Metabolic alterations associated with the antidiabetic effect of beta 3-adrenergic receptor agonists in obese mice.
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.
Arbeeny
C M
CM
Department of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Meyers
D S
DS
Hillyer
D E
DE
Bergquist
K E
KE
D000273:Adipose Tissue / Q000187:drug effects; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000473:pathology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002455:Cell Division; D003920:Diabetes Mellitus / Q000517:prevention & control*; D005260:Female; D051275:Glucose Transporter Type 4; D006321:Heart / Q000187:drug effects; D007473:Ion Channels; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008820:Mice, Obese; D024101:Mitochondrial Proteins; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000235:genetics; D013997:Time Factors; D000071256:Uncoupling Protein 1
D000318:Adrenergic beta-Agonists; D002352:Carrier Proteins; D051275:Glucose Transporter Type 4; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; C495693:Slc2a4 protein, mouse; D000071256:Uncoupling Protein 1