title: Pregnancy in obese mice protects selectively against visceral adiposity and is associated with increased adipocyte estrogen signalling.
abstract: Maternal obesity is linked with increased adverse pregnancy outcomes for both mother and child. The metabolic impact of excessive fat within the context of pregnancy is not fully understood. We used a mouse model of high fat (HF) feeding to induce maternal obesity to identify adipose tissue-mediated mechanisms driving metabolic dysfunction in pregnant and non-pregnant obese mice. As expected, chronic HF-feeding for 12 weeks preceding pregnancy increased peripheral (subcutaneous) and visceral (mesenteric) fat mass. However, unexpectedly at late gestation (E18.5) HF-fed mice exhibited a remarkable normalization of visceral but not peripheral adiposity, with a 53% reduction in non-pregnant visceral fat mass expressed as a proportion of body weight (P<0.001). In contrast, in control animals, pregnancy had no effect on visceral fat mass proportion. Obesity exaggerated glucose intolerance at mid-pregnancy (E14.5). However by E18.5, there were no differences, in glucose tolerance between obese and control mice. Transcriptomic analysis of visceral fat from HF-fed dams at E18.5 revealed reduced expression of genes involved in de novo lipogenesis (diacylglycerol O-acyltransferase 2--Dgat2) and inflammation (chemokine C-C motif ligand 20--Ccl2) and upregulation of estrogen receptor α (ERα) compared to HF non pregnant. Attenuation of adipose inflammation was functionally confirmed by a 45% reduction of CD11b+CD11c+ adipose tissue macrophages (expressed as a proportion of all stromal vascular fraction cells) in HF pregnant compared to HF non pregnant animals (P<0.001). An ERα selective agonist suppressed both de novo lipogenesis and expression of lipogenic genes in adipocytes in vitro. These data show that, in a HF model of maternal obesity, late gestation is associated with amelioration of visceral fat hypertrophy, inflammation and glucose intolerance, and suggest that these effects are mediated in part by elevated visceral adipocyte ERα signaling.
authors.affiliation: Tommy's Centre for Maternal and Fetal Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom; MRC Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Silvia M A
authors.initials: SM
authors.lastname: Pedroni
authors.affiliation: Endocrinology Unit, University/BHF Centre for Cardiovascular Science, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Sophie
authors.initials: S
authors.lastname: Turban
authors.affiliation: Endocrinology Unit, University/BHF Centre for Cardiovascular Science, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Tiina
authors.initials: T
authors.lastname: Kipari
authors.affiliation: Endocrinology Unit, University/BHF Centre for Cardiovascular Science, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Dunbar
authors.affiliation: Endocrinology Unit, University/BHF Centre for Cardiovascular Science, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Kerry
authors.initials: K
authors.lastname: McInnes
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Philippa T K
authors.initials: PT
authors.lastname: Saunders
authors.affiliation: Molecular Metabolism Group, University/BHF Centre for Cardiovascular Science, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Morton
authors.affiliation: Tommy's Centre for Maternal and Fetal Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom; MRC Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Norman
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D050154:Adiposity; D000818:Animals; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011270:Pregnancy, Animal; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D059467:Transcriptome
chemical_list: D004967:Estrogens; D011960:Receptors, Estrogen; D005947:Glucose
references.citation: Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12729-34
references.pmid: 11070086
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):11073-8
references.pmid: 9380761
references.citation: Diabetes Obes Metab. 2012 Jan;14(1):58-66
references.pmid: 21834845
references.citation: Am J Physiol Endocrinol Metab. 2002 Mar;282(3):E522-33
references.pmid: 11832353
references.citation: Proc Nutr Soc. 2011 Nov;70(4):450-6
references.pmid: 21880162
references.citation: Diabetes. 1999 Sep;48(9):1807-14
references.pmid: 10480612
references.citation: Curr Diabetes Rev. 2006 Nov;2(4):367-73
references.pmid: 18220642
references.citation: J Dairy Sci. 2011 Sep;94(9):4514-23
references.pmid: 21854923
references.citation: Endocrinology. 2011 Nov;152(11):4094-105
references.pmid: 21914778
references.citation: Diabetes Care. 2007 Jul;30 Suppl 2:S112-9
references.pmid: 17596458
references.citation: J Endocrinol. 1974 Jul;62(1):101-7
references.pmid: 4853889
references.citation: N Engl J Med. 2008 May 8;358(19):1991-2002
references.pmid: 18463375
references.citation: Int J Mol Med. 2013 Sep;32(3):723-8
references.pmid: 23857051
references.citation: Am J Physiol Endocrinol Metab. 2012 Oct 1;303(7):E832-40
references.pmid: 22811467
references.citation: Endocrinology. 2011 Nov;152(11):4443-7
references.pmid: 21933867
references.citation: Int J Obes Relat Metab Disord. 2003 Sep;27(9):1020-7
references.pmid: 12917706
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2012 Apr;86(4-5):167-74
references.pmid: 22444486
references.citation: Cell Death Differ. 2003 Sep;10(9):1025-31
references.pmid: 12934077
references.citation: Endocrine. 2003 Apr;20(3):239-45
references.pmid: 12721502
references.citation: Obesity (Silver Spring). 2013 Jan;21(1):E124-30
references.pmid: 23505192
references.citation: Placenta. 2011 Mar;32(3):247-54
references.pmid: 21232790
references.citation: Nature. 2005 Jul 21;436(7049):356-62
references.pmid: 16034410
references.citation: Mol Endocrinol. 2006 Jun;20(6):1287-99
references.pmid: 16627594
references.citation: Am J Physiol Endocrinol Metab. 2010 Feb;298(2):E304-19
references.pmid: 19920214
references.citation: Obesity (Silver Spring). 2008 Nov;16(11):2393-9
references.pmid: 18719660
references.citation: Endocr Rev. 2006 Oct;27(6):575-605
references.pmid: 16763155
references.citation: Am J Obstet Gynecol. 2011 Jun;204(6):558.e1-6
references.pmid: 21752757
references.citation: Diabetologia. 2006 Mar;49(3):588-97
references.pmid: 16463047
references.citation: Am J Obstet Gynecol. 1999 Apr;180(4):903-16
references.pmid: 10203659
references.citation: Am J Physiol Endocrinol Metab. 2008 Oct;295(4):E904-12
references.pmid: 18697913
references.citation: J Biol Chem. 2000 Apr 14;275(15):11404-11
references.pmid: 10753956
references.citation: FASEB J. 2009 Jan;23(1):271-8
references.pmid: 18827021
references.citation: Am J Physiol. 1993 Jan;264(1 Pt 1):E60-7
references.pmid: 8430789
references.citation: Endocrinology. 2013 Jul;154(7):2514-24
references.pmid: 23696566
references.citation: J Mol Endocrinol. 2011 Aug 30;47(2):157-65
references.pmid: 21697073
references.citation: Diabetologia. 2007 Dec;50(12):2526-33
references.pmid: 17879081