell endocrine signalling in metabolic homeostasis

“…In addition to its intracellular role in adipocytes, FABP4 is secreted and detected in the blood stream, with levels increasing during obesity (Cao et al 2013;Wu et al 2014b;Xu et al 2006) and familial combined hyperlipidaemia (Cabré et al 2010). Several roles have been ascribed to secreted FABP4 including regulation of cardiomyocyte contraction (Lamounier-Zepter et al 2009), uptake of NEFA into muscle (Syamsunarno et al 2013), regulation of hepatic metabolism (Cao et al 2013), supply of NEFA as a fuel source to ovarian tumour cells (Nieman et al 2011) and enhancement of GSIS during obesity (Wu et al 2014b). …”