The Epigenetics of Obesity: Individual, Social, and Environmental Influences. K. J. Claycombe, Ph.D.

Transcription

1 The Epigenetics of Obesity: Individual, Social, and Environmental Influences K. J. Claycombe, Ph.D.

2 What can happen to our gene(s) that would cause obesity?

3 Modification via Epigenetic alterations

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9 Early life determinants of overweight and obesity Obesity Reviews, Monasta et al., 11 (10): , 2010

10 Early life determinants of overweight and obesity Environmental Environmental Environmental Individual Environmental Environmental Environmental Social Social Obesity Reviews, Monasta et al., 11 (10): , 2010

11 Early life determinants of overweight and obesity Environmental Obesity Reviews, Monasta et al., 11 (10): , 2010

12 Epigenetics Epigenetics is an inheritable changes that affects gene expression without DNA base pair sequence changes Examples of epigenetic phenomena - DNA methylation - histone modifications - chromatin remodeling

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15 What your grandparents ate could affect your health For example, when a paternal grandmother experienced drastic changes in food availability as a child, then granddaughters had an increased risk for cardiovascular mortality as an adult

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19 Cover, Science, August 15 th, 2014, Vol. 345

20 Do prenatal experiences shape culinary tastes? Pregnant volunteers consumed plain flavored or garlic capsules around 24 weeks of pregnancy Sniffed unlabeled bottles of amniotic fluid and breast milk Volunteers easily sniffed out which came from the garlic consumer

21 Babies born from two groups of volunteers who consumed plain flavored or garlic capsules Videotape images were generated when babies were given garlic milk

22 Other Supporting Evidence (Animal Study) FASEB Journal, 25(7): , 2011

23 Other supporting evidence (animal study) FASEB Journal, 25(7): , 2011 Pregnant Wistar rats standard rat chow Maintained on their respective diets throughout pregnancy and lactation After weaning, offspring were fed either control chow or junk diets for either 3 weeks and for 3 months

24 Conclusions: Mice whose mothers had a junk food diet developed altered development of the central reward system, resulting in increased fat intake and altered response of the reward system to excessive junkfood intake in postnatal life

25 Example of Basic Science Studies of Epigenetics

26 Obesity and Epigenetics of Adipose tissue (USDA ARS Research Program)

27 Large for Gest. Age Normal IUGR

28 LP fed dams and offspring Phenotyes hypertension (Langley-Evans et al, Clin Nutr 1994; 13: ) increased fat deposition and altered feeding behavior (Lucas et al., Br J Nutr 1996; 76: , Bellinger et al., Br J Nutr 2004; 92: , and Bellinger et al., Int J Obes (Lond) 2006; 30: ) impaired glucose homeostasis, dyslipidaemia (Burdge et al., Prostaglandins Leukot Essent Fatty Acids 2008; 78: 73 79) impaired immunity (Calder and Yaqoob, Nutr Res 2000; 20: ) increased susceptibility to oxidative stress (Langley-Evans and Sculley, Mech Ageing Dev 2005; 126: )

29 Intrauterine growth restriction and catch-up growth Maternal under nutrition Normal diet Low birth weight Normal weight Increased propensity for catch up growth Normal growth Sutton et al., Endocrinology 2010;151(4):

30 Maternal under nutrition Epigenetic Programming? Low birth weight High Fat diet Increased propensity for catch up growth

31 Animal model of obesity and epigenetics

32 Experimental Design FO F1 2 wk Gestation Lactation 20% protein 20% protein 20% protein Experimental Diet (12 wks) Normal Energy High Energy 2 wk Gestation Lactation 8 % protein 8 % protein 8 % protein Experimental Diet (12 wks) Normal Energy High Energy

33 2 wk Gestation Lactation 20% protein 20% protein 20% protein Experimental Diet (12 wks) Normal Energy High Energy 2 wk Gestation Lactation 8 % protein 8 % protein 8 % protein Experimental Diet (12 wks) Normal Energy High Energy Adaptive and compensatory programming

34 Body weight (g) Weight (g) 2 wk Gestation Lactation 20% protein 20% protein 20% protein Experimental Diet (12 wks) Normal Energy High Energy 8 % protein 8 % protein 8 % protein Normal Energy High Energy At Birth % 20% LP NE LP HE NP NE NP HE at weaning adipose lean BW

35 How to measure fat tissue changes over time in live animals? Magnetic Resonance Imaging (EchoMRI)

36 2 wk Gestation Lactation 20% protein FO 20% protein 20% protein F1 Experimental Diet (12 wks) Normal Energy High Energy Quantitate fat mass measurement by Echo MRI 2 wk Gestation Lactation 8 % protein 8 % protein 8 % protein Experimental Diet (12 wks) Normal Energy High Energy

37 Low Adipose Tissue Weight and Catch-up Growth 10 fold increase 2.5 fold increase

38 Adipose tissue mass fold increase Adipose tissue mass fold increase LP NE NP NE LP HE NP HE week 0 week 2 week 4 week 6 week 8 week 10 week Claycombe et al., accepted, J Nutr. 2013

39 Effects of prenatal and postnatal diet on imprinted gene expression?

40 Igf2/H19 Locus Insulin-like growth factor 2 (IGF2) was the first imprinted gene identified (Cell, 64: , 1991) IGF2 is a major fetal growth factor (Nature 417: , 2002) Epigenetics is an inheritable changes that affects gene expression without DNA base pair sequence changes (e.g. DNA methylation, histone modifications)

41 IGF-2 mrna Fold increase Effects of LP prenatal and HF postnatal diet on Adipose Tissue IGF2 mrna Expression LPNF NPNF LPHF NPHF Visceral Subcutaneous Claycombe et al., J Nutr. 2013

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43 IGF2 transcription activation Igf2 DMR2 promter CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 ICR H19 E

44 IGF2 transcription repression Igf2 DMR2 promter CTCF ICR H19 E

45 ICR/ H19 DMR Methylation in Adipose Tissue

46 Dnmt3a mrna Fold increase Effects of LP prenatal and HF postnatal diet on Adipose Tissue Dnmt3a mrna Expression LPNF LPHF NPNF NPHF 0 Visceral Subcutaneous

47 Is there metabolic phenotype associated with catch-up growth?

48 AUC Blood (mg/dl) Effects of LP prenatal and HF postnatal diet on GT LPNF LPHF NPNF NPHF b a.ba a b a a b a,b a,b a a ba min 15 min 30 min 60 min 120 min b ab a a LPNF NPNF LPHF NPHF Claycombe et al., J Nutr. 143(10): , 2013

49 Insulin (pg/ml) Effects of LP prenatal and HF postnatal diet on Plasma Insulin Concentrations Prenatal Postnatal Pre x Post P=0.28 P=0.005 P= LPNF NPNF LPHF NPHF Claycombe et al., J Nutr. 143(10): , 2013

50 Fold Increase Fold Increase Adipose Tissue Mitochondrial Copy Number 2 1 LP-NF NP-NF LP-HF NP-HF ANOVA Pre NS Post p=0.06 Pre x Post NS LP-NF LP-HF a,b NP-NF NP-HF a a,b b Visceral Subcutaneous

51 Effects of LP prenatal and HF postnatal diet on Adipose Tissue IGF2 mrna Expression

52 Adipose Tissue Growth and Regulators Normal Obesity

53 Adipose Tissue Growth and Regulators IGF2 IGF2 Normal Obesity

54 Adipose Tissue Growth and Regulators High Fat Diet + IGF2 IGF2 Normal Obesity

55 Adipose Tissue Growth and Regulators High Fat Diet Exercise + IGF2 IGF2 Normal Obesity

56 Maternal Conditions Developmental Influences of Maternal Diet and Exercise F1 Response High Fat Diet and Obesity Epigenetic Changes Decreased Numbers of Beige Adipocytes and Decreased Energy Utilization Promote Obesity and Insulin Resistance Modulators? Test of Maternal exercise (Human study)

57 Maternal LP Diet Endocrine cross talk Skeletal muscle SDH, SIRT3, mt respiration Adipose tissue IGF2 Brain and BAT UCP-1, PPAR-a Insulin Resistance

58 Other metabolic tissues?

59 Effects of LP prenatal diet on Muscle Metabolism and mt Function

60 Claycombe et al., Journal of nutritional biochemistry 26(2): , 2015

61 Effects of LP prenatal diet on Brown adipose tissue function

62 Claycombe et al., Journal of Nutritional Biochemistry 26(7): , 2015

63 Acknowledgment

64 Thank you