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Title: New inducible genetic method reveals critical roles of GABA in the control of feeding and metabolism

Author
item FANTAO, MENG - Children'S Nutrition Research Center (CNRC)
item YONG, HAN - Children'S Nutrition Research Center (CNRC)
item DOLLADA, SRISAI - University Of Iowa
item VALERY, BELAKHOV - Israel Institute Of Technology
item MONICA, FARIAS - Children'S Nutrition Research Center (CNRC)
item YONG, XU - Children'S Nutrition Research Center (CNRC)
item RICHARD, PALMITER - University Of Washington
item TIMOR, BAASOV - Israel Institute Of Technology
item QI, WU - Children'S Nutrition Research Center (CNRC)

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/7/2016
Publication Date: 3/29/2016
Citation: Fantao, M., Yong, H., Dollada, S., Valery, B., Monica, F., Yong, X., Richard, P.D., Timor, B., Qi, W. 2016. New inducible genetic method reveals critical roles of GABA in the control of feeding and metabolism. Proceedings of the National Academy of Sciences. 113 (13): 3645-3650.

Interpretive Summary: Obesity and diabetes are serious global health problems. Here we showed that a neurotransmitter, GABA, can substantially induce food intake in mice. These findings highlighted the brain GABA system as a potential therapeutic target for treatment of obesity.

Technical Abstract: Currently available inducibleCre/loxPsystems, despite their considerable utility in gene manipulation, have pitfalls in certain scenarios, such as unsatisfactory recombination rates and deleterious effects on physiology and behavior. To overcome these limitations, we designed a new, inducible gene-targeting system by introducing an in-frame nonsense mutation into the coding sequence of Cre recombinase (nsCre). Mutant mRNAs transcribed from nsCre transgene can be efficiently translated into full-length, functional Cre recombinase in the presence of nonsense suppressors such as aminoglycosides. In a proof-of-concept model, GABA signaling from hypothalamic neurons expressing agouti-related peptide (AgRP) was genetically inactivated within 4 d after treatment with a synthetic aminoglycoside. Disruption of GABA synthesis in AgRP neurons in young adult mice led to a dramatic loss of body weight due to reduced food intake and elevated energy expenditure; they also manifested glucose intolerance. In contrast, older mice with genetic inactivation of GABA signaling by AgRP neurons had only transient reduction of feeding and body weight; their energy expenditure and glucose tolerance were unaffected. These results indicate that GABAergic signaling from AgRP neurons plays a key role in the control of feeding and metabolism through an age-dependent mechanism. This new genetic technique will augment current tools used to elucidate mechanisms underlying many physiological and neurological processes.