Central CART gene delivery by recombinant AAV vector attenuates body weight gain in diet-induced-obese rats.
Cocaine- and amphetamine-regulated transcript (CART) peptide is a neuro-peptide implicated in the regulation of energy homeostasis. CART mRNA and its encoded peptide have been found in many brain regions that regulate energy balance. To investigate the effects of chronic central expression of CART in the diet-induced-obese (DIO) rats, we constructed and packaged recombinant adeno-associated virus (AAV) 2 vector containing rat CART cDNA and a reporter gene encoding green fluorescence protein (AAV-rCART-hrGFP) driven by the CMV promoter. Approximately 1x10(11) particles of AAV-rCART-hrGFP or control vector AAV-IRES-hrGFP (AAV-hrGFP in short) were injected through intracerebroventricular (ICV) cannulas into adult male DIO Long-Evans rats. Throughout the 7-month study period, AAV-rCART-hrGFP-injected rats had a significantly decreased food intake and body weight gain when compared with those of AAV-hrGFP-injected rats. AAV-rCART-hrGFP injection also modulated hyperphagia following a 24-hour fasting in these rats. Body composition analysis indicated that decreased body weight gain was due to reduction in lean body mass while fat mass was not affected. Expression of green fluorescence protein (GFP) suggested that recombinant AAV virions are located at cells surrounding the third ventricle and medial eminence. Our results demonstrate that chronic expression of CART in brain can modulate energy intake in diet-induced-obese rats. The CART pathway plays an important role in body mass regulation in DIO rats.
Qing
Keyun
K
Lilly Research Laboratory, Eli Lilly and Company, Lilly Corporate Center, DC 0545, Indianapolis, IN 46285, United States.
Chen
Yanyun
Y
D000818:Animals; D001823:Body Composition / Q000235:genetics; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002151:Calorimetry; D000229:Dependovirus / Q000235:genetics; D004032:Diet / Q000009:adverse effects; D004435:Eating / Q000235:genetics / Q000502:physiology; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D051381:Rats; D020318:Rats, Long-Evans; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015430:Weight Gain / Q000235:genetics / Q000502:physiology*; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D049452:Green Fluorescent Proteins