Examining Human Obesity on a Molecular Level Using Murine Models of Obesity
Over twenty years ago, the agouti mouse was the first model cloned from which an obesity gene was described. Mutations in the agouti gene are associated with variations in coat color (stripes in cats and tigers), when an animal carries a single copy (or allele) of the gene. When the animal is homozygois for the mutation (both alleles are agouti), the animals have a tendency towards obesity. The agouti gene mutation is highly relevant for studying murine models of obesity, as it is commonly expressed in human adipose tissues. Further characterization of agouti gene expression has also led to the elucidation of the melanocortin system’s role in weight gain.
Mc4r, a member of the melanocortin receptor family, is also regularly expressed in human adipose tissues. Extensive studies on the behavior of these and other obesity genes on the molecular level has uncovered many other pathways that help paint a picture of the etiology of human obesity.
When the agouti gene is ectopically expressed in adipose tissues of transgenic mice, they become significantly heavier than their non-transgenic counterparts. An increase in weight without an increase in appetite indicates a physiological impact. Agouti is also expressed in human adipose tissues, a fact that is further suggestive of its physiological involvement (energy storage and regulation). Agonistic and antagonistic relationships between Mc4r of the melanocortin receptor family and agouti protein expression further elucidate useful relationships between the human and mouse models of obesity.
The genes ob and db are also very well known that cause obesity in mice, affecting the satiety hormone leptin and its receptor, respectively. Identification of the ob gene mutation was what led to the discovery of leptin, which also plays a significant role in human obesity studies. Mutation of either gene leads to symptoms including decreased metabolism, hyperphagia, infertility, severe obesity and insulin resistance. When exogenous leptin is administered, symptoms are reversed, indicating a direct impact. Mutations in the receptor gene or in both genes provide models to help further characterize important pathways.
Other hormone systems that are known to impact obesity, include corticotrophin-releasing hormone (CRH), neuropeptide Y (NPY), and attractin, and are important factors that are highly relevant to human obesity treatment studies, and can be examined extensively via various murine models of obesity. Important findings continue to shed light on the etiology of human obesity and obesity-associated illnesses.
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