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Metabolic alterations associated with the antidiabetic effect of beta 3-adrenergic receptor agonists in obese mice
C M Arbeeny1, D S Meyers, D E Hillyer
1Department of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Abstract:
Treatment of obese (ob/ob) mice with the beta 3-adrenergic receptor (beta 3-AR) agonist BRL-35135 (1 mg.kg body wt-1.day-1 for 20 days) normalized plasma glucose levels and significantly decreased plasma insulin and nonesterified fatty acid levels. The time frame for the hypoglycemic effect, which reached a maximum after 10 days of treatment, paralleled an increase in brown adipose tissue DNA and protein content. The basal level of mRNA for the beta 3-AR and mitochondrial uncoupling protein was found to be markedly decreased in the ob/ob animals relative to the lean group. Chronic treatment of ob/ob mice for 20 days resulted in a twofold increase in beta 3-AR mRNA and a fivefold increase in uncoupling protein mRNA in brown adipose tissue relative to the placebo group. These findings indicate that chronic treatment of ob/ob animals with a beta 3-AR agonist results in proliferation of brown adipose tissue, with an upregulation of the beta 3-AR, which is associated with a decrease in plasma glucose, insulin, and nonesterified fatty acid levels.
Insights
Treatment with a beta 3-adrenergic receptor (beta 3-AR) agonist normalized glucose levels in obese mice. This effect correlated with increased brown adipose tissue and beta 3-AR expression, suggesting a therapeutic potential for obesity.
Area of Science:
- Metabolic research
- Pharmacology
- Obesity research
Background:
- Obesity is linked to metabolic dysfunction, including hyperglycemia and dyslipidemia.
- Beta 3-adrenergic receptors (beta 3-AR) play a role in energy expenditure and thermogenesis, particularly in brown adipose tissue.
- Obese (ob/ob) mice exhibit reduced beta 3-AR and uncoupling protein mRNA levels.
Purpose of the Study:
- To investigate the effects of chronic beta 3-AR agonist treatment on metabolic parameters in obese mice.
- To determine the impact of this treatment on brown adipose tissue characteristics and gene expression.
Main Methods:
- Obese (ob/ob) mice were treated with a beta 3-AR agonist (BRL-35135) for 20 days.
- Plasma glucose, insulin, and nonesterified fatty acid levels were measured.
- Brown adipose tissue DNA, protein, and mRNA levels for beta 3-AR and uncoupling protein were analyzed.
Main Results:
- Treatment normalized plasma glucose and decreased insulin and nonesterified fatty acid levels.
- A significant increase in brown adipose tissue DNA and protein content was observed.
- Chronic agonist treatment upregulated beta 3-AR mRNA and uncoupling protein mRNA in brown adipose tissue.
Conclusions:
- Chronic beta 3-AR agonist administration promotes brown adipose tissue proliferation and upregulates key metabolic genes.
- These changes are associated with improved glycemic control and lipid profiles in obese mice.
- Beta 3-AR agonists show potential as a therapeutic strategy for managing obesity-related metabolic disorders.