Genetics, Epigenetics & Environmental Causes of Obesity (Monash University) PDF

MONASH BIOMEDICINE DISCOVERY INSTITUTE Genetics, Epigenetics and Environmental Causes of Obesity Part 2 Dr Christine Lee Department of Physiology cm.christine.lee...

MONASH BIOMEDICINE DISCOVERY INSTITUTE Genetics, Epigenetics and Environmental Causes of Obesity Part 2 Dr Christine Lee Department of Physiology [email protected] Learning Overview 1. Genetics Gene x environment interaction Single gene mutations – leptin and the melanocortin system Set-point regulation of body weight 2. Epigenetics Maternal obesity 3. Environmental causes Endocrine disruptors and obesity Learning Overview 1. Genetics Gene x environment interaction Single gene mutations – leptin and the melanocortin system Set-point regulation of body weight 2. Epigenetics Maternal obesity 3. Environmental causes Endocrine disruptors and obesity Epigenetics Epigenetic regulation of gene expression Epigenetics – “upon the genome” – the study of heritable phenotype changes caused by modification of gene expression rather than alteration of the genetic code itself. Epigenetics Epigenetic regulation of gene expression Epigenetics stands at the centre of modern medicine because epigenetic changes, unlike DNA sequence which is the same in every cell, can occur as a result of environmental triggers. Epigenetics regulates the functional aspects of genes. Epigenetics Epigenetic regulation of gene expression The epigenome is particularly susceptible to environmental influences at certain life stages, especially the early stages. Epigenetics Maternal obesity Chen, et al. (2008) Endocrinology 149: 5348 –5356 Epigenetics Maternal obesity Offspring from a high fat-fed mother show increased preferences for sucrose and high fat diet as compared to controls. Dopamine and opioid gene expression, measured using quantitative real-time PCR, revealed a significant up-regulation of dopamine reuptake transporter and increased expression of the opioid receptor in the reward circuitry. Vucetic, et al. (2010) Endocrinology 151: 4756-64 Epigenetics Maternal obesity Offspring from a high fat-fed mother show DNA hypomethylation in areas of the reward circuitry and hypothalamus. These data demonstrate that maternal consumption of a HF diet can change the offspring's epigenetic marks (DNA hypomethylation) in association with long-term alterations in gene expression (dopamine and opioids) and behaviour (preference for palatable foods). Epigenetics Maternal obesity Levels of insulin, glucose, leptin and free fatty acids are elevated in the offspring via lactation and the mothers’ milk. Maternal high fat diet feeding Hyper-insulinemia causes predisposes the offspring for obesity the impairment in POMC projections. and impaired glucose homeostasis in POMC cells are mice via an impairment of the fundamental to the control of food intake and hypothalamic melanocortin circuitry. body weight, but are also important in sensing peripheral glucose levels. Change in POMC projection causes glucose intolerance in offspring. Vogt (2014) Cell 156:495-509. Epigenetics Maternal obesity Maternal obesity disrupts the blood brain barrier in the offspring. Evans Blue diffusion into the ARC was higher in offspring from obese dams compared with controls (i.e. offspring from normal weight dams), indicating that ARC BBB permeability was compromised. Kim et al. (2016) Endocrinology 157: 2229–2242 Learning Overview 1. Genetics Gene x environment interaction Single gene mutations – leptin and the melanocortin system Set-point regulation of body weight 2. Epigenetics Maternal obesity 3. Environmental causes Endocrine disruptors and obesity Environmental Causes of Obesity Endocrine disruptors – what are they? Endocrine Disrupting Chemicals (EDCs): A compound, either natural or synthetic, which through environmental or inappropriate developmental exposures alters the hormonal and homeostatic systems that enable the organism to communicate with and respond to its environment. Environmental Causes of Obesity Endocrine disruptors – where are they found? Plant steroids (phytoestrogens) Components of detergent (alkylphenoxylates and their derivatives) Compounds leached from plastics (bisphenol A, nonylphenol and pthalates) Certain pesticides and fungicides (DDT, atrazine and vinclozline) Polychlorinated chemicals from industry (dioxins, polychorinated bisphenols) Environmental Causes of Obesity Endocrine disruptors – where do they impact the body? Neel and Sargis (2011) Diabetes 60: 1838–1848. Environmental Causes of Obesity Chemical exposure and prevalence of diabetes U.S. diabetes rates have increased in concordance with the national production of synthetic organic chemicals. Neel and Sargis (2011) Diabetes 60: 1838–1848. Environmental Causes of Obesity Example of EDC – BPA Bisphenol A an organic synthetic compound with the chemical formula (CH3)2C(C6H4OH)2 a starting material for the synthesis of plastics, primarily certain polycarbonates and epoxy resins baby and water bottles sports equipment CDs and DVDs lining water pipes Epoxy resins to coatings on the inside of many food and beverage cans Estrogen mimic BPA can leach into food or beverage if plastic container is heated Environmental Causes of Obesity Link between BPA and obesity.. Environmental Causes of Obesity Endocrine disruptors increase adipogenesis Potential mechanism by which environmental chemicals cause obesity in animals and in humans. Several EDCs and obesogens are known to activate peroxisome proliferator- activated receptor γ (PPAR-γ), which leads to weight gain and reprogramming of mesenchymal stem cell fate to favour the formation of adipogenic cells. Heindel et al. (2015) Nat Rev Endocrinol 11: 653-61 Environmental Causes of Obesity Transgenerational, epigenetic effects Effects of endocrine disrupting chemicals may be transmitted to further generations through germline epigenetic modifications. Learning Overview 1. Genetics Gene x environment interaction Single gene mutations – leptin and the melanocortin system Set-point regulation of body weight 2. Epigenetics Maternal obesity 3. Environmental causes Endocrine disruptors and obesity