title: Effect of Leptin Replacement on PCSK9 in ob/ob Mice and Female Lipodystrophic Patients.
abstract: Leptin treatment has beneficial effects on plasma lipids in patients with lipodystrophy, but the underlying mechanism is unknown. Proprotein convertase subtilisin/kexin type 9 (PCSK9) decreases low-density lipoprotein (LDL) clearance, promotes hypercholesterolemia, and has recently emerged as a novel therapeutic target. To determine the effect of leptin on PCSK9, we treated male and female ob/ob mice with leptin for 4 days via sc osmotic pumps (∼24 μg/d). Leptin reduced body weight and food intake in all mice, but the effects of leptin on plasma PCSK9 and lipids differed markedly between the sexes. In male mice, leptin suppressed PCSK9 but had no effect on plasma triglycerides or cholesterol. In female mice, leptin suppressed plasma triglycerides and cholesterol but had no effect on plasma PCSK9. In parallel, we treated female lipodystrophic patients (8 females, ages 5-23 y) with sc metreleptin injections (∼4.4 mg/d) for 4-6 months. In this case, leptin reduced plasma PCSK9 by 26% (298 ± 109 vs 221 ± 102 ng/mL; n = 8; P = .008), and the change in PCSK9 was correlated with a decrease in LDL cholesterol (r(2) = 0.564, P = .03). In summary, in leptin-deficient ob/ob mice, the effects of leptin on PCSK9 and plasma lipids appeared to be independent of one another and strongly modified by sex. On the other hand, in lipodystrophic females, leptin treatment reduced plasma PCSK9 in parallel with LDL cholesterol.
authors.affiliation: Division of Endocrinology (A.E.L., M.E.H., J.M., S.B.B.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Diabetes, Endocrinology, and Obesity Branch (R.J.B., R.M.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Cardiology (S.D.d.F.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Levenson
authors.affiliation: Division of Endocrinology (A.E.L., M.E.H., J.M., S.B.B.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Diabetes, Endocrinology, and Obesity Branch (R.J.B., R.M.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Cardiology (S.D.d.F.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Haas
authors.affiliation: Division of Endocrinology (A.E.L., M.E.H., J.M., S.B.B.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Diabetes, Endocrinology, and Obesity Branch (R.J.B., R.M.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Cardiology (S.D.d.F.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Ji
authors.initials: J
authors.lastname: Miao
authors.affiliation: Division of Endocrinology (A.E.L., M.E.H., J.M., S.B.B.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Diabetes, Endocrinology, and Obesity Branch (R.J.B., R.M.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Cardiology (S.D.d.F.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Brown
authors.affiliation: Division of Endocrinology (A.E.L., M.E.H., J.M., S.B.B.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Diabetes, Endocrinology, and Obesity Branch (R.J.B., R.M.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Cardiology (S.D.d.F.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Sarah D
authors.initials: SD
authors.lastname: de Ferranti
authors.affiliation: Division of Endocrinology (A.E.L., M.E.H., J.M., S.B.B.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Diabetes, Endocrinology, and Obesity Branch (R.J.B., R.M.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Cardiology (S.D.d.F.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Ranganath
authors.initials: R
authors.lastname: Muniyappa
authors.affiliation: Division of Endocrinology (A.E.L., M.E.H., J.M., S.B.B.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Diabetes, Endocrinology, and Obesity Branch (R.J.B., R.M.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Department of Cardiology (S.D.d.F.), Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Sudha B
authors.initials: SB
authors.lastname: Biddinger
mesh_terms: D000293:Adolescent; D000818:Animals; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D008060:Lipodystrophy / Q000097:blood* / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008820:Mice, Obese; D009765:Obesity / Q000097:blood* / Q000503:physiopathology; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
chemical_list: D008078:Cholesterol, LDL; D020738:Leptin; D014280:Triglycerides; D002784:Cholesterol; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
references.citation: Science. 2009 Jul 3;325(5936):100-4
references.pmid: 19520913
references.citation: Blood Coagul Fibrinolysis. 2015 Jul;26(5):522-6
references.pmid: 25692523
references.citation: Arterioscler Thromb Vasc Biol. 2015 Jul;35(7):1589-96
references.pmid: 26023080
references.citation: Clin Pharmacol Ther. 2016 Jan;99(1):59-71
references.pmid: 26492546
references.citation: J Clin Invest. 2009 Apr;119(4):1029-41
references.pmid: 19273907
references.citation: J Biol Chem. 2004 Nov 26;279(48):50630-8
references.pmid: 15385538
references.citation: Nat Genet. 2003 Jun;34(2):154-6
references.pmid: 12730697
references.citation: Curr Cardiol Rep. 2006 Nov;8(6):452-9
references.pmid: 17059798
references.citation: J Clin Invest. 2002 Oct;110(8):1093-103
references.pmid: 12393845
references.citation: Metabolism. 1994 May;43(5):549-53
references.pmid: 8177042
references.citation: J Clin Invest. 2000 Jan;105(2):151-9
references.pmid: 10642593
references.citation: Am J Hum Genet. 2006 Mar;78(3):410-22
references.pmid: 16465619
references.citation: J Clin Invest. 2012 Apr;122(4):1262-70
references.pmid: 22426206
references.citation: Endocr Pract. 2011 Nov-Dec;17(6):922-32
references.pmid: 22068254
references.citation: J Biol Chem. 2004 Nov 19;279(47):48865-75
references.pmid: 15358785
references.citation: Protein Expr Purif. 1996 Dec;8(4):489-500
references.pmid: 8954898
references.citation: J Lipid Res. 2010 Jun;51(6):1486-95
references.pmid: 20048381
references.citation: J Lipid Res. 2008 Feb;49(2):399-409
references.pmid: 17921436
references.citation: Nature. 2002 Jan 17;415(6869):339-43
references.pmid: 11797013
references.citation: Am J Physiol. 1999 Sep;277(3 Pt 1):E417-22
references.pmid: 10484352
references.citation: Arterioscler Thromb Vasc Biol. 2014 Jan;34(1):8-16
references.pmid: 24158514
references.citation: Diabetes Care. 2001 Mar;24(3):539-48
references.pmid: 11289482
references.citation: Nat Med. 2015 Nov;21(11):1280-9
references.pmid: 26437365
references.citation: Diabetologia. 1976 Oct;12(5):501-9
references.pmid: 185113
references.citation: Diabetes Care. 2014 Apr;37(4):1101-7
references.pmid: 24496806
references.citation: Metabolism. 2007 Apr;56(4):508-16
references.pmid: 17379009
references.citation: J Clin Endocrinol Metab. 2010 Feb;95(2):800-9
references.pmid: 19965915
references.citation: JAMA. 1994 Jul 27;272(4):305-8
references.pmid: 8028144
references.citation: J Lipid Res. 2015 Nov;56(11):2133-42
references.pmid: 26323289
references.citation: J Biol Chem. 2009 Oct 16;284(42):28885-95
references.pmid: 19687008
references.citation: Nat Rev Endocrinol. 2015 Sep;11(9):522-34
references.pmid: 26239609
references.citation: Am J Physiol Endocrinol Metab. 2008 May;294(5):E817-26
references.pmid: 18334610
references.citation: Diabetes. 2005 Jul;54(7):1994-2002
references.pmid: 15983199
references.citation: N Engl J Med. 2006 Mar 23;354(12):1264-72
references.pmid: 16554528
references.citation: J Clin Endocrinol Metab. 2011 Nov;96(11):3313-25
references.pmid: 21865368
references.citation: Lipids Health Dis. 2008;7:22
references.pmid: 18547436
references.citation: J Clin Endocrinol Metab. 2009 Jul;94(7):2537-43
references.pmid: 19351729
references.citation: J Biol Chem. 2006 Mar 10;281(10):6211-8
references.pmid: 16407292
references.citation: J Biol Chem. 2001 Oct 5;276(40):37402-8
references.pmid: 11445560
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):928-33
references.pmid: 12552133
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11041-8
references.pmid: 10500120
references.citation: J Clin Endocrinol Metab. 2014 Sep;99(9):E1676-80
references.pmid: 24926953
references.citation: Curr Atheroscler Rep. 2014 Sep;16(9):437
references.pmid: 25047893
references.citation: J Clin Endocrinol Metab. 2015 May;100(5):1802-10
references.pmid: 25734254
references.citation: J Lipid Res. 2015 Feb;56(2):463-9
references.pmid: 25535288
references.citation: Metabolism. 2015 Jan;64(1):24-34
references.pmid: 25199978
references.citation: Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):810-4
references.pmid: 22207727
references.citation: J Biol Chem. 2003 Oct 31;278(44):43224-8
references.pmid: 12917427
references.citation: J Clin Invest. 2004 Feb;113(3):414-24
references.pmid: 14755338
references.citation: N Engl J Med. 2004 Mar 18;350(12):1220-34
references.pmid: 15028826
references.citation: Arterioscler Thromb Vasc Biol. 2004 Aug;24(8):1454-9
references.pmid: 15178557
references.citation: FEBS J. 2015 Jul;282(14):2682-96
references.pmid: 25913303
references.citation: J Clin Invest. 2002 May;109(10):1345-50
references.pmid: 12021250
references.citation: Diabetologia. 2010 Jan;53(1):27-35
references.pmid: 19727665