Role of Hypothalamic Creb-Binding Protein in Obesity and Molecular Reprogramming of Metabolic Substrates.
We have reported a correlation between hypothalamic expression of Creb-binding protein (Cbp) and lifespan, and that inhibition of Cbp prevents protective effects of dietary restriction during aging, suggesting that hypothalamic Cbp plays a role in responses to nutritional status and energy balance. Recent GWAS and network analyses have also implicated Cbp as the most connected gene in protein-protein interactions in human Type 2 diabetes. The present studies address mechanisms mediating the role of Cbp in diabetes by inhibiting hypothalamic Cbp using a Cre-lox strategy. Inhibition of hypothalamic Cbp results in profound obesity and impaired glucose homeostasis, increased food intake, and decreased body temperature. In addition, these changes are accompanied by molecular evidence in the hypothalamus for impaired leptin and insulin signaling, a shift from glucose to lipid metabolism, and decreased Pomc mRNA, with no effect on locomotion. Further assessment of the significance of the metabolic switch demonstrated that enhanced expression of hypothalamic Cpt1a, which promotes lipid metabolism, similarly resulted in increased body weight and reduced Pomc mRNA.
Department of Neuroscience, and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Cesar L
CL
Moreno
Department of Neuroscience, and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Linda
L
Yang
Department of Neuroscience, and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Penny A
PA
Dacks
Department of Neuroscience, and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Fumiko
F
Isoda
Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
Jan M A van
JM
Deursen
Department of Neuroscience, and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Charles V
CV
Mobbs
D000818:Animals; D001831:Body Temperature; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D004435:Eating; D004734:Energy Metabolism; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011333:Pro-Opiomelanocortin / Q000235:genetics; D015398:Signal Transduction; D015430:Weight Gain
D019208:Brain-Derived Neurotrophic Factor; D007328:Insulin; D020738:Leptin; D011333:Pro-Opiomelanocortin; C558401:CPT1B protein, mouse; D002334:Carnitine O-Palmitoyltransferase; D050882:CREB-Binding Protein; D005947:Glucose