Fatty acid transport protein 1 (FATP1), a member of the FATP/Slc27 protein family, enhances the cellular uptake of long-chain fatty acids (LCFAs) and is expressed in several insulin-sensitive tissues. In adipocytes and skeletal muscle, FATP1 translocates from an intracellular compartment to the plasma membrane in response to insulin. Here we show that insulin-stimulated fatty acid uptake is completely abolished in FATP1-null adipocytes and greatly reduced in skeletal muscle of FATP1-knockout animals while basal LCFA uptake by both tissues was unaffected. Moreover, loss of FATP1 function altered regulation of postprandial serum LCFA, causing a redistribution of lipids from adipocyte tissue and muscle to the liver, and led to a complete protection from diet-induced obesity and insulin desensitization. This is the first in vivo evidence that insulin can regulate the uptake of LCFA by tissues via FATP1 activation and that FATPs determine the tissue distribution of dietary lipids. The strong protection against diet-induced obesity and insulin desensitization observed in FATP1-null animals suggests FATP1 as a novel antidiabetic target.

No abstract

Nonshivering thermogenesis in brown adipose tissue (BAT) generates heat through the uncoupling of mitochondrial ␤-oxidation from ATP production. The principal energy source for this process is fatty acids that are either synthesized de novo in BAT or are imported from circulation. How uptake of fatty acids is mediated and regulated has remained unclear. Here, we show that fatty acid transport protein (FATP)1 is expressed on the plasma membrane of BAT and is upregulated in response to cold stimuli, concomitant with an increase in the rate of fatty acid uptake. In FATP1-null animals, basal fatty acid uptake is reduced and remains unchanged following cold exposure. As a consequence, FATP1 knockout (KO) animals display smaller lipid droplets in BAT and fail to defend their core body temperature at 4°C, despite elevated serum free fatty acid levels. Similarly, FATP1 is expressed by the BATderived cell line HIB-1B upon differentiation, and both fatty acid uptake and FATP1 protein levels are rapidly elevated following isoproterenol stimulation. Stimulation of fatty uptake by isoproterenol required both protein kinase A and mitogen-activated kinase signaling and is completely dependent on FATP1 expression, as small-hairpin RNA-mediated knock down of FATP1 abrogated the effect. Diabetes 55:3229 -3237, 2006

No abstract

In many tissues, fatty acid binding protein (FABP) expression is stimulated by exposure to elevated fatty acid levels. In contrast to the FABP genes expressed in other tissues, the molecular mechanisms that mediate the upregulation of the muscle FABP gene have not been elucidated. We have studied the expression of locust flight muscle FABP, a protein that is highly homologous to the mammalian H-FABPs. A 130-bp promoter fragment of the locust gene, which includes a canonical TATA box and several GC boxes, is sufficient for the transcription of a reporter gene in mammalian L6 myoblasts. Twofold higher expression rates are observed when the promoter contains 280 bp or more of upstream sequence. Treatment of myoblasts with various fatty acids leads to a marked increase of expression in the longer constructs, but not in the minimal promoter. We have identified a 19-bp inverted repeat (2162/2180) as the element responsible for the fatty acid-mediated induction of gene expression. Deletion of this element eliminates the fatty acid response, and gel shift analysis demonstrates specific binding to nuclear proteins from both L6 myoblasts and locust flight muscle cells. This fatty acid response element bears no similarity to any known transcription factor binding site. A similar palindrome was also found in the promoter of the Drosophila melanogaster muscle FABP gene, and in reverse orientation upstream of all mammalian heart FABP genes. Given the structural and functional conservation of muscle FABPs and their genes, it is possible that this fatty acid response element also modulates the expression of the mammalian H-FABP genes.Keywords: fatty acid binding protein; gene regulation; FARE; myoblast; gel-shift analysis.Among the most energy-demanding tasks performed by animals is migratory flight of insects that requires many hours of sustained muscle activity [1]. Fatty acids are the preferred substrates to fuel such work, and the extreme metabolic rates encountered during locust migration demand a very large flux of fatty acids through the muscle cell. These muscles appear to be optimally adapted to safely retrieve, transport and metabolize large amounts of fatty acids [2]. One important factor in these processes is the intracellular fatty acid binding protein (FABP), which binds free fatty acids and thus prevents damage due to a fatty acid overload [3,4]. In previous studies we have demonstrated that the expression of FABP in locust flight muscle not only varies with muscle differentiation, but is also upregulated sharply in response to increased lipid flow. Extended flight and increased lipid delivery to the flight muscle lead to a marked increase in FABP expression [5]. This increase parallels similar effects seen for heart FABP (H-FABP ) genes in mammalian species.In mammalian muscles, H-FABP concentrations generally reflect the rates of fatty acid metabolism, with highest levels found in cardiomyocytes [6]. In vivo and in vitro studies have demonstrated that increased fatty acid delivery or utilization lead to eleva...