TY - JOUR
T1 - Striatal Rgs4 regulates feeding and susceptibility to diet-induced obesity
AU - Michaelides, Michael
AU - Miller, Michael L.
AU - Egervari, Gabor
AU - Primeaux, Stefany D.
AU - Gomez, Juan L.
AU - Ellis, Randall J.
AU - Landry, Joseph A.
AU - Szutorisz, Henrietta
AU - Hoffman, Alexander F.
AU - Lupica, Carl R.
AU - Loos, Ruth J.F.
AU - Thanos, Panayotis K.
AU - Bray, George A.
AU - Neumaier, John F.
AU - Zachariou, Venetia
AU - Wang, Gene Jack
AU - Volkow, Nora D.
AU - Hurd, Yasmin L.
N1 - Publisher Copyright:
© 2018, Macmillan Publishers Limited, part of Springer Nature.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Consumption of high fat, high sugar (western) diets is a major contributor to the current high levels of obesity. Here, we used a multidisciplinary approach to gain insight into the molecular mechanisms underlying susceptibility to diet-induced obesity (DIO). Using positron emission tomography (PET), we identified the dorsal striatum as the brain area most altered in DIO-susceptible rats and molecular studies within this region highlighted regulator of G-protein signaling 4 (Rgs4) within laser-capture micro-dissected striatonigral (SN) and striatopallidal (SP) medium spiny neurons (MSNs) as playing a key role. Rgs4 is a GTPase accelerating enzyme implicated in plasticity mechanisms of SP MSNs, which are known to regulate feeding and disturbances of which are associated with obesity. Compared to DIO-resistant rats, DIO-susceptible rats exhibited increased striatal Rgs4 with mRNA expression levels enriched in SP MSNs. siRNA-mediated knockdown of striatal Rgs4 in DIO-susceptible rats decreased food intake to levels comparable to DIO-resistant animals. Finally, we demonstrated that the human Rgs4 gene locus is associated with increased body weight and obesity susceptibility phenotypes, and that overweight humans exhibit increased striatal Rgs4 protein. Our findings highlight a novel role for involvement of Rgs4 in SP MSNs in feeding and DIO-susceptibility.
AB - Consumption of high fat, high sugar (western) diets is a major contributor to the current high levels of obesity. Here, we used a multidisciplinary approach to gain insight into the molecular mechanisms underlying susceptibility to diet-induced obesity (DIO). Using positron emission tomography (PET), we identified the dorsal striatum as the brain area most altered in DIO-susceptible rats and molecular studies within this region highlighted regulator of G-protein signaling 4 (Rgs4) within laser-capture micro-dissected striatonigral (SN) and striatopallidal (SP) medium spiny neurons (MSNs) as playing a key role. Rgs4 is a GTPase accelerating enzyme implicated in plasticity mechanisms of SP MSNs, which are known to regulate feeding and disturbances of which are associated with obesity. Compared to DIO-resistant rats, DIO-susceptible rats exhibited increased striatal Rgs4 with mRNA expression levels enriched in SP MSNs. siRNA-mediated knockdown of striatal Rgs4 in DIO-susceptible rats decreased food intake to levels comparable to DIO-resistant animals. Finally, we demonstrated that the human Rgs4 gene locus is associated with increased body weight and obesity susceptibility phenotypes, and that overweight humans exhibit increased striatal Rgs4 protein. Our findings highlight a novel role for involvement of Rgs4 in SP MSNs in feeding and DIO-susceptibility.
UR - http://www.scopus.com/inward/record.url?scp=85049138017&partnerID=8YFLogxK
U2 - 10.1038/s41380-018-0120-7
DO - 10.1038/s41380-018-0120-7
M3 - Article
C2 - 29955167
AN - SCOPUS:85049138017
SN - 1359-4184
VL - 25
SP - 2058
EP - 2069
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 9
ER -