Contributions of dysregulated energy metabolism to type 2 diabetes development in NZO/H1Lt mice with polygenic obesity

Metabolism. 2004 Jun;53(6):799-808. doi: 10.1016/j.metabol.2003.12.024.


New Zealand Obese (NZO) male mice develop a polygenic juvenile-onset obesity and maturity-onset hyperinsulinemia and hyperglycemia (diabesity). Here we report on metabolic and molecular changes associated with the antidiabesity action of CL316,243 (CL), a beta(3)-adrenergic receptor agonist. Dietary CL treatment initiated at weaning reduced the peripubertal rise in body weight and adiposity while promoting growth without suppressing hyperphagia. The changes in adiposity, in turn, suppressed development of hyperinsulinemia, hyperleptinemia, hyperlipidemia, and hyperglycemia. These CL-induced alterations were reflected by decreased adipose tissue mass, increased expression of transcripts for uncoupling protein-1 (UCP-1), peroxisome proliferator-activated receptor alpha (PPARalpha), peroxisome proliferater-activated receptor coactivator-1 (PGC-1), and robust development of brown adipocyte function in white fat. Increased drug-mediated energy dissipation elicited a 1.5 degrees C increase in whole body temperature under conditions of increased food intake but with no change in physical activity. Indirect calorimetry of mice treated with CL showed both increased energy expenditure and a restoration of a prominent diurnal pattern in the respiratory exchange ratio suggesting improved nutrient sensing. Our data suggest that CL promotes increased energy dissipation in white and brown fat depots by augmenting thermogenesis and by metabolic re-partitioning of energy in a diabesity-protective fashion. This is the first report demonstrating the effects of dietary beta(3)-agonist in preventing the onset of diabesity in a polygenic rodent model of type 2 diabetes.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Blood Glucose / metabolism
  • Body Weight / drug effects
  • Carrier Proteins / biosynthesis
  • Diabetes Mellitus / metabolism*
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Dioxoles / pharmacology
  • Eating / drug effects
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology*
  • Insulin / blood
  • Ion Channels
  • Islets of Langerhans / cytology
  • Islets of Langerhans / ultrastructure
  • Leptin / blood
  • Liver / metabolism
  • Male
  • Membrane Proteins / biosynthesis
  • Mice
  • Mice, Inbred Strains
  • Mitochondrial Proteins
  • Muscle, Skeletal / metabolism
  • Obesity*
  • Receptors, Cytoplasmic and Nuclear / biosynthesis
  • Thermogenesis / drug effects
  • Transcription Factors / biosynthesis
  • Uncoupling Protein 1


  • Adrenergic beta-Agonists
  • Blood Glucose
  • Carrier Proteins
  • Dioxoles
  • Insulin
  • Ion Channels
  • Leptin
  • Membrane Proteins
  • Mitochondrial Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate