Spontaneous caloric restriction associated with increased leptin levels in obesity-resistant αMUPA mice.
BACKGROUND
αMUPA mice carry as a transgene the cDNA encoding urokinase-type plasminogen activator, a member of the plasminogen/plasmin system that functions in fibrinolysis and extracellular proteolysis. These mice spontaneously consume less food when fed ad libitum and live longer compared with wild-type (WT) control mice. αMUPA mice are obesity resistant and they share many similarities with calorically restricted animals. However, extensive metabolic characterization of this unique transgenic model has never been performed.


METHODS
Metabolism of αMUPA mice was analyzed by measuring hormone, lipid and glucose levels in the serum, as well as gene and protein expression levels in the liver, hypothalamus and brainstem.


RESULTS
αMUPA mice were found to be leaner than WT mice mainly because of reduced fat depots. Serum analyses showed that αMUPA mice have high levels of the anorexigenic hormones insulin and leptin, and low levels of the orexigenic hormone ghrelin. Analyses of brain neuropeptides showed that the transcript of the anorexigenic neuropeptide Pomc is highly expressed in the brainstem, whereas the expression of the orexigenic neuropeptides Npy, Orexin and Mch is blunted in the hypothalamus of αMUPA mice. In addition, adenosine monophosphate (AMP)-activated protein kinase (AMPK) levels were higher in the liver and lower in the hypothalamus, thus promoting simultaneously central reduction in appetite and peripheral loss of fat. The levels of SIRT1 were low in the liver, but high in the hypothalamus, a feature that αMUPA mice share with calorically restricted animals.


CONCLUSIONS
Taken together, αMUPA mice exhibit a unique metabolic phenotype of low-calorie intake and high leptin levels, and could serve as a model for both spontaneous calorie restriction and resistance to obesity.
Froy
O
O
Robert H. Smith Faculty of Agriculture, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot, Israel. froy@agri.huji.ac.il
Sherman
H
H
Bhargava
G
G
Chapnik
N
N
Cohen
R
R
Gutman
R
R
Kronfeld-Schor
N
N
Miskin
R
R
D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D001933:Brain Stem / Q000378:metabolism; D002149:Energy Intake / Q000235:genetics / Q000502:physiology*; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D005247:Feeding Behavior / Q000502:physiology*; D005260:Female; D054439:Ghrelin / Q000097:blood; D007031:Hypothalamus / Q000378:metabolism; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism; D008136:Longevity / Q000502:physiology; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000378:metabolism; D013851:Thinness / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics*
D001786:Blood Glucose; D054439:Ghrelin; D007328:Insulin; D020738:Leptin; D008055:Lipids; D009479:Neuropeptides; D014568:Urokinase-Type Plasminogen Activator