Perilipin overexpression in mice protects against diet-induced obesity

Abstract

Perilipin A is the most abundant phosphoprotein on adipocyte lipid droplets and is essential for lipid storage and lipolysis. Perilipin null mice exhibit diminished adipose tissue, elevated basal lipolysis, reduced catecholamine-stimulated lipolysis, and increased insulin resistance. To understand the physiological consequences of increased perilipin expression in vivo, we generated transgenic mice that overexpressed either human or mouse perilipin using the adipocyte-specific aP2 promoter/enhancer. Phenotypes of female transgenic and wild-type mice were characterized on chow and high-fat diets (HFDs). When challenged with an HFD, transgenic mice exhibited lower body weight, fat mass, and adipocyte size than wild-type mice. Expression of oxidative genes was increased and lipogenic genes decreased in brown adipose tissue of transgenic mice. Basal and catecholamine-stimulated lipolysis was decreased and glucose tolerance significantly improved in transgenic mice fed a HFD. Perilipin overexpression in adipose tissue protects against HFD-induced adipocyte hypertrophy, obesity, and glucose intolerance. Alterations in brown adipose tissue metabolism may mediate the effects of perilipin overexpression on body fat, although the mechanisms by which perilipin overexpression alters brown adipose tissue metabolism remain to be determined. Our findings demonstrate a novel role for perilipin expression in adipose tissue metabolism and regulation of obesity and its metabolic complications. Perilipin A is the most abundant phosphoprotein on adipocyte lipid droplets and is essential for lipid storage and lipolysis. Perilipin null mice exhibit diminished adipose tissue, elevated basal lipolysis, reduced catecholamine-stimulated lipolysis, and increased insulin resistance. To understand the physiological consequences of increased perilipin expression in vivo, we generated transgenic mice that overexpressed either human or mouse perilipin using the adipocyte-specific aP2 promoter/enhancer. Phenotypes of female transgenic and wild-type mice were characterized on chow and high-fat diets (HFDs). When challenged with an HFD, transgenic mice exhibited lower body weight, fat mass, and adipocyte size than wild-type mice. Expression of oxidative genes was increased and lipogenic genes decreased in brown adipose tissue of transgenic mice. Basal and catecholamine-stimulated lipolysis was decreased and glucose tolerance significantly improved in transgenic mice fed a HFD. Perilipin overexpression in adipose tissue protects against HFD-induced adipocyte hypertrophy, obesity, and glucose intolerance. Alterations in brown adipose tissue metabolism may mediate the effects of perilipin overexpression on body fat, although the mechanisms by which perilipin overexpression alters brown adipose tissue metabolism remain to be determined. Our findings demonstrate a novel role for perilipin expression in adipose tissue metabolism and regulation of obesity and its metabolic complications. Obesity is associated with metabolic dysfunction and increased risk for diabetes, cardiovascular disease, cancer, and early mortality (1Reaven G. Metabolic syndrome: pathophysiology and implications for management of cardiovascular disease.Circulation. 2002; 106: 286-288Crossref PubMed Scopus (466) Google Scholar, 2Hjartaker A. Langseth H. Weiderpass E. Obesity and diabetes epidemics: cancer repercussions.Adv. Exp. Med. Biol. 2008; 630: 72-93Crossref PubMed Scopus (141) Google Scholar). In both lean and obese states, triacylglycerol is predominately stored within lipid droplets of adipocytes. Perilipin A (PeriA) is the most abundant phosphoprotein on adipocyte lipid droplets and is an important regulator of lipid storage and release (lipolysis) (3Greenberg A.S. Egan J.J. Wek S.A. Garty N.B. Blanchette-Mackie E.J. Londos C. Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets.J. Biol. Chem. 1991; 266: 11341-11346Abstract Full Text PDF PubMed Google Scholar, 4Londos C. Sztalryd C. Tansey J.T. Kimmel A.R. Role of PAT proteins in lipid metabolism.Biochimie. 2005; 87: 45-49Crossref PubMed Scopus (220) Google Scholar). In the absence of hormonal stimulation (basal state), PeriA functions to inhibit the actions of lipases on stored neutral lipids, thereby maintaining a low rate of constitutive lipolysis (promotes lipid storage) (5Brasaemle D.L. Rubin B. Harten I. Gruia-Gray J. Kimmel A. Londos C. Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis.J. Biol. 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USA. 2001; 98: 6494-6499Crossref PubMed Scopus (609) Google Scholar, 9Souza S.C. Muliro K. Liscum L. Lien P. Yamamoto Y. Schaffer J. Dallal G. Wang X. Kraemer F. Obin M. et al.Modulation of hormone-sensitive lipase and protein kinase-A-mediated lipolysis by perilipin A in an adenoviral reconstituted system.J. Biol. Chem. 2002; 277: 8267-8272Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar, 10Miyoshi H. Souza S.C. Zhang H.H. Strissel K.J. Christoffolete M.A. Kovsan J. Rudich A. Kraemer F.B. Bianco A.C. Obin M.S. et al.Perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms.J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). adipocyte lipolysis by and protein A which perilipin and hormone-sensitive lipase (3Greenberg A.S. Egan J.J. Wek S.A. Garty N.B. Blanchette-Mackie E.J. Londos C. Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets.J. Biol. Chem. 1991; 266: 11341-11346Abstract Full Text PDF PubMed Google Scholar, P. G. H. P. regulation of adipose tissue lipolysis by of hormone-sensitive Biol. Google Scholar, J.J. Greenberg A.S. Chang Wek S.A. Londos C. of lipolysis in of hormone-sensitive lipase to the lipid storage Natl. Acad. Sci. USA. PubMed Scopus Google Scholar). of on perilipin the lipid in enhanced of adipose lipase A. G. M. G. M. P. G. lipase-mediated lipolysis of fat is by and in 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, M. G. A. C. P. H. lipase and hormone-sensitive lipase the major in adipose tissue triacylglycerol Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google and enhanced to lipid C. Sztalryd C. Tansey J.T. Kimmel A.R. Role of PAT proteins in lipid metabolism.Biochimie. 2005; 87: 45-49Crossref PubMed Scopus (220) Google Scholar, D.L. 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PubMed Scopus Google Scholar). a of lipolysis is Perilipin mice important the role of perilipin in J. Andreson J. Tessler D. Lapillojnne A. Hung-Junn Chang B. Quast M. Gorenstein D. Chen K-H. Chan L. Absence of perilipin results in leanness and reverses obesity in Leprdb/db mice.Nat. Genet. 2000; 26: 474-479Crossref PubMed Scopus (495) Google Scholar, 8Tansey J.T. Sztalryd C. Gruia-Gray J. Roush D. Zeo J. Gavrilova O. Reitman M. Deng C-X. Ki C. Kimmel A. et al.Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity.Proc. Natl. Acad. Sci. USA. 2001; 98: 6494-6499Crossref PubMed Scopus (609) Google Scholar). Perilipin null mice exhibit basal lipolysis and lipolysis and characterized by a in fat which adipocytes. increased and the mice to be to both diet-induced and obesity J. Andreson J. Tessler D. Lapillojnne A. Hung-Junn Chang B. Quast M. Gorenstein D. Chen K-H. Chan L. 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P. for an important role of perilipin in the regulation of human adipocyte PubMed Scopus Google that PeriA expression in is reduced with with increases in associated with a in perilipin and increased size of Souza S.C. M. Obin M.S. Greenberg A.S. regulation of and of and regulation of lipogenic and oxidative Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). human perilipin expression Y. M. Y. Greenberg A.S. Perilipin expression in human adipose effects of obesity, and PubMed Scopus Google Scholar, M. P. G. J. I. P. for an important role of perilipin in the regulation of human adipocyte PubMed Scopus Google Scholar, J. A. M. C. A. et is associated with lipid droplets and insulin in Natl. Acad. Sci. USA. 2008; PubMed Scopus Google Scholar). the perilipin expression in adipose tissue or perilipin and obesity, and glucose and lipid metabolism L. H. I. E.J. Greenberg A.S. D. of a perilipin with obesity risk in a PubMed Scopus Google Scholar, D. L. M. 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In the effects of the human PeriA were with the effects of the mouse PeriA were and were generated S.C. Muliro K. Liscum L. Lien P. Yamamoto Y. Schaffer J. Dallal G. Wang X. Kraemer F. Obin M. et al.Modulation of hormone-sensitive lipase and protein kinase-A-mediated lipolysis by perilipin A in an adenoviral reconstituted system.J. Biol. Chem. 2002; 277: 8267-8272Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar, H. Souza S.C. Zhang H.H. Kraemer F.B. Obin M.S. Greenberg A.S. of adipose lipase by of perilipin A protein lipolysis in adipocytes.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). was generated a mouse PeriA with a the using a H. Souza Muliro K. Kraemer F. Obin M. Greenberg A.S. of A constitutive and protein Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the human PeriA were a the aP2 the tumor and a by B. M. mice the in adipose tissue to PubMed Scopus Google Scholar). A the PeriA or was of mice. of the or in mice was by were with and transgenic mouse were or on the mice for the were for the that the were mice were generated the for and to the on mice were generated the were in a the in with mice were on a to and fed a chow high-fat mice were fed an the of to and body were the to tissue was for an adipose tissue and and and brown adipose tissue were and for were the using and Londos D. protein and lipolysis in I. and in Biol. Chem. Full Text PDF PubMed Google with were and and with was were in to lipolysis basal and rate was the for using a Souza S.C. M. Obin M.S. Greenberg A.S. regulation of and of and regulation of lipogenic and oxidative Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). was of was to M. J. A to fat size and in J. PubMed Scopus Google Scholar). was by of adipocytes. were using a and a was using of lipid and adipocyte M. J. A to fat size and in J. PubMed Scopus Google Scholar). glucose tolerance and insulin tolerance were on mice that were or for was to the the glucose were and and of glucose body using an the mice an of human insulin body and glucose was and and the or was for and and the K.J. H. J. Greenberg A.S. Obin M.S. adipose tissue and obesity PubMed Scopus Google Scholar). and were in and K.J. H. J. Greenberg A.S. Obin M.S. adipose tissue and obesity PubMed Scopus Google Scholar). were with and were with an was and using a lipid was by and was of was in on an in using were using were by K.J. of expression using and the 2001; PubMed Scopus Google and to an of was by of mouse were generated of mice H. Souza S.C. Zhang H.H. Strissel K.J. Christoffolete M.A. Kovsan J. Rudich A. Kraemer F.B. Bianco A.C. Obin M.S. et al.Perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms.J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Souza S.C. Zhang H.H. Kraemer F.B. Obin M.S. Greenberg A.S. of adipose lipase by of perilipin A protein lipolysis in adipocytes.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, H. Obin M.S. Greenberg A.S. lipase basal lipolysis and lipid size in adipocytes.J. 2008; PubMed Scopus Google Scholar, M.S. H. Souza S.C. Greenberg A.S. N.B. protein is a of lipolysis in the and physiological Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). the protein and were generated and H. Souza Muliro K. Kraemer F. Obin M. Greenberg A.S. of A constitutive and protein Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). was with on of of was to of expression of the PeriA which was by on H. Souza S.C. Zhang H.H. Strissel K.J. Christoffolete M.A. Kovsan J. Rudich A. Kraemer F.B. Bianco A.C. Obin M.S. et al.Perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms.J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Souza S.C. Zhang H.H. Kraemer F.B. Obin M.S. Greenberg A.S. of adipose lipase by of perilipin A protein lipolysis in adipocytes.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M.S. H. Souza S.C. Greenberg A.S. N.B. protein is a of lipolysis in the and physiological Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). of and was via lipolysis in with and release were of the and for protein H. Souza S.C. Zhang H.H. Strissel K.J. Christoffolete M.A. Kovsan J. Rudich A. Kraemer F.B. Bianco A.C. Obin M.S. et al.Perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms.J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Souza S.C. Zhang H.H. Kraemer F.B. Obin M.S. Greenberg A.S. of adipose lipase by of perilipin A protein lipolysis in adipocytes.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, H. Souza Muliro K. Kraemer F. Obin M. Greenberg A.S. of A constitutive and protein Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M.S. H. Souza S.C. Greenberg A.S. N.B. protein is a of lipolysis in the and physiological Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). were using a and was a In to demonstrate the and we in perilipin null which exhibit of perilipin H. Souza S.C. Zhang H.H. Strissel K.J. Christoffolete M.A. Kovsan J. Rudich A. Kraemer F.B. Bianco A.C. Obin M.S. et al.Perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms.J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Souza S.C. Zhang H.H. Kraemer F.B. Obin M.S. Greenberg A.S. of adipose lipase by of perilipin A protein lipolysis in adipocytes.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, H. Obin M.S. Greenberg A.S. lipase basal lipolysis and lipid size in adipocytes.J. 2008; PubMed Scopus Google Scholar, M.S. H. Souza S.C. Greenberg A.S. N.B. protein is a of lipolysis in the and physiological Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Zhang H.H. Souza Obin M. Greenberg A.S. of lipid proteins hormonally lipolysis in and lipid of adipocyte 2006; PubMed Scopus Google Scholar). to or a in the on of expression of or in the were by and were to that in of basal lipolysis and of lipolysis were in either or that in the absence of and In to the effects of perilipin overexpression in vivo, the aP2 was to of PeriA transgenic and with a its for Expression of both and was to and with of H.H. M. F. Greenberg A. necrosis lipolysis in human of and elevated and of 2002; PubMed Scopus Google overexpressed a on with mouse PeriA to PeriA protein were increased in and in of both and mice protein expression of adipocyte proteins in lipolysis and was in either or mice In we generated of transgenic mice or PeriA in adipose of female and mice was to fed a chow In female mice were fed a HFD, both and mice than mice a in body fed a with in on an HFD. both female and mice a with transgenic the on female mice. of of both and mice than in body the and of of was and mice and was a factor to the in body on the In of leptin was significantly lower in mice with mice which is by adipocyte in mice. When mice were fed the in the of adipose tissue were in mice in to mice with the of mice were significantly than mice to be in mice. In mice were challenged with an HFD, adipose in both were reduced with mice in for the lower body with reduced adipose in mice fed an HFD, were significantly in both and mice In to effects of expression in both adipocyte and lipid size was significantly in of mice with mice to by which PeriA adipocyte size and adipose tissue mass, on genes in and increases in the expression of the oxidative genes and B in of both of mice were in in expression were with decreased adipocyte the lipogenic genes and were significantly in of mice and to be reduced in mice to we rate a in female mice fed a HFD. for the of was significantly increased in mice on an with the for mice weight, was in and mice by and When on the and mice to glucose and insulin for the mice were fed an HFD, for both and were significantly lower in mice with mice with insulin a of insulin was significantly lower in mice with mice that mice were to HFD-induced glucose and insulin resistance. lipolysis were with adipose was to lipolysis. When mice were on chow basal lipolysis was in and lipolysis was significantly in both and When mice were challenged by an HFD, both basal and lipolysis were reduced in mice with basal and lipolysis was in mice In lipolysis in both of transgenic was in to HFD, the exhibited reduced lipolysis. PeriA to the of lipid droplets and lipid storage in adipose tissue (3Greenberg A.S. Egan J.J. Wek S.A. Garty N.B. Blanchette-Mackie E.J. Londos C. Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets.J. Biol. Chem. 1991; 266: 11341-11346Abstract Full Text PDF PubMed Google Scholar, Greenberg A.S. Obin M.S. of protein and in adipocytes.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D.L. G. L. Wang of proteins associated with lipid droplets of basal and 3T3-L1 adipocytes.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). PeriA that regulated by PeriA a stored neutral lipid and lipases in the and an of lipolysis in the C. Sztalryd C. Tansey J.T. Kimmel A.R. Role of PAT proteins in lipid metabolism.Biochimie. 2005; 87: 45-49Crossref PubMed Scopus (220) Google Scholar, 7Martinez-Botas J. Andreson J. Tessler D. Lapillojnne A. Hung-Junn Chang B. Quast M. Gorenstein D. Chen K-H. Chan L. Absence of perilipin results in leanness and reverses obesity in Leprdb/db mice.Nat. Genet. 2000; 26: 474-479Crossref PubMed Scopus (495) Google Scholar, 8Tansey J.T. Sztalryd C. Gruia-Gray J. Roush D. Zeo J. Gavrilova O. Reitman M. Deng C-X. Ki C. Kimmel A. et al.Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity.Proc. Natl. Acad. Sci. USA. 2001; 98: 6494-6499Crossref PubMed Scopus (609) Google Scholar, 10Miyoshi H. Souza S.C. Zhang H.H. Strissel K.J. Christoffolete M.A. Kovsan J. Rudich A. Kraemer F.B. Bianco A.C. Obin M.S. et al.Perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms.J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, D.L. perilipin of lipid of lipid droplets and of Full Text Full Text PDF PubMed Scopus Google Scholar). human and perilipin expression and lipid and glucose Y. M. Y. Greenberg A.S. Perilipin expression in human adipose effects of obesity, and PubMed Scopus Google Scholar, M. P. G. J. I. P. for an important role of perilipin in the regulation of human adipocyte PubMed Scopus Google Scholar, Souza S.C. M. Obin M.S. Greenberg A.S. regulation of and of and regulation of lipogenic and oxidative Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, J. A. M. C. A. et is associated with lipid droplets and insulin in Natl. Acad. Sci. USA. 2008; PubMed Scopus Google Scholar). perilipin null mice exhibit lipolysis and metabolism and diet-induced obesity J. Andreson J. Tessler D. Lapillojnne A. Hung-Junn Chang B. Quast M. Gorenstein D. Chen K-H. Chan L. Absence of perilipin results in leanness and reverses obesity in Leprdb/db mice.Nat. Genet. 2000; 26: 474-479Crossref PubMed Scopus (495) Google Scholar, 8Tansey J.T. Sztalryd C. Gruia-Gray J. Roush D. Zeo J. Gavrilova O. Reitman M. Deng C-X. Ki C. Kimmel A. et al.Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity.Proc. Natl. Acad. Sci. USA. 2001; 98: 6494-6499Crossref PubMed Scopus (609) Google Scholar). In we generated of transgenic mice in which or was overexpressed in adipose tissue to for the the metabolic and physiological consequences of PeriA PeriA mice and were on both a chow and challenged by an for When fed a chow and mice body although we of adipose in mice. challenged with an HFD, both of mice lower body weight, adipocyte and adipose with expression that the resistance to HFD-induced obesity in PeriA mice is an of oxidative genes in to a in on enhanced oxidative in is to the to diet-induced obesity, brown fat to obesity in mice A. brown fat to diet-induced obesity, diabetes, and PubMed Scopus Google Scholar). with a mice exhibited improved glucose tolerance and insulin than the of a of Y. M. K. J. K. I. K. et of an in PubMed Scopus Google Scholar, C. C. H. adipocyte size and expression and PubMed Scopus Google Scholar, Y. M. M. M. et of and of and metabolic Med. PubMed Scopus Google may to the effects of PeriA overexpression on glucose perilipin overexpression increased oxidative expression in is by which perilipin overexpression in increases oxidative expression is in that perilipin is in the regulation of basal and catecholamine-stimulated lipolysis. In both of overexpression of perilipin reduced catecholamine-stimulated lipolysis. using 3T3-L1 that in overexpression of either or for PeriA thereby the of lipolysis the mice reduced lipolysis with is and the of PeriA overexpression in to the lean and the of reduced body and and improved glucose tolerance was in the female mice both transgenic by that PeriA protein were significantly in adipose tissue of than Y. M. Y. Greenberg A.S. Perilipin expression in human adipose effects of obesity, and PubMed Scopus Google Scholar, M. P. G. J. I. P. for an important role of perilipin in the regulation of human adipocyte PubMed Scopus Google Scholar). In that a perilipin was a for obesity risk and that to the effects of perilipin than L. H. I. E.J. Greenberg A.S. D. of a perilipin with obesity risk in a PubMed Scopus Google Scholar). we that perilipin expression is in mice with and is associated with and reduced adipose tissue mass, a in PeriA mice Souza S.C. M. Obin M.S. Greenberg A.S. regulation of and of and regulation of lipogenic and oxidative Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). In that expression of the in a with expression of the for the the of mice is may the in and mouse PeriA A.S. Egan J.J. Wek S.A. Londos C. Kimmel A.R. of for A and and expression of lipid proteins of Natl. Acad. Sci. USA. PubMed Scopus Google Scholar, J. Y. and of the human of a adipose by 1998; PubMed Scopus Google Scholar). to the and in and for and the for in and the for of for of mice adipose triacylglycerol lipase the brown adipose tissue protein glucose tolerance high-fat human perilipin A hormone-sensitive lipase insulin tolerance mouse perilipin A chow perilipin A protein A transgenic adipose tissue