Impaired Activation of Phosphatidylinositol 3-Kinase by Leptin Is a Novel Mechanism of Hepatic Leptin Resistance in Diet-induced Obesity

Abstract

Obesity is associated with the development of leptin resistance. However, the effects of leptin resistance on leptin-regulated metabolic processes and the biochemical defects that cause leptin resistance are poorly understood. We have addressed in rats the effect of dietinduced obesity (DIO), a situation of elevated tissue lipid levels, on the well described lipid-lowering effect of leptin in liver, an action that is proposed to be important for the prevention of tissue lipotoxicity and insulin resistance. In addition, we have addressed the role of phosphatidylinositol 3-kinase (PI 3-kinase) in mediating the acute effects of leptin on hepatic lipid levels in lean and DIO animals. A 90-min leptin (∼10 ng/ml) perfusion of isolated livers from lean animals decreased triglyceride levels by 42 ± 5% (p = 0.006). However, leptin concentrations ranging from ∼10 to ∼90 ng/ml had no effect on triglyceride levels in livers from DIO animals. The acute lipid-lowering effect of leptin on livers from lean animals was mediated by a PI 3-kinase-dependent mechanism, because wortmannin and LY294002, the PI 3-kinase inhibitors, blocked the effects of leptin on hepatic triglyceride levels and leptin increased liver PI 3-kinase activity by 183 ± 6% (p = 0.003) and insulin receptor substrate 1 tyrosine phosphorylation by 185 ± 30% (p = 0.02) in the absence of PI 3-kinase inhibitors. Contrary to the effects of leptin in lean livers, leptin did not activate PI 3-kinase in livers from DIO rats. These data present evidence for a role for 1) leptin resistance in contributing to the excessive accumulation of tissue lipid in obesity, 2) PI 3-kinase in mediating the acute lipid-lowering effects of leptin in liver, and 3) defective leptin activation of PI 3-kinase as a novel mechanism of leptin resistance. Obesity is associated with the development of leptin resistance. However, the effects of leptin resistance on leptin-regulated metabolic processes and the biochemical defects that cause leptin resistance are poorly understood. We have addressed in rats the effect of dietinduced obesity (DIO), a situation of elevated tissue lipid levels, on the well described lipid-lowering effect of leptin in liver, an action that is proposed to be important for the prevention of tissue lipotoxicity and insulin resistance. In addition, we have addressed the role of phosphatidylinositol 3-kinase (PI 3-kinase) in mediating the acute effects of leptin on hepatic lipid levels in lean and DIO animals. A 90-min leptin (∼10 ng/ml) perfusion of isolated livers from lean animals decreased triglyceride levels by 42 ± 5% (p = 0.006). However, leptin concentrations ranging from ∼10 to ∼90 ng/ml had no effect on triglyceride levels in livers from DIO animals. The acute lipid-lowering effect of leptin on livers from lean animals was mediated by a PI 3-kinase-dependent mechanism, because wortmannin and LY294002, the PI 3-kinase inhibitors, blocked the effects of leptin on hepatic triglyceride levels and leptin increased liver PI 3-kinase activity by 183 ± 6% (p = 0.003) and insulin receptor substrate 1 tyrosine phosphorylation by 185 ± 30% (p = 0.02) in the absence of PI 3-kinase inhibitors. Contrary to the effects of leptin in lean livers, leptin did not activate PI 3-kinase in livers from DIO rats. These data present evidence for a role for 1) leptin resistance in contributing to the excessive accumulation of tissue lipid in obesity, 2) PI 3-kinase in mediating the acute lipid-lowering effects of leptin in liver, and 3) defective leptin activation of PI 3-kinase as a novel mechanism of leptin resistance. Human obesity and diet-induced obesity in rodents are associated with the development of leptin resistance (1Unger R.H. Annu. Rev. 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Chem. 2001; 276: 5629-5635Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar), whereas administration of leptin to gold-thioglucose-treated mice that lack hypothalamic leptin function decreases hepatic lipogenesis (15Bryson J.M. Phuyal J.L. Swan V. Caterson I.D. Am. J. Physiol. 1999; 277: E417-E422PubMed Google Scholar). Taken together, these studies demonstrate potent lipid-lowering effects of leptin that are at least partially mediated by direct action of leptin on liver. Unlike situations of leptin deficiency and leptin receptor mutations, human obesity and diet-induced obesity (DIO) 1The abbreviations used are: DIO, diet-induced obesity; PI 3-kinase, phosphatidylinositol 3-kinase; PDE3B, phosphodiesterase 3B; RPA, ribonuclease protection assay; ObRa, short form of leptin receptor; ObRb long form of leptin receptor; STAT, signal transducers and activators of transcription; PI(3)P, phosphatidylinositol 3-phosphate; AMPK, 5′-AMP′-activated protein kinase; IRS-1, insulin receptor substrate 1. in rodents are characterized by hyperleptinemia and functional leptin receptors, but leptin resistance is also present (1Unger R.H. Annu. Rev. Physiol. 2003; 65: 333-347Crossref PubMed Scopus (177) Google Scholar, 2Ahima R.S. Flier J.S. Annu. Rev. Physiol. 2000; 62: 413-437Crossref PubMed Scopus (1488) Google Scholar, 3Friedman J.M. Nutr. Rev. 2002; 84: 85-117Google Scholar). 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A. 2002; PubMed Scopus Google Scholar, D. M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Nature. 2001; PubMed Scopus Google Scholar), and phosphodiesterase S. R. A. 2002; PubMed Scopus Google Scholar, D. M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) have in mediating the metabolic actions of but the role in the lipid-lowering effects of leptin and the role of defects in these in leptin resistance are The was to of these we the effects of DIO in rats on the acute effects of leptin in liver. we addressed the role of PI 3-kinase, and activation in the of hepatic triglyceride levels by leptin and these are defective in The data demonstrate that DIO rat liver is to the acute lipid-lowering effects of that leptin on liver a PI 3-kinase-dependent mechanism to liver triglyceride levels, and that a mechanism of hepatic leptin resistance is defective PI 3-kinase our is the that a role for activation of PI 3-kinase by leptin in leptin resistance. and rats from at a of rats on a with to and with rat of from a of from for or or a of from J. S. K. N. Rossetti L. Diabetes. 2001; PubMed Scopus Google Scholar) for of the by the and of the of and in with the for the and of isolated liver perfusion of a a as a in a an and a and a perfusion of the was by 5% of in the for liver metabolism the R.L. J. Full Text PDF PubMed Google Scholar). K. PubMed Scopus Google Scholar) the in A rat was with an The hepatic was isolated from the hepatic and the and was by a The was by and to the perfusion of the liver with that of was The was and and the and the The liver was and a was and the of the the liver was a liver the perfusion was with and in a at the of liver. a rat leptin in or was the a at a of for and at a of for the of the 90-min perfusion administration was on studies with a and that the leptin in the a and the 90-min perfusion In leptin the of leptin was increased or the PI 3-kinase wortmannin or or the 1 livers for with the to a 90-min of the with or the was by tissue and and liver PubMed Scopus Google Scholar). The and of the the an absence of PubMed Scopus Google Scholar). was tissue the and for normal hepatic function PubMed Scopus Google Scholar, Investig. Google Scholar). The of the was on the in of the and the liver. and leptin was a and concentrations and of the by a as described R. Newgard C.B. O'Doherty Am. J. Physiol. 2000; PubMed Google Scholar). of liver tissue was in 1 of a the lipid with of and of the the and as PI 3-kinase activity was to a of PI 3-kinase was by of liver protein from tissue with of for by the of protein for The for at with phosphatidylinositol in the of was by and was by the from the by of phosphorylation of IRS-1, of liver protein was with and the by and with or receptor protein was by an receptor and receptor was the ribonuclease protection from rat leptin receptor that for the rat long form receptor or that of the rat leptin receptor as described A. L. O'Doherty J. 2002; PubMed Scopus Google Scholar). A as an as described A. L. O'Doherty J. 2002; PubMed Scopus Google Scholar). The with of for at in of of a of a was and at for was and the and on a 6% The by and the was of for ObRb and levels to protein activity was by the of a substrate as described N. A.J. R.L. S. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). was from a liver the N. A.J. R.L. S. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). was activity was in a in the of a and at for of the are as ± was by the was at The of on in the effects of leptin on liver triglyceride levels in isolated livers from lean and diet-induced animals. In leptin was the at a that in a leptin in the of ∼10 ng/ml with leptin concentrations in rodents. A 90-min leptin perfusion decreased liver triglyceride levels by 42 ± 5% (p = in livers from lean animals with livers also increased liver by ± (p = 0.02) with a in processes However, the activity of AMPK, a proposed of leptin effects on was in with livers ± ± = In livers from rats for on a to obesity (DIO), hepatic levels increased by ± (p with livers from lean animals Contrary to the effects of leptin on livers from lean leptin had no effects on triglyceride levels in livers from DIO rats liver was in and DIO livers that acute leptin effects on processes in leptin is elevated in DIO, we that triglyceride levels in livers from DIO rats be reduced by leptin in the to concentrations associated with was not the from DIO animals with a leptin of or ∼90 ng/ml had levels of as livers not These data demonstrate that livers from DIO animals to the acute lipid-lowering effects of Wang J. S. K. N. Rossetti L. Diabetes. 2001; PubMed Scopus Google Scholar) that of of a that increased by in the development of resistance to the effects of leptin on hepatic of the leptin at a of ∼10 ng/ml was to liver triglyceride levels by ± 6% (p = However, the of Wang J. S. K. N. Rossetti L. Diabetes. 2001; PubMed Scopus Google Scholar), rats on the used in not with R. Newgard C.B. O'Doherty Am. J. Physiol. 2000; PubMed Google Scholar). In with of the J. S. K. N. Rossetti L. Diabetes. 2001; PubMed Scopus Google Scholar), rats increased ± to ± = and triglyceride levels not reduced by the of leptin resistance of of leptin perfusion on in livers from lean and diet-induced rats. isolated and as described in 1. was as described are as in in livers with livers at the of the 90-min perfusion The a and = of are as ± of of a or a on decreases in liver triglyceride isolated from rats of a or a and with or leptin for livers in and and triglyceride was The a and = for and = for are as ± in Obesity with of PI 3-kinase, a of the of in of have proposed to leptin signal and the metabolic effects of leptin activation of PI 3-kinase R. S. J. Charron M.J. Friedman J.M. Diabetes. 1999; PubMed Scopus Google Scholar, S. R. A. 2002; PubMed Scopus Google Scholar, D. M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Nature. 2001; PubMed Scopus Google Scholar), S. R. A. 2002; PubMed Scopus Google Scholar, D. M. J. Biol. 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J. 2001; PubMed Google Scholar), leptin had no effects on phosphorylation not PI 3-kinase activation is for the effects of leptin in livers from lean we the effects of leptin on PI 3-kinase activity in livers from DIO rats and Unlike in livers from lean leptin had no effects on PI 3-kinase activity or on tyrosine phosphorylation of in DIO livers, a mechanism for hepatic leptin resistance. DIO did not phosphorylation of with lean not the of leptin to activate PI 3-kinase in DIO was not associated with a of leptin receptor expression in liver that leptin resistance is a the short form leptin receptor was by and RPA, we to ObRb in liver by not These data that the effects of leptin in liver. In these data demonstrate that leptin decreases hepatic triglyceride levels a PI 3-kinase mechanism that is of and activation and that leptin activation of PI 3-kinase is defective in of leptin perfusion on PI 3-kinase activity and tyrosine or phosphorylation of in livers from lean and rats. isolated and as described in 1. PI 3-kinase activity and tyrosine or phosphorylation of as described A and of PI 3-kinase activity and tyrosine or phosphorylation of in and livers or leptin is a of PI 3-kinase activity as and from of on is a of tyrosine phosphorylation of by The a and = a of are as ± of diet-induced obesity on hepatic leptin receptor isolated from of lean or diet-induced rats. receptor protein and leptin receptor by and RPA, as described The of protein and in liver from lean and diet-induced rats. = a of The a of important and novel on the of the action of leptin in liver and hepatic leptin resistance in diet-induced rats. we demonstrate that excessive hepatic storage of lipid in obesity is associated with the development of resistance to the acute lipid-lowering effects of we demonstrate that PI 3-kinase activation is for the acute lipid-lowering effects of leptin on liver. we demonstrate that a mechanism of hepatic leptin resistance is the leptin activation of PI 3-kinase, and we demonstrate that hepatic leptin resistance is at least partially to the of direct actions of leptin on liver as to an hypothalamic studies have addressed the effects of obesity such as diet-induced obesity and human obesity on leptin-regulated metabolic In DIO leptin of and lipid in skeletal muscle is decreased with lean Am. 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