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Endocrine
Published in: Endocrine 3/2016

Open Access 01-06-2016 | Original Article

Increased diet-induced fatty streak formation in female mice with deficiency of liver-derived insulin-like growth factor-I

Authors: Johan Svensson, Klara Sjögren, Malin Levin, Jan Borén, Åsa Tivesten, Claes Ohlsson

Published in: Endocrine | Issue 3/2016

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Abstract

The role of endocrine IGF-I for atherosclerosis is unclear. We determined the importance of circulating, liver-derived IGF-I for fatty streak formation in mice. Mice with adult, liver-specific IGF-I inactivation (LI-IGF-I−/− mice, serum IGF-I reduced by approximately 80 %) and control mice received an atherogenic (modified Paigen) diet between 6 and 12 months of age. At study end, Oil Red O staining of aortic root cryosections showed increased fatty streak area and lipid deposition in female but not in male LI-IGF-I−/− mice compared to controls. Mac-2 staining of aortic root and measurements of CD68 mRNA level in femoral artery revealed increased macrophage accumulation in proportion to the increased fatty streak area in female LI-IGF-I−/− mice. Moreover, female LI-IGF-I−/− mice displayed increased serum cholesterol and interleukin-6 as well as increased vascular cell-adhesion molecule 1 (VCAM1) mRNA levels in the femoral artery and elevated VCAM1 protein expression in the aortic root. Thus, increased diet-induced fatty streak formation in female LI-IGF-I−/− mice was associated with increased serum cholesterol and signs of systemic inflammation, endothelial activation, lipid deposition, and macrophage infiltration in the vascular wall.
Literature
1.
C. Ohlsson, S. Mohan, K. Sjögren, A. Tivesten, J. Isgaard, O. Isaksson, J. Jansson, J. Svensson, The role of liver-derived insulin-like growth factor-I. Endocr. Rev. 30, 494–535 (2009)CrossRefPubMedPubMedCentral
2.
K. Sjögren, J. Liu, K. Blad, S. Skrtic, O. Vidal, V. Wallenius, D. LeRoith, J. Törnell, O. Isaksson, J. Jansson, C. Ohlsson, Liver-derived insulin-like growth factor I (IGF-I) is the principle source of IGF-I in blood but is not required for postnatal body growth in mice. Proc. Natl. Acad. Sci. USA 96, 7088–7092 (1999)CrossRefPubMedPubMedCentral
3.
S. Yakar, J. Liu, B. Stannard, A. Butler, D. Accili, B. Sauer, D. LeRoith, Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc. Natl. Acad. Sci. USA 96, 7324–7329 (1999)CrossRefPubMedPubMedCentral
4.
A. Schut, J. Janssen, J. Deinum, J. Vergeer, A. Hofman, S. Lamberts, B. Oostra, H. Pols, J. Witteman, C. van Duijn, Polymorphism in the promoter region of the insulin-like growth factor I gene is related to carotid intima-media thickness and aortic pulse wave velocity in subjects with hypertension. Stroke 34, 1623–1627 (2003)CrossRefPubMed
5.
G. Sesti, G. Mannino, F. Andreozzi, A. Greco, M. Perticone, A. Sciacqua, M. Marini, F. Perticone, A polymorphism at IGF1 locus is associated with carotid intima media thickness and endothelium-dependent vasodilatation. Atherosclerosis 232, 25–30 (2014)CrossRefPubMed
6.
T. Rosén, B.-Å. Bengtsson, Premature mortality due to cardiovascular diseases in hypopituitarism. Lancet 336, 285–288 (1990)CrossRefPubMed
7.
J. Tomlinson, N. Holden, R. Hills, K. Wheatley, R. Clayton, A. Bates, M. Sheppard, P. Stewart, West Midlands Prospective Hypopituitary Study Group, Association between premature mortality and hypopituitarism. Lancet 357, 425–431 (2001)CrossRefPubMed
8.
J. Svensson, B.-Å. Bengtsson, T. Rosén, A. Odén, G. Johannsson, Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. J. Clin. Endocrinol. Metab. 89, 3306–3312 (2004)CrossRefPubMed
9.
A. Juul, T. Scheike, M. Davidsen, J. Gyllenborg, T. Jorgensen, Low serum insulin-like growth factor-I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation 106, 939–944 (2002)CrossRefPubMed
10.
R. Vasan, L. Sullivan, R. D’Agostino, R. Roubenoff, T. Harris, D. Sawyer, D. Levy, P. Wilson, Serum insulin-like growth factor I and risk for heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart Study. Ann. Intern. Med. 139, 642–648 (2003)CrossRefPubMed
11.
A. Burgers, N. Biermasz, J. Schoones, A. Pereira, A. Renehan, M. Zwahlen, M. Egger, O. Dekkers, Meta-analysis and dose-response metaregression: circulating insulin-like growth factor I (igf-I) and mortality. J. Clin. Endocrinol. Metab. 96, 2912–2920 (2011)CrossRefPubMed
12.
J. Svensson, D. Carlzon, M. Petzold, M. Karlsson, O. Ljunggren, A. Tivesten, D. Mellström, C. Ohlsson, Both low and high serum IGF-I levels associate with cancer mortality in older men. J. Clin. Endocrinol. Metab. 97, 4623–4630 (2012)CrossRefPubMed
13.
D. Carlzon, J. Svensson, M. Petzold, M. Karlsson, O. Ljunggren, A. Tivesten, D. Mellström, C. Ohlsson, Both low and high serum insulin-like growth factor-I levels associate with increased risk of cardiovascular events in elderly men. J. Clin. Endocrinol. Metab. 99, E2308–E2316 (2014)CrossRefPubMedPubMedCentral
14.
M. Arcopinto, J. Isgaard, A. Marra, P. Formisano, E. Bossone, O. Vriz, C. Vigorito, L. Saccà, P. Douglas, A. Cittadini, IGF-1 predicts survival in chronic heart failure. Insights from the T.O.S.CA. (Trattamento Ormonale Nello Scompenso CArdiaco) registry. Int. J. Cardiol. 176, 1006–1008 (2014)CrossRefPubMed
15.
16.
S. Harrington, R. Simari, C. Conover, Genetic deletion of pregnancy-associated plasma protein-A is associated with resistance to atherosclerotic lesion development in apolipoprotein E-deficient mice challenged with a high-fat diet. Circ. Res. 100, 1696–1702 (2007)CrossRefPubMed
17.
H. Hirai, R. Kanaya, M. Maeda, D. Qungfang, K. Ina, T. Hayashi, The role of insulin growth factor on atherosclerosis and endothelial function: the effect on hyperlipidemia and aging. Life Sci. 88, 425–431 (2011)CrossRefPubMed
18.
B. Cercek, M. Fishbein, J. Forrester, R. Helfant, J. Fagin, Induction of insulin-like growth factor I messenger RNA in rat aorta after balloon denudation. Circ. Res. 66, 1755–1760 (1990)CrossRefPubMed
19.
L. Maile, B. Capps, Y. Ling, G. Xi, D. Clemmons, Hyperglycemia alters the responsiveness of smooth muscle cells to insulin-like growth factor-I. Endocrinology 148, 2435–2443 (2007)CrossRefPubMed
20.
J. von der Thüsen, K. Borensztajn, S. Moimas, S. van Heiningen, P. Teeling, T. van Berkel, E. Biessen, IGF-1 has plaque-stabilizing effects in atherosclerosis by altering vascular smooth muscle cell phenotype. Am. J. Pathol. 178, 924–934 (2011)CrossRefPubMedPubMedCentral
21.
S. Shai, S. Sukhanov, Y. Higashi, C. Vaughn, J. Kelly, P. Delafontaine, Smooth muscle cell-specific insulin-like growth factor-1 overexpression in Apoe−/− mice does not alter atherosclerotic plaque burden but increases features of plaque stability. Arterioscler. Thromb. Vasc. Biol. 30, 1916–1924 (2010)CrossRefPubMedPubMedCentral
22.
S. Sukhanov, Y. Higashi, S. Shai, C. Vaughn, J. Mohler, Y. Li, Y. Song, J. Titterington, P. Delafontaine, IGF-1 reduces inflammatory responses, suppresses oxidative stress, and decreases atherosclerosis progression in ApoE-deficient mice. Arterioscler. Thromb. Vasc. Biol. 27, 2684–2690 (2007)CrossRefPubMed
23.
S. Sukhanov, Y. Higashi, S.-Y. Shai, C. Blackstock, S. Galvez, C. Vaughn, J. Titterington, P. Delafontaine, Differential requirement for nitric oxide in IGF-1-induced anti-apoptotic, anti-oxidant and anti-atherosclerotic effects. FEBS Lett. 585, 3065–3072 (2011)CrossRefPubMedPubMedCentral
24.
S. Shai, S. Sukhanov, Y. Higashi, C. Vaughn, C. Rosen, P. Delafontaine, Low circulating insulin-like growth factor I increases atherosclerosis in ApoE-deficient mice. Am. J. Physiol. Heart Circ. Physiol. 300, H1898–H1906 (2011)CrossRefPubMedPubMedCentral
25.
Y. Higashi, A. Pandey, B. Goodwin, P. Delafontaine, Insulin-like growth factor-1 regulates glutathione peroxidase expression and activity in vascular endothelial cells: implications for atheroprotective actions of insulin-like growth factor-1. Biochim. Biophys. Acta 1832, 391–399 (2013)CrossRefPubMedPubMedCentral
26.
J. Liu, A. Grinberg, H. Westphal, B. Sauer, D. Accili, M. Karas, D. LeRoith, Insulin-like growth factor-I affects perinatal lethality and postnatal development in a gene dosage-dependent manner: manipulation using the Cre/loxP system in transgenic mice. Mol. Endocrinol. 12, 1452–1462 (1998)CrossRefPubMed
27.
R. Kuhn, F. Schwenk, M. Aguet, K. Rajewsky, Inducible gene targeting in mice. Science 269, 1427–1429 (1995)CrossRefPubMed
28.
B. Paigen, A. Morrow, C. Brandon, D. Mitchell, P. Holmes, Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis 57, 65–73 (1985)CrossRefPubMed
29.
K. Sjögren, K. Wallenius, J. Liu, M. Bohlooly-Y, G. Pacini, L. Svensson, J. Tornell, O. Isaksson, B. Ahren, J. Jansson, C. Ohlsson, Liver-derived IGF-I is of importance for normal carbohydrate and lipid metabolism. Diabetes 50, 1539–1545 (2001)CrossRefPubMed
30.
K. Wallenius, K. Sjögren, X. Peng, S. Park, V. Wallenius, J. Liu, M. Umaerus, H. Wennbo, O. Isaksson, L. Frohman, R. Kineman, C. Ohlsson, J. Jansson, Liver-derived IGF-I regulates GH secretion at the pituitary level in mice. Endocrinology 142, 4762–4770 (2001)CrossRefPubMed
31.
K. Sjögren, M. Sheng, S. Moverare, J. Liu, K. Wallenius, J. Tornell, O. Isaksson, J. Jansson, S. Mohan, C. Ohlsson, Effects of liver-derived insulin-like growth factor I on bone metabolism in mice. J. Bone Miner. Res. 17, 1977–1987 (2002)CrossRefPubMed
32.
A. Tivesten, E. Bollano, I. Andersson, S. Fitzgerald, K. Caidahl, K. Sjogren, O. Skott, J. Liu, R. Mobini, O. Isaksson, J. Jansson, C. Ohlsson, G. Bergstrom, J. Isgaard, Liver-derived insulin-like growth factor-I is involved in the regulation of blood pressure in mice. Endocrinology 143, 4235–4242 (2002)CrossRefPubMed
33.
J. Svensson, B. Söderpalm, K. Sjögren, J. Engel, C. Ohlsson, Liver-derived IGF-I regulates exploratory activity in old mice. Am. J. Physiol. Endocrinol. Metab. 289, E466–E473 (2005)CrossRefPubMed
34.
M. Lindberg, J. Svensson, K. Venken, T. Chavoshi, N. Andersson, S. Movérare Skrtic, O. Isaksson, D. Vanderschueren, H. Carlsten, C. Ohlsson, Liver-derived IGF-I is permissive for ovariectomy-induced trabecular bone loss. Bone 38, 85–92 (2006)CrossRefPubMed
35.
J. Svensson, M. Diez, J. Engel, C. Wass, Å. Tivesten, J. Jansson, O. Isaksson, T. Archer, T. Hökfelt, C. Ohlsson, Endocrine, liver-derived IGF-I is of importance for spatial learning and memory in old mice. J. Endocrinol. 189, 617–627 (2006)CrossRefPubMed
36.
J. Svensson, Å. Tivesten, K. Sjögren, O. Isaksson, G. Bergström, S. Mohan, J. Mölne, J. Isgaard, C. Ohlsson, Liver-derived IGF-I regulates kidney size, sodium reabsorption, and renal IGF-II expression. J. Endocrinol. 193, 359–366 (2007)CrossRefPubMed
37.
J. Svensson, J. Kindblom, R. Shao, S. Movérare-Skrtic, M. Lagerquist, N. Andersson, K. Sjögren, K. Venken, D. Vanderschueren, J.-O. Jansson, O. Isaksson, C. Ohlsson, Liver-derived IGF-I enhances the androgenic response in prostate. J. Endocrinol. 199, 489–497 (2008)CrossRefPubMed
38.
J. Svensson, K. Sjögren, J. Fäldt, N. Andersson, O. Isaksson, J. Jansson, C. Ohlsson, Liver-derived igf-I regulates mean life span in mice. PLoS One 6, e22640 (2011)CrossRefPubMedPubMedCentral
39.
M. Scharin Täng, B. Redfors, M. Lindbom, J. Svensson, T. Ramunddal, C. Ohlsson, Y. Shao, E. Omerovic, Importance of circulating IGF-1 for normal cardiac morphology, function and post infarction remodeling. Growth Horm. IGF Res. 22, 206–211 (2012)CrossRefPubMed
40.
B. Iresjö, J. Svensson, C. Ohlsson, K. Lundholm, Liver-derived endocrine IGF-I is not critical for activation of skeletal muscle protein synthesis following oral feeding. BMC Physiol. 13, 7 (2013)CrossRefPubMedPubMedCentral
41.
S. Yakar, J.L. Liu, A.M. Fernandez, Y. Wu, A.V. Schally, J. Frystyk, S.D. Chernausek, W. Mejia, D. Le Roith, Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity. Diabetes 50, 1110–1118 (2001)CrossRefPubMed
42.
S. Yakar, J. Setser, H. Zhao, B. Stannard, M. Haluzik, V. Glatt, M. Bouxsein, J. Kopchick, D. LeRoith, Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1-deficient mice. J. Clin. Invest. 113, 96–105 (2004)CrossRefPubMedPubMedCentral
43.
M. Holzenberger, J. Dupont, B. Ducos, P. Leneuve, A. Geloen, P. Even, P. Cervera, Y. Le Bouc, IGF-I receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187 (2003)CrossRefPubMed
44.
G. Sesmilo, B. Biller, J. Llevadot, D. Hayden, G. Hanson, N. Rifai, A. Klibanski, Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial. Ann. Intern. Med. 133, 111–122 (2000)CrossRefPubMed
45.
W. Drake, S. Howell, J. Monson, S. Shalet, Optimizing gh therapy in adults and children. Endocr. Rev. 22, 425–450 (2001)CrossRefPubMed
46.
J. Svensson, J. Fowelin, K. Landin, B.-Å. Bengtsson, J.-O. Johansson, Effects of 7 years of GH-replacement therapy on insulin sensitivity in GH-deficient adults. J. Clin. Endocrinol. Metab. 87, 2121–2127 (2002)CrossRefPubMed
47.
K. Caidahl, S. Edén, B.-Å. Bengtsson, Cardiovascular and renal effects of growth hormone. Clin. Endocrinol. (Oxf.) 40, 393–400 (1994)CrossRef
48.
V. Markussis, S. Beshyah, C. Fisher, P. Sharp, A. Nicolaides, D. Johnston, Detection of premature atherosclerosis by high-resolution ultrasonography in symptom-free hypopituitary adults. Lancet 340, 1188–1192 (1992)CrossRefPubMed
49.
B. Capaldo, L. Patti, U. Oliviero, S. Longobardi, F. Pardo, F. Vitale, S. Fazio, F. Di Rella, B. Biondi, G. Lombardi, L. Sacca, Increased arterial intima-media thickness in childhood-onset growth hormone deficiency. J. Clin. Endocrinol. Metab. 82, 1378–1381 (1997)CrossRefPubMed
50.
B. Bülow, L. Hagmar, J. Eskilsson, E. Erfurth, Hypopituitary women have a high incidence of cardiovascular morbidity and an increased prevalence of cardiovascular risk factors. J. Clin. Endocrinol. Metab. 85, 574–584 (2000)PubMed
51.
B. Bülow, L. Hagmar, Z. Mikoczy, C. Nordström, E. Erfurth, Increased cerebrovascular mortality in patients with hypopituitarism. Clin. Endocrinol. (Oxf.) 46, 75–81 (1997)CrossRef
52.
E. Succurro, F. Andreozzi, A. Sciaqua, M. Hribal, F. Perticone, G. Sesti, Reciprocal association of plasma IGF-1 and interleukin-6 levels with cardiometabolic risk factors in nondiabetic subjects. Diabetes Care 31, 1886–1888 (2008)CrossRefPubMedPubMedCentral
53.
S. Yakar, E. Canalis, H. Sun, W. Mejia, Y. Kawashima, P. Nasser, H. Courtland, V. Williams, M. Bouxsein, C. Rosen, K. Jepsen, Serum IGF-1 determines skeletal strength by regulating subperiosteal expansion and trait interactions. J. Bone Miner. Res. 24, 1481–1492 (2009)CrossRefPubMedPubMedCentral
54.
I. Andersson, A. Ljungberg, L. Svensson, L. Gan, J. Oscarsson, G. Bergström, Increased atherosclerotic lesion area in apoE deficient mice overexpressing bovine growth hormone. Atherosclerosis 188, 331–340 (2006)CrossRefPubMed
Metadata
Title
Increased diet-induced fatty streak formation in female mice with deficiency of liver-derived insulin-like growth factor-I
Authors
Johan Svensson
Klara Sjögren
Malin Levin
Jan Borén
Åsa Tivesten
Claes Ohlsson
Publication date
01-06-2016
Publisher
Springer US
Published in
Endocrine / Issue 3/2016
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-015-0809-1

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