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Targeted expression of a toxin gene to adipose tissue: transgenic mice resistant to obesity
S R Ross1, R A Graves, B M Spiegelman
1Department of Biochemistry (m/c 536), University of Illinois College of Medicine, Chicago 60612.
Abstract:
Obesity is characterized by increased adipose tissue mass and is often accompanied by a number of other disorders, such as diabetes, hypertension, and hyperlipidemia. To investigate the interrelationship between excessive adipose tissue mass and these associated disorders, we have attempted to reduce adiposity via targeted expression of an attenuated diphtheria toxin A chain to adipose tissue, using the 5' regulatory region of the adipocyte P2 (aP2) gene. Transgenic mice with high levels of toxin expression developed chylous ascites and died shortly after birth. Transgenic mice expressing lower levels of the transgene had normal adiposity and survived to adulthood; however, they showed a complete resistance to chemically induced obesity. Nevertheless, these animals developed hyperlipidemia equal to or greater than their nontransgenic obese littermates. Moreover, MSG-treated transgenic females were fertile, unlike their obese nontransgenic littermates. These data demonstrate the feasibility of gentle manipulation of adiposity and allow a functional dissection of obesity and its metabolic sequelae.
Insights
Researchers targeted adipose tissue to reduce obesity in mice. Lower toxin levels prevented obesity but caused hyperlipidemia, demonstrating a complex link between adiposity and metabolic disorders.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Obesity, characterized by excess adipose tissue, is linked to diabetes, hypertension, and hyperlipidemia.
- Understanding the interplay between adiposity and associated metabolic disorders is crucial.
Purpose of the Study:
- To investigate the relationship between excessive adipose tissue and associated disorders.
- To explore the feasibility of reducing adiposity using targeted gene expression.
Main Methods:
- Utilized transgenic mice with targeted expression of an attenuated diphtheria toxin A chain to adipose tissue.
- Employed the 5' regulatory region of the adipocyte P2 (aP2) gene for targeted delivery.
- Administered MSG (monosodium glutamate) to assess fertility in transgenic females.
Main Results:
- High toxin expression led to early mortality in transgenic mice.
- Lower toxin expression resulted in resistance to chemically induced obesity but normal adiposity.
- Transgenic mice exhibited hyperlipidemia comparable to or exceeding obese non-transgenic littermates.
- MSG-treated transgenic females remained fertile, unlike their obese non-transgenic counterparts.
Conclusions:
- Demonstrated the feasibility of modulating adiposity through genetic manipulation.
- Provided insights into the functional dissection of obesity and its metabolic consequences.
- Highlighted the complex relationship between reduced adiposity and metabolic health, including hyperlipidemia and fertility.