Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle

Abstract

Insulin resistance in skeletal muscle plays a major role in the development of type 2 diabetes and may be causally associated with increases in intramuscular fatty acid metabolites. Fatty acid transport protein 1 (FATP1) is an acyl-CoA synthetase highly expressed in skeletal muscle and modulates fatty acid uptake and metabolism by converting fatty acids into fatty acyl-CoA. To investigate the role of FATP1 in glucose homeostasis and in the pathogenesis of insulin resistance, we examined the effect of acute lipid infusion or chronic high-fat feeding on insulin action in FATP1 KO mice. Whole-body adiposity, adipose tissue expression of adiponectin, intramuscular fatty acid metabolites, and insulin sensitivity were not altered in FATP1 KO mice fed a regular chow diet. In contrast, FATP1 deletion protected the KO mice from fat-induced insulin resistance and intramuscular accumulation of fatty acyl-CoA without alteration in whole-body adiposity. These findings demonstrate an important role of intramuscular fatty acid metabolites in causing insulin resistance and suggest that FATP1 may be a novel therapeutic target for the treatment of insulin resistance and type 2 diabetes

Fatty acid metabolism in adipocytes: functional analysis of fatty acid transport proteins 1 and 4

“…Various overexpression systems and a knockout mouse model have implicated FATP1 in fatty acid uptake (13,15). FATP1 transcription is regulated by multiple systems: negatively by insulin and positively by a PPARg-dependent mechanism (33,34).…”

“…Error bars indicate SD. Role of FATPs in adipocyte fatty acid uptake and effluxnull for FATP1 exhibit reduced skeletal muscle LCFA uptake and resistance to high-fat diet-induced insulin resistance (15,35). In fat cells, rosiglitazone, a PPARg agonist, increases the expression of both CD36 and FATP1, suggesting that the lipid-lowering effects of this insulinsensitizing drug may be exerted at the level of adipose LCFA influx (36).…”

“…A transgenic mouse model with cardiac-specific expression of FATP1 demonstrated increased myocardial LCFA uptake (13). Disruption of the FATP1 homolog expressed in yeast, fat1p, markedly impaired LCFA uptake (14), and a murine FATP1 knockout mouse exhibited reduced muscle acyl-CoA levels and increased insulin sensitivity (15).…”

Kruppel-like Factor 15 Is a Critical Regulator of Cardiac Lipid Metabolism

“…Pdk4 and Fatp1 (Slc27a1) were used as exemplary targets, given the essential role of these genes in myocellular lipid flux and extensive functional knowledge of their proximal promoters (30,(42)(43)(44)(45). The proximal promoters of both genes were induced by KLF15 in cultured cardiomyocytes (Fig.…”

Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism

“…This, in turn, inhibits insulin signaling, resulting in insulin resistance in liver and skeletal muscle, the organs responsible for the majority of glucose disposal. Studies in transgenic (TG) and knockout mice have demonstrated that alterations in fatty acid delivery (5,7), synthesis (8), or mitochondrial (9-11)/ peroxisomal (12) fatty acid oxidation can alter this balance, resulting in insulin resistance when there is a net increase in intracellular diacylglycerol content and protection from insulin resistance when there is a net reduction in intracellular diacylglycerol content.…”