Dysregulation of energy homeostasis in mice overexpressing insulin-like growth factor-binding protein 6 in the brain.
OBJECTIVE
IGFs, IGF receptors and IGF binding proteins (IGFBPs) are widely expressed in the central nervous system. To investigate the physiological significance of IGFBP-6 in the brain we established two transgenic mouse lines overexpressing human (h)-IGFBP-6 under the control of glial fibrillary acidic protein promoter. Increasing evidence suggests that insulin/IGF signalling pathways could be implicated in the neuroendocrine regulation of energy homeostasis. We explored the impact of brain IGFBP-6 overexpression on the regulation of food intake and energy balance.


METHODS
Transgenic mice were fed either a control diet or a high-fat diet for up to 3 months. Glucose and insulin tolerance tests were carried out before and after the diet period. Plasma parameters (insulin, leptin, glucose, NEFAs and triglycerides) were measured, and uncoupling protein 1 (UCP-1) expression was quantified in brown adipose tissue. Oxygen consumption was also measured in both groups.


RESULTS
The transgenic mice fed a high-fat diet for 3 months developed obesity, showing increases in plasma leptin, glucose and insulin levels and mild insulin resistance. As compared with wild-type mice, no significant differences were found in the quantity of food intake. However, UCP-1 expression was down-regulated in the brown adipose tissue of the transgenic mice.


CONCLUSIONS
Our results show that brain IGFBP-6 has an impact on the regulation of energy homeostasis. These transgenic h-IGFBP-6 mice may be considered a new tool for studies of the involvement of the brain IGF system in metabolism control and obesity.
Bienvenu
G
G
National Institute of Health and Medical Research (INSERM) Unit 515, St-Antoine Hospital, University of Paris, Paris, France.
Seurin
D
D
Le Bouc
Y
Y
Even
P
P
Babajko
S
S
Magnan
C
C
D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D002149:Energy Intake; D004734:Energy Metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000494:pharmacology; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000097:blood; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000235:genetics*; D007473:Ion Channels; D020738:Leptin / Q000097:blood; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins; D010101:Oxygen Consumption / Q000187:drug effects; D014280:Triglycerides / Q000097:blood; D000071256:Uncoupling Protein 1
D001786:Blood Glucose; D002352:Carrier Proteins; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D018976:Insulin-Like Growth Factor Binding Protein 6; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D014280:Triglycerides; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D005947:Glucose