High Fructose Corn Syrup-Moderate Fat Diet Potentiates Anxio-Depressive Behavior and Alters Ventral Striatal Neuronal Signaling

Abstract

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.

The Impact of Gut Microbiome on Maternal Fructose Intake-Induced Developmental Programming of Adult Disease

“…The metabolic profiling from high-fructose- and salt-fed rats showed the increase of TMAO in urine was associated with metabonomic progression axes, progressing from normal to insulin resistance and hypertension status [ 38 ]. This final status of hypertension is an observation regarding mice fed a HFCS-moderate fat diet and displayed anxio-depressive behavior coinciding with altered gut microbiota compositions and tryptophan metabolites [ 39 ]. Altogether, these studies indicate that fructose is able to induce gut microbiota dysbiosis in three ways: it disrupts the gut barrier triggering endotoxemia and inflammation; it alters gut microbial profile and diversity; and it influences key microbial metabolites.…”

A modified standard American diet induces physiological parameters associated with metabolic syndrome in C57BL/6J mice

“…Reports of gut dysbiosis associated with WD consumption have led to increased interest in the role of the microbiome in the development of obesity and MetS. Several studies have linked WD-induced pathologies to altered populations of microbes ( 1 , 24 , 56 ) and reversion of gut dysbiosis has been shown to attenuate WD-induced dysfunction ( 57 ). The limited amount of microbiome data reported from previous NHANES-based WD studies prompted us to investigate the composition of the fecal microbiome of mSAD-fed mice.…”

“…Quantitative Magnetic Resonance (QMR) was performed according to previously published methods ( 24 ) on mice at weeks 4, 6, 7, 10, and 12 to measure in vivo fat and lean-tissue mass (EchoMRI™ 3-in-1; Echo Medical Systems, Houston, TX, United States). Due to technical issues, QMR could not be performed at the termination of the study; however, QMR lean mass values for week 15 were predicted using a simple linear regression.…”

Systemic Administration of a Brain Permeable Cdk5 Inhibitor Alters Neurobehavior

“…The OFT was performed as described ( Chakraborti et al, 2021 ). With the adaptation duration of the test being 1 h for each mouse, briefly, the mice were placed in a square box (40 cm × 40 cm) and allowed to freely explore.…”