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.
Highlights
Obesity is a major global health concern and in the last 50 years, its prevalence has increased worldwide, approaching pandemic levels (Blüher, 2019)
To better understand the relationship between consumption of a HFCS-MFD and altered metabolic state, following the experimental design shown in Figure 1A, 5-week-old male C57BL/6J mice were fed a HFCS-MFD or control diet (CD) for 16 weeks
Posthoc Bonferroni analysis revealed that HFCS-MFD mice became significantly heavier in weeks 8-16 compared to those given the CD (p < 0.05 at week 8; p < 0.01 at week 9; p < 0.001 at week 10-16) There was a trend for HFCS-MFD exposed mice to weigh more at the 7th week of dietary exposure (p = 0.06)
Summary
Obesity is a major global health concern and in the last 50 years, its prevalence has increased worldwide, approaching pandemic levels (Blüher, 2019). Obesity is a major type 2 diabetes mellitus (T2DM) risk factor and a core component of metabolic syndrome (MetS). The increasing prevalence of obesity is paralleled by similar increases in T2DM or MetS incidence (Ginsberg and MacCallum, 2009). Anxiety disorders are more common in patients with T2DM than in the general population and can impact both diabetes severity and quality of life. Patients with diabetes and depressive symptoms have mortality rates nearly twice that of diabetics lacking depression symptoms (Kota et al, 2012). Despite this clear pathophysiological relationship, the molecular mechanisms that link neuropsychiatric disorders to obesity and MetS remain poorly understood
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