TY - JOUR
T1 - Metabolic, Molecular, and Behavioral Effects of Western Diet in Serotonin Transporter-Deficient Mice
T2 - Rescue by Heterozygosity?
AU - Veniaminova, Ekaterina
AU - Cespuglio, Raymond
AU - Chernukha, Irina
AU - Schmitt-Boehrer, Angelika G.
AU - Morozov, Sergey
AU - Kalueff, Allan V.
AU - Kuznetsova, Oxana
AU - Anthony, Daniel C.
AU - Lesch, Klaus-Peter
AU - Strekalova, Tatyana
N1 - Funding Information:
We thank Collette Rousset and Donia Amrouni from C. Bernard University, Anna Gorlova from Sechenov University, and Anastasiya Kibitkina and Galina Tolmacheva from the Gorbatov Research Center for their valuable contribution to this work. Funding. The authors’ work reported here was supported by the Deutsche Forschungsgemeinschaft (DFG: CRC TRR 58 A1/A5), the European Union’s Seventh Framework Programme (FP7/2007–2013) under Grant No. 602805 (Aggressotype), ERA-Net NEURON/RESPOND, No. 01EW1602B and ERA-Net NEURON/DECODE, No. 01EW1902 (to K-PL), the Horizon 2020 Research and Innovation Programme under Grant No. 728018 (Eat2beNICE) and Grant No. 643051 (MiND), 5-100 Russian Academic Excellence Project (to K-PL and TS), the Russian Science Foundation (RSF) Project No. 16-16-10073 (to IC and OK), and the University of Würzburg in the funding programme Open Access Publishing (to KP-L).
Publisher Copyright:
© Copyright © 2020 Veniaminova, Cespuglio, Chernukha, Schmitt-Boehrer, Morozov, Kalueff, Kuznetsova, Anthony, Lesch and Strekalova.
PY - 2020/2/18
Y1 - 2020/2/18
N2 - Reduced function of the serotonin transporter (SERT) is associated with increased susceptibility to anxiety and depression and with type-2 diabetes, which is especially true in older women. Preference for a "Western diet" (WD), enriched with saturated fat, cholesterol, and sugars, may aggravate these conditions. In previous studies, decreased glucose tolerance, central and peripheral inflammation, dyslipidemia, emotional, cognitive, and social abnormalities were reported in WD-fed young female mice. We investigated the metabolic, molecular, and behavioral changes associated with a 3-week-long dietary regime of either the WD or control diet in 12-month-old female mice with three different Sert genotypes: homozygous (Slc6a4) gene knockout (Sert(-/-): KO), heterozygous (Sert(+/-): HET), or wild-type mice (Sert(+/+): WT). In the WT-WD and KO-WD groups, but not in HET-WD-fed mice, most of changes induced by the WD paralleled those found in the younger mice, including brain overexpression of inflammatory marker Toll-like receptor 4 (Tlr4) and impaired hippocampus-dependent performance in the marble test. However, the 12-month-old female mice became obese. Control diet KO mice exhibited impaired hippocampal-dependent behaviors, increased brain expression of the serotonin receptors Htr2c and Htr1b, as well as increased Tlr4 and mitochondrial regulator, peroxisome proliferator-activated receptor gamma-coactivator-1a (Ppargc1a). Paradoxically, these, and other changes, were reversed in KO-WD mutants, suggesting a complex interplay between Sert deficiency and metabolic factors as well as potential compensatory molecular mechanisms that might be disrupted by the WD exposure. Most, but not all, of the changes in gene expression in the brain and liver of KO mice were not exhibited by the HET mice fed with either diet. Some of the WD-induced changes were similar in the KO-WD and HET-WD-fed mice, but the latter displayed a "rescued" phenotype in terms of diet-induced abnormalities in glucose tolerance, neuroinflammation, and hippocampus-dependent performance. Thus, complete versus partial Sert inactivation in aged mice results in distinct metabolic, molecular, and behavioral consequences in response to the WD. Our findings show that Sert(+/-) mice are resilient to certain environmental challenges and support the concept of heterosis as evolutionary adaptive mechanism.
AB - Reduced function of the serotonin transporter (SERT) is associated with increased susceptibility to anxiety and depression and with type-2 diabetes, which is especially true in older women. Preference for a "Western diet" (WD), enriched with saturated fat, cholesterol, and sugars, may aggravate these conditions. In previous studies, decreased glucose tolerance, central and peripheral inflammation, dyslipidemia, emotional, cognitive, and social abnormalities were reported in WD-fed young female mice. We investigated the metabolic, molecular, and behavioral changes associated with a 3-week-long dietary regime of either the WD or control diet in 12-month-old female mice with three different Sert genotypes: homozygous (Slc6a4) gene knockout (Sert(-/-): KO), heterozygous (Sert(+/-): HET), or wild-type mice (Sert(+/+): WT). In the WT-WD and KO-WD groups, but not in HET-WD-fed mice, most of changes induced by the WD paralleled those found in the younger mice, including brain overexpression of inflammatory marker Toll-like receptor 4 (Tlr4) and impaired hippocampus-dependent performance in the marble test. However, the 12-month-old female mice became obese. Control diet KO mice exhibited impaired hippocampal-dependent behaviors, increased brain expression of the serotonin receptors Htr2c and Htr1b, as well as increased Tlr4 and mitochondrial regulator, peroxisome proliferator-activated receptor gamma-coactivator-1a (Ppargc1a). Paradoxically, these, and other changes, were reversed in KO-WD mutants, suggesting a complex interplay between Sert deficiency and metabolic factors as well as potential compensatory molecular mechanisms that might be disrupted by the WD exposure. Most, but not all, of the changes in gene expression in the brain and liver of KO mice were not exhibited by the HET mice fed with either diet. Some of the WD-induced changes were similar in the KO-WD and HET-WD-fed mice, but the latter displayed a "rescued" phenotype in terms of diet-induced abnormalities in glucose tolerance, neuroinflammation, and hippocampus-dependent performance. Thus, complete versus partial Sert inactivation in aged mice results in distinct metabolic, molecular, and behavioral consequences in response to the WD. Our findings show that Sert(+/-) mice are resilient to certain environmental challenges and support the concept of heterosis as evolutionary adaptive mechanism.
KW - 5-HT6 RECEPTOR
KW - BRAIN
KW - DEPRESSION
KW - EXPRESSION
KW - INSULIN
KW - OBESITY
KW - POLYMORPHISM
KW - REDUCES FOOD-INTAKE
KW - RISK-FACTOR
KW - Sert-deficient mice
KW - TLR4 UP-REGULATION
KW - Toll-like receptor 4 (TLR4)
KW - Western diet
KW - aging
KW - glucose tolerance
KW - heterosis
KW - obesity
KW - serotonin receptors
U2 - 10.3389/fnins.2020.00024
DO - 10.3389/fnins.2020.00024
M3 - Article
C2 - 32132889
SN - 1662-453X
VL - 14
JO - Frontiers in Neuroscience
JF - Frontiers in Neuroscience
M1 - 24
ER -