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Effect of the genetic background and specific mutation on adenylate cyclase activity in obesity syndromes
1Department of Biochemistry, University of Ottawa, Canada.
Abstract:
Adenylate cyclase activity and its modulation by guanine nucleotides and isoproterenol were assessed in adipocyte membranes of mice with mutations causing different genetic obesity syndromes. The object was to determine whether the defect in inhibitory modulation observed in the obese (ob/ob) mouse was also present in the diabetes (db/db) mouse. The data show that adipocyte adenylate cyclase in both the ob/ob and the db/db mouse is resistant to activation by isoproterenol. The response to guanosine triphosphate (GTP) differed between the two mutants, such that an inhibitory phase was visible in the db/db but not in the ob/ob membranes. Moreover, pertussis toxin attenuated the inhibitory effect of GTP and significantly stimulated cyclase activity in the db/db but not in the ob/ob membranes. The data show that the two mutations affect the expression of adenylate cyclase activity via different mechanisms.
Insights
Genetic obesity in mice involves distinct mechanisms affecting adenylate cyclase activity. Studies reveal differences in how obese (ob/ob) and diabetic (db/db) mouse models respond to inhibitory and stimulatory signaling pathways.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Obesity is linked to altered cellular signaling pathways.
- Adenylate cyclase is a key enzyme in cellular signal transduction.
- Previous studies identified defects in inhibitory modulation in obese (ob/ob) mice.
Purpose of the Study:
- To investigate adenylate cyclase activity in adipocyte membranes of genetically obese mouse models.
- To compare the modulation of adenylate cyclase by guanine nucleotides and isoproterenol in ob/ob and db/db mice.
- To determine if the inhibitory modulation defect in ob/ob mice is also present in db/db mice.
Main Methods:
- Assessed adenylate cyclase activity in adipocyte membranes.
- Utilized guanine nucleotides (GTP) and isoproterenol for modulation studies.
- Administered pertussis toxin to assess G-protein involvement.
Main Results:
- Adipocyte adenylate cyclase in both ob/ob and db/db mice showed resistance to isoproterenol activation.
- Guanosine triphosphate (GTP) response differed: an inhibitory phase was observed in db/db but not ob/ob membranes.
- Pertussis toxin attenuated GTP's inhibitory effect and stimulated cyclase activity in db/db mice, but not ob/ob mice.
Conclusions:
- The ob/ob and db/db mouse models exhibit distinct mechanisms affecting adenylate cyclase activity.
- These findings highlight differential impacts of genetic mutations on cellular signaling in obesity and diabetes.