TY - JOUR
T1 - High Fructose Corn Syrup-Moderate Fat Diet Potentiates Anxio-Depressive Behavior and Alters Ventral Striatal Neuronal Signaling
AU - Chakraborti, Ayanabha
AU - Graham, Christopher
AU - Chehade, Sophie
AU - Vashi, Bijal
AU - Umfress, Alan
AU - Kurup, Pradeep
AU - Vickers, Benjamin
AU - Chen, H. Alexander
AU - Telange, Rahul
AU - Berryhill, Taylor
AU - Van Der Pol, William
AU - Powell, Mickie
AU - Barnes, Stephen
AU - Morrow, Casey
AU - Smith, Daniel L.
AU - Mukhtar, M. Shahid
AU - Watts, Stephen
AU - Kennedy, Gregory
AU - Bibb, James
N1 - Funding Information:
This research was supported by NIH R01MH116896 (JB).
Funding Information:
We thank the UAB Diabetes Research Center (NIH P30 DK-079626) for providing pilot grant funding and outstanding core services including the UAB Small Animal Phenotyping Core supported by the NIH Nutrition & Obesity Research Center P30DK056336 in support of this research. The UAB Nathan Shock Center (P30AG050886A) is gratefully acknowledged. The Yale Neuroproteomics Center is gratefully acknowledged for providing pilot grant funding. The UAB Center for Clinical and Translational Science (Grant No. UL1TR001417 from the National Center for Advancing Translational Sciences, NIH) is acknowledged for Bioinformatics support. We are also thank Dr. Shelly Nason for helpful discussion during preparation and revision of the manuscript.
Funding Information:
We thank the UAB Diabetes Research Center (NIH P30 DK-079626) for providing pilot grant funding and outstanding core services including the UAB Small Animal Phenotyping Core supported by the NIH Nutrition & Obesity Research Center P30DK056336 in support of this research. The UAB Nathan Shock Center (P30AG050886A) is gratefully acknowledged. The Yale Neuroproteomics Center is gratefully acknowledged for providing pilot grant funding. The UAB Center for Clinical and Translational Science (Grant No. UL1TR001417 from the National Center for Advancing Translational Sciences, NIH) is acknowledged for Bioinformatics support. We are also thank Dr. Shelly Nason for helpful discussion during preparation and revision of the manuscript. Funding. This research was supported by NIH R01MH116896 (JB).
Publisher Copyright:
© Copyright © 2021 Chakraborti, Graham, Chehade, Vashi, Umfress, Kurup, Vickers, Chen, Telange, Berryhill, Van Der Pol, Powell, Barnes, Morrow, Smith, Mukhtar, Watts, Kennedy and Bibb.
PY - 2021/5/26
Y1 - 2021/5/26
N2 - The neurobiological mechanisms that mediate psychiatric comorbidities associated with metabolic disorders such as obesity, metabolic syndrome and diabetes remain obscure. High fructose corn syrup (HFCS) is widely used in beverages and is often included in food products with moderate or high fat content that have been linked to many serious health issues including diabetes and obesity. However, the impact of such foods on the brain has not been fully characterized. Here, we evaluated the effects of long-term consumption of a HFCS-Moderate Fat diet (HFCS-MFD) on behavior, neuronal signal transduction, gut microbiota, and serum metabolomic profile in mice to better understand how its consumption and resulting obesity and metabolic alterations relate to behavioral dysfunction. Mice fed HFCS-MFD for 16 weeks displayed enhanced anxiogenesis, increased behavioral despair, and impaired social interactions. Furthermore, the HFCS-MFD induced gut microbiota dysbiosis and lowered serum levels of serotonin and its tryptophan-based precursors. Importantly, the HFCS-MFD altered neuronal signaling in the ventral striatum including reduced inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β), increased expression of ΔFosB, increased Cdk5-dependent phosphorylation of DARPP-32, and reduced PKA-dependent phosphorylation of the GluR1 subunit of the AMPA receptor. These findings suggest that HFCS-MFD-induced changes in the gut microbiota and neuroactive metabolites may contribute to maladaptive alterations in ventral striatal function that underlie neurobehavioral impairment. While future studies are essential to further evaluate the interplay between these factors in obesity and metabolic syndrome-associated behavioral comorbidities, these data underscore the important role of peripheral-CNS interactions in diet-induced behavioral and brain function. This study also highlights the clinical need to address neurobehavioral comorbidities associated with obesity and metabolic syndrome.
AB - The neurobiological mechanisms that mediate psychiatric comorbidities associated with metabolic disorders such as obesity, metabolic syndrome and diabetes remain obscure. High fructose corn syrup (HFCS) is widely used in beverages and is often included in food products with moderate or high fat content that have been linked to many serious health issues including diabetes and obesity. However, the impact of such foods on the brain has not been fully characterized. Here, we evaluated the effects of long-term consumption of a HFCS-Moderate Fat diet (HFCS-MFD) on behavior, neuronal signal transduction, gut microbiota, and serum metabolomic profile in mice to better understand how its consumption and resulting obesity and metabolic alterations relate to behavioral dysfunction. Mice fed HFCS-MFD for 16 weeks displayed enhanced anxiogenesis, increased behavioral despair, and impaired social interactions. Furthermore, the HFCS-MFD induced gut microbiota dysbiosis and lowered serum levels of serotonin and its tryptophan-based precursors. Importantly, the HFCS-MFD altered neuronal signaling in the ventral striatum including reduced inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β), increased expression of ΔFosB, increased Cdk5-dependent phosphorylation of DARPP-32, and reduced PKA-dependent phosphorylation of the GluR1 subunit of the AMPA receptor. These findings suggest that HFCS-MFD-induced changes in the gut microbiota and neuroactive metabolites may contribute to maladaptive alterations in ventral striatal function that underlie neurobehavioral impairment. While future studies are essential to further evaluate the interplay between these factors in obesity and metabolic syndrome-associated behavioral comorbidities, these data underscore the important role of peripheral-CNS interactions in diet-induced behavioral and brain function. This study also highlights the clinical need to address neurobehavioral comorbidities associated with obesity and metabolic syndrome.
KW - anxiety
KW - depression
KW - diet
KW - high fructose corn syrup (HFCS)
KW - nucleus accumbens
KW - serotonin
KW - tryptophan
UR - http://www.scopus.com/inward/record.url?scp=85107526249&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85107526249&partnerID=8YFLogxK
U2 - 10.3389/fnins.2021.669410
DO - 10.3389/fnins.2021.669410
M3 - Article
C2 - 34121997
AN - SCOPUS:85107526249
SN - 1662-4548
VL - 15
JO - Frontiers in Neuroscience
JF - Frontiers in Neuroscience
M1 - 669410
ER -