Mouse, genetically obese

The leptin story has been augmented by a second mouse genetic defect leading to obesity. These mice are known as db/db they are very similar to ob/ob mice. However, these mice have normal levels of leptin. Scientists at Millennium Pharmaceuticals identified the molecular defect in db/db mice. They lack the normal leptin receptor. Therefore, we have both sides of the coin ob/ob mice cannot make leptin, eat too much, and are therefore obese db/db mice make leptin, cannot respond to it for lack of the leptin receptor, eat too much, and are obese. Administration of leptin to ob/ob mice normalizes their body weight but administration of leptin to db/db mice has... 

Murphy, J. E., Zhou, S., Giese, K., Williams, L. T., Escobedo, J. A. and Dwarki, V. J. (1997). Long-term correction of obesity and diabetes in genetically obese mice by a single intramuscular injection of recombinant adeno-associated virus encoding mouse leptin. Proc. Natl. Acad. Sci. USA 94, 13921-13926. 

Genetically obese mice were treated with fluoxetine to assess the ability of fluoxetine to produce weight loss. In this model, fluoxetine did produce initial weight loss but overtime had no positive impact on mouse weight. 

When leptin was first discovered, there was great hope that, as in the obese mouse, human obesity (see Chapter 6) might be due to a failure of leptin synthesis or secretion, and that administration of synthetic leptin might be a useful treatment for severe obesity. However, most obese people secrete more leptin than lean people (because they have more adipose tissue), and it is likely that the problem is due not to lack of leptin, but rather to a loss of sensitivity of the leptin receptors. Only in a very small number of people has obesity been found to be genetically determined by a mutation in the leptin gene. 

This chapter will present methods that are widely used for screening and validating new therapeutic drugs using in vivo mouse models. These models can roughly be divided in two types first, genetic models where animals develop symptoms of diabetes, even in absence of environmental changes, and second, diet-induced obesity, which results in increased insulin resistance (see Note 1). 

Che FY, Biswas R, Fricker LD. Relative quantitation of peptides in wild-type and Cpe(fat/fat) mouse pituitary using stable isotopic tags and mass spectrometry. J. Mass Spectrom. 2005 40 227-237. Decaillot FM, Che FY, Fricker LD, Devi LA. Peptidomics of Cpefat/fat mouse hypothalamus and striatum effect of chronic morphine administration. J. Mol. Neurosci. 2006 28 277-284. Naggert JK, Fricker LK, Varlamov O, Nishina PM, Rouille Y, Steiner DF, Carroll RJ, Paigen BJ, Leiter EH. Hyperproinsuli-naemia in obese fat/fat mice associated with a carboxypepti-dase E mutation which reduces enzyme activity. Nat. Genet. 1995 10 135-142. 

Genetic Factors in Human Obesity Genetic Factors in Mouse Obesity Obese Gene and Leptin Summary of the t hysiotogy of Adipose Tissue gulation Diabetes Gene and the Lcpiin Receptor... 

Thus, an appreciation of the genetic factors of mouse obesity requires some background in the physiology of the hypothalamus. 

Type 2 Diabetes Mellitus This is the most prevalent form of diabetes and is characterized by both an insulin secretion defect and insulin resistance. Maturity-onset diabetes of the young (MODY), attributable to mutations of the glucose kinase gene (discussed earlier), may also be classified as type 2 diabetes mellitus. Obesity is a contributory factor and may predispose to insulin resistance with eventual development of type 2 diabetes mellitus. The precise mechanism by which obesity leads to insulin resistance in the target tissues is not understood. However, in several animal models (e.g., ob/ob mouse, db/db mouse) mutations have been identified that cause both obesity and diabetes mellitus. Unlike type 1 diabetes mellitus, type 2 is not an autoimmune disease. Studies with monozygotic twins have revealed a 90% concordance rate for type 2 diabetes mellitus, suggesting the involvement of genetic factors in the development of the disease. 

Mouse on the right an obese mouse that does not produce leptin because of a genetic mutation in the leptin gene. Mouse in the middle a mouse that does not produce leptin but maintains relatively normal body weight because of its enhanced fat metabolism caused by the lack of perilipin. Mouse on the left a wild-type, normal mouse that produces leptin as well as perilipin. (Courtesy ofDrs. Lawrence Chan and Pradip Saha, Baylor College of Medicine.)... 

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