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Molecular Genetic Approaches to Obesity
Published in Claude Bouchard, The Genetics of Obesity, 2020
Streamson C. Chua, Rudolph L. Leibel
Several autosomal mutations producing obesity have been mapped genetically in the mouse and rat: Yellow (Ay), mouse chromosome 2; diabetes (db), chromosome 4; obese (ob), chromosome 6; tubby (tub), chromosome 7; fat (fat), chromosome 8; Adipose (Ad), chromosome 7; fatty (fa), rat chromosome 5.9–13 While Ay and Ad are dominant, the others are recessive. All of these rodent mutations are in regions of the mouse genome with high homology to regions of the human genome. The Ay mutation in the agouti (a) locus which produces obesity was recently cloned. The agouti gene codes for a protein which apparently has paracrine activity and which has a sequence with no significant homology to known proteins. The Ay mutation is in the regulatory sequence for this gene, causing it to be expressed in tissues in which it is not usually expressed.14 The molecular basis for the obesity in these animals remains unknown. In no other instance of rodent obesity has the culpable gene been identified.
Noninsulin-Dependent Animal Models of Diabetes Mellitus
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Christopher H. S. McIntosh, Raymond A. Pederson
The agouti gene is approximately 18 kb in length.139,140 It contains two identified promoters that utilize three common coding exons. This results in four types of mature 0.7- to 0.8-kb mRNA transcripts with identical coding regions. The 131 amino acid precursor agouti protein contains an N-terminal signal sequence, cleavage of which results in the production of an 108 amino acid-secreted protein. It has a very basic central region and cysteine-rich C-terminus. The agouti gene is normally expressed in cells just below the hair bulb, with minor levels of mRNA found in the epidermis.132 Although humans do not appear to develop agouti-pigmented hair, there is a human version of the mouse agouti gene, which maps to chromosome 20q11.2,141,142 and is 85% identical to the mouse gene. The 132 amino acid human agouti signaling protein (ASP)142 is 80% identical to the mouse protein, and both proteins share similarities with toxins produced by snails and spiders: the ω-conotoxins and plectotoxins. The agouti gene is expressed more widely in humans, predominantly in adipose tissue, testis, ovary, and heart, but at lower levels in liver, kidney, and foreskin.141,142 This suggests that it may play a broader regulatory role in humans.
Epigenetics, Nutrition, and Infant Health
Published in Crystal D. Karakochuk, Kyly C. Whitfield, Tim J. Green, Klaus Kraemer, The Biology of the First 1,000 Days, 2017
Philip T. James, Matt J. Silver, Andrew M. Prentice
Perhaps the most famous animal experiments demonstrating how epigenetic changes driven by maternal diet in pregnancy can dramatically alter phenotype in the offspring come from the agouti mouse. In one experiment, pregnant dams were fed a diet that varied in methyl donor content (folic acid, choline, betaine, and vitamin B12). Their isogenic pups showed variable methylation at an intracisternal A particle (IAP), a retrotransposon upstream of the agouti gene that is a metastable epiallele. The degree of methylation at this locus altered expression of the agouti gene, resulting in permanent phenotypic differences. The most obvious change was in fur color, but differences were also found in appetite, adiposity, and glucose tolerance, factors highly relevant to life-long chronic disease risk [19,27]. A similar experiment in a different strain of kinky-tailed mice showed that methyl donor content of the maternal diet also altered methylation at an IAP on the Axin gene, producing pups with varying levels of tail kink [51].
Epigenetics, nutrition and mental health. Is there a relationship?
Published in Nutritional Neuroscience, 2018
Aaron J. Stevens, Julia J. Rucklidge, Martin A. Kennedy
In addition to an individual’s epigenome being modified by environmental factors, mammals can inherit epigenetic patterns from both maternal and paternal DNA sources. This means that parental diet at the time of conception can potentially influence gene expression in the offspring. This effect is highly pronounced at genomic regions that are called metastable epialleles.44 Normally, when the levels of tissue-specific methylation are compared among individuals the variation is relatively low;45,46 however, certain regions display an unusually high level of variation and these are called metastable epialleles. At these regions, establishment of methylation patterns during development may result in variable gene expression and phenotypic outcomes.44 The mouse Agouti locus is a metastable epiallele that has been used extensively as a model for investigating how maternal diet during pregnancy can impact phenotype in the developing foetus.44,47 The locus encodes a signalling molecule that determines coat colour by regulating the production of either black or yellow pigmentation proteins within hair follicles. Agouti gene expression can be silenced by DNA methylation48 and the extent of methylation is correlated with environmental stimuli and maternal diet during early development.49 Mice that lack methylation in regulatory regions of this gene have a yellow coat phenotype, are obese, and more likely to get cancer and diabetes. Conversely, mice that have high methylation levels (hypermethylation) in this region display reduced expression levels and as a consequence have a lean phenotype, reduced disease risk, and brown coat colour.50–52 When pregnant mice that display the yellow coat colour are fed a methyl-rich diet including folic acid, choline, vitamin B12, and betaine they generally produce brown, healthy offspring.5,7
From leptin to lasers: the past and present of mouse models of obesity
Published in Expert Opinion on Drug Discovery, 2021
Joshua R. Barton, Adam E. Snook, Scott A. Waldman
Other mouse models of obesity have shown promising correlation to human obesity. Research on the melanocortin 4 receptor (MC4R) is a prime example of the modern interplay between mouse models, the genetic basis for human obesity, and development of effective anti-obesity pharmaceuticals. The viable yellow Agouti mouse (Avy) was one of the original mouse models of obesity, characterized by its late-onset obesity (Agouti obesity syndrome) and unique coloring [10]. The Agouti gene was the first obesity factor cloned (2 years before leptin), and cloning revealed that the mutation in the Avy mouse caused ectopic expression of Agouti peptide [111]. Unlike ob and db mice, the Avy mouse at the time did not have a reciprocal receptor knockout mouse. This changed in 1997, when researchers developed a MC4R knockout mouse, which recapitulated the phenotype of Agouti obesity syndrome and implicated MC4R as the receptor that mutant Agouti antagonized [112]. Like LepR, MC4R is a hypothalamic receptor that induces satiety when stimulated by ligands from neurons in the arcuate nucleus (ARC) [113]. Using these data from mouse models, it was revealed that mutations in MC4R produce the most common monogenic form of human obesity [114]. The strong evidence that MC4R receptor regulates mouse and human body weight led to the development of additional mouse models that modulate MC4R function. One such model disrupts Melanocortin 2 Receptor Accessory Protein 2 (MRAP2), a protein that interacts directly with MC4R, leading to profound obesity in mice [115]. Human studies revealed that loss-of-function mutations in MRAP2 lead to hyperphagic obesity associated with hyperglycemia and hypertension in children and adults [115,116]. Notably, a second generation MC4R agonist, setmelanotide, has shown promising results in reducing hyperphagia and obesity in patients with rare genetic obesities, and is currently in a phase III clinical trial for patients with BBS (Clinical trial # NCT03746522) [117].
Evolving paradigms for the biological response to low dose ionizing radiation; the role of epigenetics
Published in International Journal of Radiation Biology, 2018
Paul N. Schofield, Monika Kondratowicz
This question remains one of the most challenging we now face. How does the deposition of energy or exposure to a bystander factor or a bystander ‘environment’ result in epigenetic change? In recent years, there have been major paradigmatic shifts in our understanding of the interaction between the environment and epigenetic mechanisms, particularly nutrition and oxidative stress. In a critical experiment in the early 2000s, Randy Jirtle and his co-investigators probed the possibility that an epigenetic change might be produced by modification of the maternal environment which would change the phenotype of the fetus in utero through alterations in transposable element expression following hypermethylation caused by feeding of single carbon metabolism precursors (Waterland and Jirtle 2003). The link between methylation, transgenerational inheritance, and maternal environment has since been established for low dose radiation exposure, using the viable yellow agouti (Avy) ‘reporter’ system developed by this group. Bernal et al. (2013) reported that at doses of between 1 and 3 cGy they could induce an increase in methylation of the Avy locus which was associated with inactivation of the endogenous retrovirus driving expression of the agouti gene and, critically, that this could be mitigated by feeding antioxidants to the mother. So, in a single experiment radiation oxidative stress and methylation were definitively linked, supporting the proposition that low dose radiation increases DNA methylation at least in part through the generation of ROS. Evidence linking oxidative stress originating in a variety of stressors such as ionizing radiation, heavy metals, cigarette smoke, and in utero hypoxic/reperfusion damage has been well reviewed in Jirtle (2013). Similar suggestions of converging stress pathways were originally proposed to explain the long-term delayed effects of oxidative stressors on the endothelial cell (Schofield and Garcia-Bernardo 2007) as evidence began to emerge about the importance of the cardiovascular system as the most important target for low dose ionizing radiation (Reviewed in Kreuzer et al. 2015 and Tapio 2016).