Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation

Abstract

Excessive circulating FAs have been proposed to promote insulin resistance (IR) of glucose metabolism by increasing the oxidation of FAs over glucose. Therefore, inhibition of FA oxidation (FAOX) has been suggested to ameliorate IR. However, prolonged inhibition of FAOX would presumably cause lipid accumulation and thereby promote lipotoxicity. To understand the glycemic consequences of acute and prolonged FAOX inhibition, we treated mice with the carnitine palmitoyltransferase 1 (CPT-1) inhibitor, etomoxir (eto), in combination with short-term 45% high fat diet feeding to increase FA availability. Eto acutely increased glucose oxidation and peripheral glucose disposal, and lowered circulating glucose, but this was associated with increased circulating FAs and triacylglycerol accumulation in the liver and heart within hours. Several days of FAOX inhibition by daily eto administration induced hepatic steatosis and glucose intolerance, specific to CPT-1 inhibition by eto. Lower whole-body insulin sensitivity was accompanied by reduction in brown adipose tissue (BAT) uncoupling protein 1 (UCP1) protein content, diminished BAT glucose clearance, and increased hepatic glucose production. Collectively, these data suggest that pharmacological inhibition of FAOX is not a viable strategy to treat IR, and that sufficient rates of FAOX are required for maintaining liver and BAT metabolic function. Excessive circulating FAs have been proposed to promote insulin resistance (IR) of glucose metabolism by increasing the oxidation of FAs over glucose. Therefore, inhibition of FA oxidation (FAOX) has been suggested to ameliorate IR. However, prolonged inhibition of FAOX would presumably cause lipid accumulation and thereby promote lipotoxicity. To understand the glycemic consequences of acute and prolonged FAOX inhibition, we treated mice with the carnitine palmitoyltransferase 1 (CPT-1) inhibitor, etomoxir (eto), in combination with short-term 45% high fat diet feeding to increase FA availability. Eto acutely increased glucose oxidation and peripheral glucose disposal, and lowered circulating glucose, but this was associated with increased circulating FAs and triacylglycerol accumulation in the liver and heart within hours. Several days of FAOX inhibition by daily eto administration induced hepatic steatosis and glucose intolerance, specific to CPT-1 inhibition by eto. Lower whole-body insulin sensitivity was accompanied by reduction in brown adipose tissue (BAT) uncoupling protein 1 (UCP1) protein content, diminished BAT glucose clearance, and increased hepatic glucose production. Collectively, these data suggest that pharmacological inhibition of FAOX is not a viable strategy to treat IR, and that sufficient rates of FAOX are required for maintaining liver and BAT metabolic function. Excess calorie intake, physical inactivity, and obesity are risk factors for developing insulin resistance (IR) and are often accompanied by an increase in circulating FAs. Several paradigms attempt to mechanistically link augmented FA availability and IR in peripheral tissues. Randle et al. (1Randle P.J. Garland P.B. Hales C.N. Newholme E.A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.Lancet. 1963; 1: 785-789Abstract PubMed Scopus (3769) Google Scholar) proposed that increased FA availability for mitochondrial β-oxidation increased mitochondrial acetyl-CoA, NADH to NAD+ ratio, and citrate levels, which collectively signal to downregulate glucose oxidation and insulin-stimulated glucose disposal. Applying this model to human IR, it has been hypothesized that augmented availability of FAs induces an increase in β-oxidation, which, by virtue of the substrate competition model, impairs glucose utilization. Therefore, it has been suggested that inhibition of FA oxidation (FAOX) should be pursued as a pharmacological strategy to improve IR by forcing increased glucose oxidation (2Zhang L. Keung W. Samokhvalov V. Wang W. Lopaschuk G.D. Role of fatty acid uptake and fatty acid beta-oxidation in mediating insulin resistance in heart and skeletal muscle.Biochim. Biophys. Acta. 2010; 1801: 1-22Crossref PubMed Scopus (190) Google Scholar, 3Ratheiser K. Schneeweiss B. Waldhausl W. Fasching P. Korn A. Nowotny P. Rohac M. Wolf H.P. Inhibition by etomoxir of carnitine palmitoyltransferase I reduces hepatic glucose production and plasma lipids in non-insulin-dependent diabetes mellitus.Metabolism. 1991; 40: 1185-1190Abstract Full Text PDF PubMed Scopus (74) Google Scholar). At the same time, IR has been shown to be accompanied by an impaired metabolic flexibility to (up)regulate FAOX in response to feeding, fasting, and exercise (4Felber J.P. Ferrannini E. Golay A. Meyer H.U. Theibaud D. Curchod B. Maeder E. Jequier E. DeFronzo R.A. Role of lipid oxidation in pathogenesis of insulin resistance of obesity and type II diabetes.Diabetes. 1987; 36: 1341-1350Crossref PubMed Google Scholar, 5Kelley D.E. Goodpaster B. Wing R.R. Simoneau J.A. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss.Am. J. Physiol. 1999; 277: E1130-E1141PubMed Google Scholar, 6Blaak E.E. Basic disturbances in skeletal muscle fatty acid metabolism in obesity and type 2 diabetes mellitus.Proc. Nutr. Soc. 2004; 63: 323-330Crossref PubMed Scopus (70) Google Scholar). This mismatch can further exacerbate IR due to the accumulation of cytosolic and intra-mitochondrial lipid metabolites (7Koves T.R. Ussher J.R. Noland R.C. Slentz D. Mosedale M. Ilkayeva O. Bain J. Stevens R. Dyck J.R. Newgard C.B. et al.Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance.Cell Metab. 2008; 7: 45-56Abstract Full Text Full Text PDF PubMed Scopus (1414) Google Scholar). To this end, it seems imprudent to treat IR with pharmacological inhibition of FAOX. This conundrum exemplifies the uncertainty surrounding the question of whether inhibition of FAOX can improve glucose metabolism (8Timmers S. Nabben M. Bosma M. van Bree B. Lenaers E. van Beurden D. Schaart G. Westerterp-Plantenga M.S. Langhans W. Hesselink M.K. et al.Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity.Proc. Natl. Acad. Sci. USA. 2012; 109: 11711-11716Crossref PubMed Scopus (66) Google Scholar, 9Hübinger A. Knode O. Susanto F. Reinauer R. Gries F.A. Effects of the carnitine-acyltransferase inhibitor etomoxir on insulin sensitivity, energy expenditure and substrate oxidation in NIDDM.Horm. Metab. Res. 1997; 29: 436-439Crossref PubMed Scopus (34) Google Scholar, 10Keung W. Ussher J.R. Jaswal J.S. Raubenheimer M. Lam V.H. Wagg C.S. Lopaschuk G.D. Inhibition of carnitine palmitoyltransferase-1 activity alleviates insulin resistance in diet-induced obese mice.Diabetes. 2013; 62: 711-720Crossref PubMed Scopus (92) Google Scholar) or whether such a strategy would aggravate metabolic complications (11Dobbins R.L. Szczepaniak L.S. Bentley B. Esser V. Myhill J. McGarry J.D. Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats.Diabetes. 2001; 50: 123-130Crossref PubMed Scopus (250) Google Scholar). Carnitine palmitoyltransferase 1 (CPT-1) is one of the key enzymes for mitochondrial β-oxidation, facilitating the import of long-chain FAs (LCFAs) into the mitochondria. Located on the outer mitochondrial membrane, CPT-1 catalyzes the reaction between long-chain acyl-CoAs and carnitine to form acylcarnitine, which is then shuttled via carnitine-acylcarnitine translocase into the mitochondria, converted back into acyl-CoA (by CPT-2), and then released to undergo β-oxidation (3Ratheiser K. Schneeweiss B. Waldhausl W. Fasching P. Korn A. Nowotny P. Rohac M. Wolf H.P. Inhibition by etomoxir of carnitine palmitoyltransferase I reduces hepatic glucose production and plasma lipids in non-insulin-dependent diabetes mellitus.Metabolism. 1991; 40: 1185-1190Abstract Full Text PDF PubMed Scopus (74) Google Scholar). We herein used the CPT-1 inhibitor, ethyl-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate [etomoxir (eto)], to inhibit FAOX in mice (12Ceccarelli S.M. Chomienne O. Gubler M. Arduini A. Carnitine palmitoyltransferase (CPT) modulators: a medicinal chemistry perspective on 35 years of research.J. Med. Chem. 2011; 54: 3109-3152Crossref PubMed Scopus (69) Google Scholar, 13Schönke M. Massart J. Zierath J.R. Effects of high-fat diet and AMPK modulation on the regulation of whole-body lipid metabolism.J. Lipid Res. 2018; 59: 1276-1282Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar) and, for the first time, compared how acute versus prolonged inhibition of FAOX impacts glucose homeostasis. Eto has been shown to inhibit CPT-1 activity in both rat heart mitochondria (14Lilly K. Chung C. Kerner J. VanRenterghem R. Bieber L.L. Effect of etomoxiryl-CoA on different carnitine PubMed Scopus Google Scholar, J.R. M. McGarry J.R. of the mitochondrial carnitine palmitoyltransferase of Chem. 1987; Full Text PDF PubMed Google of rat heart and liver J.R. M. McGarry J.R. of the mitochondrial carnitine palmitoyltransferase of Chem. 1987; Full Text PDF PubMed Google and rat skeletal muscle mitochondria A. carnitine inhibition in does not long-chain fatty acid uptake and oxidation J. PubMed Scopus Google for and whole-body FAOX To increase circulating FA availability increasing we a high-fat diet for days to inhibition of whole-body FAOX by eto. we diet with FAs to for eto in L. K. et by Metab. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, D. K. E. glucose induces mitochondrial via fatty acid oxidation in PubMed Scopus Google Scholar). by the and with the for of used for mice used for on a cycle. mice to a diet and to and both the acute and prolonged mice days and the prolonged for the in mice to a The diet fat and with 35 and and the fat in this diet of we to this diet as to this we used an in prolonged this the fat was of triacylglycerol and and The diet was to have the same energy and to be with the We to this diet as of the and the fat in and The was of and in a the fat in and The was of and Eto was by weight as in (8Timmers S. Nabben M. Bosma M. van Bree B. Lenaers E. van Beurden D. Schaart G. Westerterp-Plantenga M.S. Langhans W. Hesselink M.K. et al.Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity.Proc. Natl. Acad. Sci. USA. 2012; 109: 11711-11716Crossref PubMed Scopus (66) Google in of was as prolonged eto was daily to the cycle. or eto was in mice for and glucose in with a and then to and glucose was or eto was in mice for glucose was in At was glucose was and for and mice by was and adipose tissue and brown adipose tissue and in days of glucose clearance, and fat by to metabolic days to and to and uptake and production a oxidation was as uptake of shown for the mice with eto for in At glucose was in and mice with or eto At or a glucose was with an of 2 of glucose and glucose in and The muscle was mice and in an in glucose, acid of eto or as for The was to eto or was and was with 1 acid and with of in was by mice a and mice a in in days on the of the mice on diet daily of or eto. days of a was as the the diet feeding and or eto and the mice the a and muscle and for of lipid mice a days on the mice daily of or eto days of daily a was the the mice At glucose was in and of the of eto the of the and the with At a was as glucose was in the days of or eto a 2 glucose At and glucose was in and was into At mice by and was and for insulin sensitivity and glucose of on days of or eto in a with an of of and and on a was into a for administration of and glucose. was by of the a of was a was with a of insulin and glucose was and by of glucose was the and for of plasma glucose and plasma activity by to the plasma specific At for plasma insulin was the by insulin and by The of plasma FA and on an BAT and liver was an was with a was with the BAT and liver was to and are in in for 1 and M. J.R. R. L. M. D.E. E.A. of 2 muscle glucose uptake exercise in Physiol. PubMed Scopus Google Scholar). to protein to the same protein and to and as M. J.R. R. L. M. D.E. E.A. of 2 muscle glucose uptake exercise in Physiol. PubMed Scopus Google Scholar). The are in a to for and and skeletal muscle content was as for of PubMed Scopus Google Scholar). content was in of tissue as L.S. E. J.R. et insulin high fat Metab. 29: Full Text Full Text PDF PubMed Scopus Google Scholar). heart and muscle content, in 1 of in a II then for of and was by for The was and content was by a in and in by and on The and with then and on with The in a and a activity was in of by to of tissue used to the accumulation of by the P. A. L. J. to glucose in in skeletal muscle and adipose tissue of the J. PubMed Scopus Google Scholar). was by the tissue in over or by the in this D.E. to insulin-stimulated glucose PubMed Google Scholar). the glucose into different on and fat by Skeletal muscle was to of the energy and of metabolic in 1997; PubMed Scopus Google and heart and BAT to be and as for a with of FAOX inhibition impairs glucose in glucose was in mice to prolonged FAOX inhibition, with the or eto the glucose and plasma insulin with glucose with glucose into skeletal in and BAT glucose of prolonged eto in BAT mice the to and E. of prolonged eto in BAT mice as in or are as in and B. in and and are compared with the in mice in and mice in prolonged eto. data are as are as to the The are in was as in on a for days to eto This was with the to increase circulating FA availability obesity and to the in a glucose in mice days of eto (8Timmers S. Nabben M. Bosma M. van Bree B. Lenaers E. van Beurden D. Schaart G. Westerterp-Plantenga M.S. Langhans W. Hesselink M.K. et al.Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity.Proc. Natl. Acad. Sci. USA. 2012; 109: 11711-11716Crossref PubMed Scopus (66) Google Scholar). of eto lowered glucose over to with a to eto increased glucose into skeletal and by and of the glucose the was by skeletal muscle and heart of muscle an increase in glucose oxidation within skeletal muscle with acute eto in mice that whole-body glucose oxidation increased acute eto and for acute the of glucose was circulating plasma insulin and plasma FA increased by but of increased plasma was increased by At the same time, liver content was by with acute eto with for reduction of content in both heart and skeletal muscle content was increased and heart by muscle content by acute eto a was 1 eto with the increased peripheral glucose clearance, the the was lowered by eto with the increased plasma FAs and liver the was increased by the was the of content in and However, glucose compared with as glucose the of the plasma insulin response the was for and acute eto of liver and heart but not skeletal muscle was 1 with the increased glucose oxidation Collectively, these data suggest that the glucose with acute FAOX inhibition, which can be as is by a in circulating accumulation of liver and glucose a the circulating FAs acute inhibition of FAOX with eto over days in was hypothesized to cause lipid accumulation and glucose of the Prolonged with eto not to for of eto L. K. et by Metab. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, D. K. E. glucose induces mitochondrial via fatty acid oxidation in PubMed Scopus Google we of the of to the mitochondria and undergo β-oxidation of the CPT-1 W. A. is impaired in mice and by or fatty Natl. Acad. Sci. USA. PubMed Scopus Google Scholar, P. L. and fatty in energy the Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, S. L. J. S.M. contribute to the production the carnitine is Biophys. Acta. 2013; PubMed Scopus Google Scholar). FAOX should not be by CPT-1 To this end, prolonged eto in mice or was not by diet or The of and as the fat the was to the of prolonged eto in mice the should not be in prolonged eto an increase in glucose and glucose and glucose a the prolonged eto not glucose or glucose in mice this that the glucose prolonged eto is specific to the inhibition of CPT-1 by eto and the availability of mitochondrial for mice glucose mice plasma FA was not by prolonged eto but was increased in mice prolonged eto induced a increase in liver was of prolonged eto on liver content in mice was was a increase in skeletal muscle with prolonged eto of diet that prolonged FAOX inhibition by eto on glucose in mice (8Timmers S. Nabben M. Bosma M. van Bree B. Lenaers E. van Beurden D. Schaart G. Westerterp-Plantenga M.S. Langhans W. Hesselink M.K. et al.Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity.Proc. Natl. Acad. Sci. USA. 2012; 109: 11711-11716Crossref PubMed Scopus (66) Google Scholar). This on whether glucose is glucose or the glucose to the acute of we hypothesized that of the eto would have on To we glucose days of eto with eto or the was impaired prolonged eto in with data in the prolonged in the glucose was However, to glucose levels, glucose to be to the with acute eto in and The glucose in the prolonged eto was with plasma FA the of the the FA was increased in the eto The increased eto was of liver and reduction of muscle in the Collectively, these that inhibition of FAOX by eto impairs glucose and lipid accumulation in the The glucose was not by acute inhibition of FAOX. we to understand whether the glucose prolonged eto is to in peripheral insulin sensitivity or insulin with glucose, plasma glucose in prolonged eto mice compared with a increase in circulating insulin that insulin is by prolonged eto. glucose into skeletal and was in both but prolonged eto glucose into the BAT by was not impaired in skeletal or liver prolonged eto a protein content of glucose was with uncoupling protein 1 (UCP1) protein and mitochondrial with a of BAT content was for and with prolonged eto these in BAT prolonged eto mice BAT prolonged mice a to a in BAT glucose clearance, the in hepatic content prolonged eto that in liver glucose metabolism contribute to the glucose To understand whether hepatic glucose was by prolonged a was insulin and glucose the in the and prolonged eto reduction in the glucose was prolonged eto and this was accompanied by increased hepatic glucose production the liver content was not in prolonged eto mice be that hepatic increased hepatic to the increased glucose the of liver of hepatic in prolonged eto plasma was increased by with prolonged eto protein and an increase in the protein content of of a key for FA uptake protein content was increased with increased and diminished protein this a hepatic of the liver prolonged eto. of hepatic FAOX such as and not Collectively, these data suggest that the glucose prolonged FAOX inhibition is a of IR in the liver and We that long-chain FAOX with eto glucose and whole-body and skeletal muscle glucose peripheral glucose in and to an reduction in glucose a The of glucose accompanied by a in circulating accumulation of in liver and and a glucose to glucose FAOX is over metabolic in liver and IR. a we that these to the of mitochondrial oxidation of FAs and not to of eto. that acute FAOX inhibition lowered glucose is with in of that acid metabolism by different in with diabetes.Diabetes. PubMed Scopus Google Scholar, A. and are in the rat by an inhibitor of fatty acid J. 7: PubMed Scopus (14) Google Scholar, acute and of with 1987; 36: PubMed Scopus Google Scholar) and (3Ratheiser K. Schneeweiss B. Waldhausl W. Fasching P. Korn A. Nowotny P. Rohac M. Wolf H.P. Inhibition by etomoxir of carnitine palmitoyltransferase I reduces hepatic glucose production and plasma lipids in non-insulin-dependent diabetes mellitus.Metabolism. 1991; 40: 1185-1190Abstract Full Text PDF PubMed Scopus (74) Google Scholar, 9Hübinger A. Knode O. Susanto F. Reinauer R. Gries F.A. Effects of the carnitine-acyltransferase inhibitor etomoxir on insulin sensitivity, energy expenditure and substrate oxidation in NIDDM.Horm. Metab. Res. 1997; 29: 436-439Crossref PubMed Scopus (34) Google Scholar, P. Langhans W. Westerterp-Plantenga M.S. The of etomoxir on substrate oxidation and in J. Nutr. PubMed Scopus Google Scholar, P. V. Hesselink M.K. Schaart G. E. Westerterp-Plantenga M. Langhans W. increase in a role of uncoupling protein as a mitochondrial fatty acid J. PubMed Scopus Google Scholar). However, data we for the first glucose by key metabolic that contribute to whole-body glucose and that glucose was increased by acute FAOX inhibition, to FAs a substrate for heart energy production A. M. of the human on and acid J. Med. Full Text PDF PubMed Scopus Google Scholar). with the glucose into skeletal muscle was induced to a with glucose increasing acute FAOX However, this increase in muscle glucose is to the of insulin in muscle in M. L. J.R. G. P. et inhibition induces insulin resistance and substrate in Metab. PubMed Scopus Google and into of the glucose was presumably by skeletal At the same time, it was shown in skeletal muscle that with eto acutely increased glucose of glucose a was acute inhibition of FAOX. the of with acute FAOX inhibition by eto to be associated with a of glucose for the glucose the of acute eto is the in circulating FAs M. Massart J. Zierath J.R. Effects of high-fat diet and AMPK modulation on the regulation of whole-body lipid metabolism.J. Lipid Res. 2018; 59: 1276-1282Abstract Full Text Full Text PDF PubMed Scopus (14) Google to the of whole-body FAOX with acute as plasma not increased whole-body to high FA availability can acutely downregulate insulin-stimulated glucose (1Randle P.J. Garland P.B. Hales C.N. Newholme E.A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.Lancet. 1963; 1: 785-789Abstract PubMed Scopus (3769) Google Scholar, J. C. B. et insulin resistance and is not accompanied by or impaired insulin 2011; PubMed Scopus (92) Google Scholar). with the increased plasma FA levels, hepatic content was and it be whether increased hepatic glucose the to the to prolonged eto. was increased induced by the that of eto on J. P.B. K. on is via fatty acid Metab. Res. PubMed Scopus Google Scholar). the whole-body response to eto administration metabolic the of pharmacological FAOX inhibition to treat in The glycemic consequences of pharmacological FAOX inhibition treated with eto for a prolonged to be insulin (11Dobbins R.L. Szczepaniak L.S. Bentley B. Esser V. Myhill J. McGarry J.D. Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats.Diabetes. 2001; 50: 123-130Crossref PubMed Scopus (250) Google Scholar). prolonged FAOX inhibition in mice lowered the glucose a of skeletal muscle (8Timmers S. Nabben M. Bosma M. van Bree B. Lenaers E. van Beurden D. Schaart G. Westerterp-Plantenga M.S. Langhans W. Hesselink M.K. et al.Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity.Proc. Natl. Acad. Sci. USA. 2012; 109: 11711-11716Crossref PubMed Scopus (66) Google Scholar). The data that the by et al. (8Timmers S. Nabben M. Bosma M. van Bree B. Lenaers E. van Beurden D. Schaart G. Westerterp-Plantenga M.S. Langhans W. Hesselink M.K. et al.Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity.Proc. Natl. Acad. Sci. USA. 2012; 109: 11711-11716Crossref PubMed Scopus (66) Google Scholar) to the that eto in that was a to the prolonged FAOX inhibition by eto glucose by IR in both liver and The of hepatic glucose production was to an increase in hepatic content and a accumulation the of hepatic FAOX the daily eto with the in plasma FA availability peripheral FAOX inhibition with a of the FA in the liver over with carnitine which impairs the of the hepatic accumulation M. M. Carnitine and fatty acid Biophys. Acta. PubMed Scopus Google Scholar, Carnitine Full Text PDF PubMed Scopus Google Scholar). eto was to obese for the of plasma FAs increased by (3Ratheiser K. Schneeweiss B. Waldhausl W. Fasching P. Korn A. Nowotny P. Rohac M. Wolf H.P. Inhibition by etomoxir of carnitine palmitoyltransferase I reduces hepatic glucose production and plasma lipids in non-insulin-dependent diabetes mellitus.Metabolism. 1991; 40: 1185-1190Abstract Full Text PDF PubMed Scopus (74) Google Scholar). prolonged FAOX inhibition, we that protein content of an facilitating the first in a perspective on the of years Chem. Full Text Full Text PDF PubMed Scopus Google was content of with on J. alleviates insulin resistance via the or in Res. PubMed Scopus Google was with an increased content, these data that prolonged inhibition of FAOX the for hepatic glucose The IR in the BAT was not associated with insulin as by and seems to be to the of content and the impaired we the of a in protein content prolonged FAOX has been shown that are to A. of uncoupling in brown fat 2012; Full Text Full Text PDF PubMed Scopus Google Scholar, mitochondria. The role of fatty in the of the of the J. PubMed Scopus Google and that BAT and impaired in the of Wang R. D. B. et in brown is not for in Metab. Full Text Full Text PDF PubMed Scopus Google Scholar, J. fatty acid oxidation is required for and Full Text Full Text PDF PubMed Scopus Google Scholar, E. J. J. acid oxidation is required for and brown adipose tissue and Metab. 2018; 7: PubMed Scopus Google Scholar). To this end, availability by administration of the whole-body inhibitor, in BAT F. S. B. E.E. F. D. Inhibition of brown adipose tissue metabolism and in Metab. Full Text Full Text PDF PubMed Scopus Google Scholar). FAOX to be for BAT function. and BAT eto was in this that the metabolic of BAT was specific to mitochondrial FA availability and we that acute inhibition of FAOX reduces glucose to a and that prolonged FAOX inhibition induces both glucose and IR. acute inhibition of FAOX glucose, due to increased glucose in skeletal muscle and the the increase in circulating FAs the liver was the for the glucose into FAOX Prolonged inhibition of FAOX to IR in liver and of a increase in circulating FA levels, to tissue metabolic hepatic to be an for the impaired glucose homeostasis. Collectively, data suggest that pharmacological FAOX inhibition, the of glucose does not to be a viable strategy to treat IR. for Basic is an the of and is by an the protein brown adipose tissue weight of carnitine palmitoyltransferase 1 etomoxir adipose tissue FA oxidation glucose glucose high-fat diet the insulin resistance long-chain FA long-chain high-fat diet FA high-fat diet triacylglycerol uncoupling protein 1