Nu fs 356 Before Midterm

• Central Dogma of Biology

  1. DNA
  2. Transcription
  3. RNA
  4. Translation
  5. Protein
• Nutrigenetics:

  Study of how genetic differences arising from polymorphisms modifies dietary effects

  
  

  Genes to Metabolism
• Genetic Variation:

  Single nucleotide polymorphisms: Snps
• SNPS examples:

  Sickle Cell Disease happens when T is switched to A resulting in Glutamic acid to Valine
• SNPs in response to diet (high fat)

  Sterol Response Element Binding Protein (SREBP-1c)

  ▪ gene that regulates lipid metabolism

  ▪ Snp + high fat diet

  ▪ overexpression associated with dyslipidemia, impaired glucose metabolism, Type-2 diabetes
• Response to diet pt 2:

  Apolipoprotein E4 (vs E1, E2, E3)

  ▪ regulates lipoprotein - cholesterol clearance from plasma

  ▪ApoE4 allele + high fat diet results in higher LDL levels (which is what we don't want)
• Body Composition SNPS

  Myostatin: hormone that inhibits muscle protein synthesis

  Whippets (racing dogs) have a MSTN gene variant mh(deletion)

  ▪ +/+ normal muscle and speed

  ▪ + /mh more muscle and faster speed

  ▪ mh /mh bulky muscle and slower
• SNPS Example: Prader-Willi Syndrome (PWS)

  ▪ chromosomal deletion with multiple genes affected (no code on one copy)

  ▪ hypothalamic dysfunction: growth hormone, hunger-satiety hormones, other endocrine

  ▪ short stature, lower lean mass, hyperphagia (lack of satiety), developmental delays

  ▪ failure-to-thrive in infancy

   food seeking in early childhood
• Summary Nutrigenetics

  ▪ genetic differences arising from polymorphisms can alter metabolism

  ▪ genetic polymorphisms can not be changed

  ▪ dietary modifications: amount of energy and nutrients, type of diets
• Nutrigenomics

  The application of nutrition to the entirety of gene expression: the interaction between diet and genes
• Nutrigenomics

  Study of how nutrition influences gene expression (on/off)

  Food to Gene Expression

  
  

  Change in phenotype without a change in genotype
• Epigenetics

  ▪ changes in gene expression (phenotype) caused by mechanisms other than changes in the underlying DNA

  ▪non-genetic factors cause the organism's genes to be expressed differently

  ▪ allows for adaptations to environment

  ▪changes remain through cell divisions

  “Metabolic Programming”
• Epigenetic Modifications Possible epigenetic modifications:

  ▪DNA methylation

  ▪ Chromatin modifications including modifications to histones by methylation, phosphorylation, acetylation, etc

  ▪ chromatin: mixture of DNA and proteins that form chromosomes

  ▪ histones are proteins that compact DNA and have a role in DNA regulation
• DNA methylation along with histone modifications = the epigenetic code and it is the epigenetic code that determines what genes are expressed
• DNA Methylation:

  DNA Methyltransferases

  Many histone modifications, by adding methyl groups
• DNA methylation turns genes off

  Which means that although they have the same DNA, a liver cell is a liver cell and brain cell a brain cell because they have different epigenetic codes
• Epigenetic Modifications happen all throughout life-environment - diet, alcohol, weather, drugs
• Insights from Identical Twins

  ■ Identical twins begin with the same genome + epigenome

  ■However, over time, life events and the environment change the epigenome

  ❑contributes to differing appearances and disease risk as the twins age
• How are genes affect us

  Starts at conception

  1. Fetal life
  2. Infancy childhood
  3. Adolescence
  4. Adults
  5. Risks based on behaviours, what they eat, how much stress
• Epigenetics Across the Lifespan

  ■ alterations to epigenetic patterns may contribute to diseases that are more common with age

  ■ epigenetics may also contribute to the process of aging itself

  ■ can epigenetic changes be reversed?

  ■ remains unknown; would be positive as this could change one’s disease risk
• Barker Hypothesis

  The environment encountered during fetal life and infancy appears to be strongly related to risk of chronic disease in adult life

  ■ the process through which a stimulus or insult during a critical window of development results in permanent responses that produce long-term changes in tissue structure or function

  Developmental Origins of Disease Hypothesis
• Thrifty Gene Hypothesis

  Alterations in organ structure or function as a result of this environment is permanent
• Study looked at mortality ratios on CVD below 60 years which isnt that common

  Shows that between men/women Strong association with birth weight, lowest means increased risk for mortality related to CVD
• Developmental Origins of Disease

  Intra-uterine growth is associated with increased risk of chronic disease

  Inadequate growth (SGA or LBW) increases risk of dyslipidemia, hypertension, glucose intolerance, CVD, type 2 diabetes, obesity

  Excessive growth (LGA) increases risk of:

  ▪ less well studied but evidence of dyslipidemia, hypertension, glucose intolerance, obesity

  Hypothesis: related to maternal nutritional status but inappropriate growth could be from other factors
• early influences that give late replies”

  What happened at conception to birth may not affect you until much later
• Dutch famine Low amounts of food during WWII

  • Calories were kept track of

  • Severe famine, seen in early 1945

  • Late - meaning late in pregnancy at the time of the famine

  -Grey boxes are when birth happens Based on this data

  Those that were born from LATE had glucose issues

  • But higher rate problems in LDL and CVD (chd=heard disease)

  • Kidney function affected - microalbuminia
• Limitations of Study

  1. Can’t ethically reproduce this study
  2. Not strictly controlled
  3. Pregnant women-maybe they got more food outside of allowed rations so we don’t know their exact intake
  4. Type of diet was different-very disrupted diet, so is it calories or nutritional component that caused this?
• Maternal Diet and Fetal Programming

  ■ Choline, methionine, vitamin B12 and folate are nutrients involved in methyl-group metabolism. Both deficiency or supplementation can alter DNA and histone methylation.

  ❑Choline deficiencies have been associated with irreversible changes in brain structure + function

  ■ Dutch famine was associated with changes in DNA methylation in genes related to growth

  ■ Low protein maternal diet associated with many changes in offspring (pancreatic islet cells, GLUT4 expression, adipose tissue, heart tissue, and leptin regulation)
• Choline is very important = forgotten nutrient, but needed for brain function
• Animal models - endothelial function - affects the movement of blood and effects of that

  Animals have a shorter life span which makes it easier to research changes as you age
• Animal Models Energy restriction in-utero changes in: ▪ liver and pancreatic cell differentiation (alterations in metabolism)

  ▪ distribution of muscle cell type and muscle cell glucose transport (insulin sensitivity)

  ▪ number of nephrons in kidney (fluid and electrolyte balance)

  ▪ endothelial function

  ▪ bone density
• Thrifty Phenotype Model

  1. Fetus
  2. Nutrients restricted
  3. growth slows = small baby
  4. Thrifty adaptation
• 1. Postnatal environment nutrient poor
  2. thrift is a survival advantage
• 1. Postnatal environment is nutrient rich
  2. Obesity and Metabolic syndrome
• Does the father’s diet impact the offspring’s health? ■ Yes, an association has been found in animal models

  ■ Males were put on a restrictive protein diet from weaning to puberty

  ❑ offspring had increased gene expression for cholesterol/lipid synthesis

  Emerging Research: Are the findings similar for humans?
• Summary Epigenetics

  ▪ Epigenetic modifications occur through-out life in response to multiple types of exposures

  ▪ Maternal dietary intake and nutritional status during pregnancy affects long term disease risk in offspring

  ▪ fetal adaptations in response to in utero environment

  ■ Epigenetic programming may help the fetus survive in utero, however it may be detrimental later in life if environment changes
• Human research has some challenges:

  ■mostly retrospective studies, emerging prospective studies and recent findings

  ■measuring exposures, ethics, establishing causation
• Challengesof Epigenetic Research

  ■ Extent of epigenetic modifications may differ depending on: animal species, sex, genotype, exposure, length of exposure and timing (adulthood vs. puberty vs. infant vs fetal development)

  ■ How much of epigenetic modification are transmitted to next generation; transmission across multiple generations

  ■ Relative contribution of epigenome and genome in chronic disease risk
• Females

   Born with immature ova (eggs)

   Starting at puberty – ova mature about every

  28 days (ovulation)

   Ova mature within follicles in the ovaries
• Males

   Born with sperm-producing systems

   Start producing sperm at puberty – ongoing,

  not cyclic