Sharmila Ahmad 1 , Lise K. Lyngman 1 , Rajan Dhakal 1 , Morteza Mansouryar 1 , Mohammad Moradi 3 , Prabhat Khanal 2 and Mette O. Nielsen 1 1 Section for Production, Nutrition and Health, Department of Veterinary and Animal Sciences (IVH), University of Copenhagen 2 Department of Nutrition, Lipid Droplets Research Group, Norwegian Transgenic Centre (NTS), University of Oslo 3 Department of Animal Science, Sari Agricultural Science and Natural Resources University (SANRU), Iran Impacts of prenatal malnutrition and an early obesogenic diet on adipose tissue morphology and gene expression in adult sheep
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Sharmila Ahmad1, Lise K. Lyngman1, Rajan Dhakal1,
Morteza Mansouryar1, Mohammad Moradi3, Prabhat
Khanal2 and Mette O. Nielsen1
1Section for Production, Nutrition and Health, Department of Veterinary and
Animal Sciences ( IVH), University of Copenhagen 2Department of Nutrition, Lipid Droplets Research Group, Norwegian
Transgenic Centre (NTS) , University of Oslo 3Department of Animal Science, Sari Agricultural Science and Natural Resources
University (SANRU), Iran
Impacts of prenatal malnutrition and an
early obesogenic diet on adipose tissue
morphology and gene expression in
adult sheep
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Introduction: Adipose tissue and metabolic disorders
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In obesity, adipose tissue expansion; 1.) Hypertrophic (increased adipocyte size) 2). Hyperplasic (increased adipocyte number) (Cheo et al., 2016)
• Adipose tissue- appear from mid gestation onwards (Symonds et al., 2012) • Sensitive to in utero nutritional insults (under- and overnutrition)~predisposed for
abdominal adiposity and metabolic disorders (Khanal et al., 2014) • Adipose tissue expansion occurs by two differents mechanisms
regulated by environmental and genetic factors but still uncertain how these two modes of adipose tissue expansion are controlled at the molecular level.
Objectives
• In the present study, we aimed to investigate whether;
1) phenotypic manifestations in adulthood of such a prenatal programming on adipose tissue structure and function al traits (gene expression) can be affected by the nutrition exposure in early postnatal life, and
2) whether dietary correction later in life can reverse the long-term consequences of early life malnutrition
3) whether mechanisms of expansion are affected?
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Materials and methods 15/11/2017 4
Late gestation (15 weeks)
NORM (100% energy and
protein)
CONV
(n=6)
HCHF
(n=4)
LOW (50% NORM)
CONV
(n=9)
HCHF
(n=7)
HIGH (150% energy and
110% protein)
CONV
(n=5)
HCHF
(n=6)
Adipose tissue histology (subcutaneous, mesenteric,
perirenal and epicardial
Visiopharm APP(adipose tissue) Gene expression:
Lipolysis (ATGL, CGI-58, FABP4, HSL, leptin, PLIN-1) Lipogenesis (LPL, FAS) Glucose metabolism (FBPase, GLUT-1) Insulin signaling (AdipoQ, GLUT-4) Cell differentiation/proliferation (CD34, CD44, GcR, IGF1R, PPARγ, TGF-β1) Angiogenesis (VEGF, VEGF-A) Inflammation (IL6, MCP-1, TLR-4)
Sheep: Cross breed Texel ewes Prenatal (late gestational) diet; NORM: Normal; LOW: Undernutrition; HIGH: Overnutrition Early postnatal; CONV: Conventional/ moderate (hay and milk replacer (only until 8 weeks)) HCHF; High-starch-high-fat (cream milk replacer mix in a 1:1 ratio supplemented with rolled maize)
6 months-21/2 years: All animals fed the
same moderate diet
Fed with high quality hay grass+ rolled barley (firsts month)
Dietary correction
Prenatal malnutrition
Early postnatal obesogenic
diet
Effect of ewe diet*lamb diet*sex on adipocytes size
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F M F M F M F M F M F M
CONV HCHF CONV HCHF CONV HCHF
NORM HIGH LOW
<200 6.16 7.06 8 8.78 6.49 6.06 7.98 6.48 6.83 5.86 7.09 6.49
<400 8.11 8.65 10.12 11.37 8.01 7.11 9.54 7.93 8.68 6.86 9.04 7.59
<800 12.26 12.16 14.66 15.69 12.27 10.63 13.12 11.72 13.25 10.4 13.11 11.14
<1600 18.24 17.41 19.64 18.84 19.32 15.59 18.3 17.1 21.36 16.97 17.96 16.5
<3200 27.64 29.54 27.1 21.76 34.67 28.34 26.96 28.65 36.55 31.75 26.12 26.3
<6400 14.37 23.85 16.11 18.44 18.18 29.21 18.16 23.63 13.83 23.9 21.3 24.29
<12800 4.49 1.01 3.49 6.97 2.19 1.62 4.68 4.11 1.3 3.33 3.79 5.82
<25600 8.51 0.39 0.56 1.2 0.46 0.8 0.94 0.16 0.37 0.71 0.55 0.77
<36000 0.002 0.05 0.08 0.003 0.01 0.06 0.09 0.01 0.07 0.13 0.16 0.08
-10
-5
0
5
10
15
20
25
30
35
40
45
Ad
ipo
cyte
s (
%)
Epicardial adipocytes size
<200
<400
<800
<1600
<3200
<6400
<12800
<25600
<36000
Subcutaneous adipose tissue 15/11/2017 10
NORM CONV: M
LOW CONV: M
HIGH CONV: M
NORM HCHF: M
LOW HCHF: M
HIGH HCHF: M
NORM CONV: F
LOW CONV: F
HIGH CONV: F
NORM HCHF: F
LOW HCHF: F
HIGH HCHF: F
Males Females
Subcutaneous adipose tissue
• Reduced hyperplasic growth
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Genes involved in adipogenesis and angiogenesis:
Prenatal x gender: Prenatal x postnatal:
(Adapted from Lise K. Lyngman’master thesis (2017))
Mesenteric adipose tissue 15/11/2017 12
NORM CONV: M
LOW CONV: M
NORM HCHF: M
LOW HCHF: M
NORM CONV: F
LOW CONV: F
NORM HCHF: F
LOW HCHF: F
HIGH CONV: M HIGH HCHF: F HIGH CONV: F HIGH HCHF: M
Males Females
Perirenal adipose tissue
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NORM CONV: M
LOW CONV: M
NORM HCHF: M
LOW HCHF: M
NORM CONV: F
LOW CONV: F
NORM HCHF: F
LOW HCHF: F
HIGH CONV: M HIGH HCHF: F HIGH CONV: F HIGH HCHF: M
Males Females
Perirenal adipose tissue • The HIGH-HCHF and LOW-HCHF groups showed distinct fat
deposition patterns
• These groups do not stand out in terms of gene expression
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(Adapted from Lise K. Lyngman’master thesis (2017))
Epicardial adipose tissue 15/11/2017 17
NORM CONV: M
LOW CONV: M
NORM HCHF: M
LOW HCHF: M
NORM CONV: F
LOW CONV: F
NORM HCHF: F
LOW HCHF: F
HIGH CONV: M HIGH HCHF: F HIGH CONV: F HIGH HCHF: M
Males Females
Epicardial adipose tissue • Targeted by postnatal diet
• Genes lipid metabolism (lipid synthesis and breakdown) and adipogenesis- up-regulated (HCHF groups)
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(Adapted from Lise K. Lyngman’master thesis (2017))
Conclusion • Subcutaneous and perirenal, but not mesenteric and epicardial adipose tissues
were targets of fetal programming with long-term implications for structure and gene expression, which were expressed in LOW irrespective of the postnatal diet, but surprisingly in HIGH mostly upon exposure to the mismatching CONV diet.
• Implications of early obesity development were not reversed by dietary correction later in life, and were expressed mostly in epicardial tissue.
• Pre- and/or early postnatal malnutrition predisposes for (presumably less healthy) hypertrophic rather than hyperplasic growth, and males appeared to attain a more female-like phenotype upon exposure to malnutrition in early life.
• Structural changes in particularly mesenteric and perirenal adipose tissue could not be explained by altered expression of the studied genes, and other mechanisms must be involved.
• Fetal programming is ”heritable” – programmed animals should not enter reproduction
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Funded by Danish Council for Strategic Research (grants 09-059921 and 09-067124)
References
• Symonds ME, Pope M, Sharkey D, Budge H. Adipose tissue and fetal programming. Diabetologia. 2012 Jun 1;55(6):1597-606.
• Khanal P, Axel AM, Johnsen L, Hansen P, Kongsted AH, Lyckegaard NB, Nielsen MO. Long-term consequences of late gestation malnutrition and an early postnatal high-fat diet on growth characteristics and metabolic adaptabilities in adult sheep. In2nd Copenhagen Symposium on Fetal Programming 2014.
• Choe SS, Huh JY, Hwang IJ, Kim JI, Kim JB. Adipose tissue remodeling: its role in energy metabolism and metabolic disorders. Frontiers in endocrinology. 2016;7.
Thanks:
• Jørgen Agerholm
• Heidi
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