Neurochemical Modifications in the Hippocampus, Cortex and Hypothalamus of Mice Exposed to Long-Term High-Fat Diet

Abstract

Metabolic syndrome and diabetes impact brain function and metabolism. While it is well established that rodents exposed to diets rich in saturated fat develop brain dysfunction, contrasting results abound in the literature, likely as result of exposure to different high-fat diet (HFD) compositions and for varied periods of time. In the present study, we investigated alterations of hippocampal-dependent spatial memory by measuring Y-maze spontaneous alternation, metabolic profiles of the hippocampus, cortex and hypothalamus by 1H magnetic resonance spectroscopy (MRS), and levels of proteins specific to synaptic and glial compartments in mice exposed for 6 months to different amounts of fat (10, 45, or 60% of total energy intake). Increasing the dietary amount of fat from 10 to 45% or 60% resulted in obesity accompanied by increased leptin, fasting blood glucose and insulin, and reduced glucose tolerance. In comparison to controls (10%-fat), only mice fed the 60%-fat diet showed increased fed glycemia, as well as plasma corticosterone that has a major impact on brain function. HFD-induced metabolic profile modifications measured by 1H MRS were observed across the three brain areas in mice exposed to 60%- but not 45%-fat diet, while both HFD groups displayed impaired hippocampal-dependent memory. HFD also affected systems involved in neuro- or gliotransmission in the hippocampus. Namely, relative to controls, 60%-fat-fed mice showed reduced SNAP-25, PSD-95 and syntaxin-4 immunoreactivity, while 45%-fat-fed mice showed reduced gephyrin and syntaxin-4 immunoreactivity. For both HFD levels, reductions of the vesicular glutamate transporter vGlut1 and levels of the vesicular GABA transporter were observed in the hippocampus and hypothalamus, relative to controls. Immunoreactivity against GFAP and/or Iba-1 in the hypothalamus was higher in mice exposed to HFD than controls, suggesting occurrence of gliosis. We conclude that different levels of dietary fat result in distinct neurochemical alterations in the brain.

Daisaikoto Prevents Post-dieting Weight Regain by Reversing Dysbiosis and Reducing Serum Corticosterone in Mice

“…We found that recurrent obesity or long-term consumption of a high-fat diet elevated the serum levels of corticosterone, as previously observed (Shen et al, 2017;Lizarbe et al, 2019), as well as the serum levels of glucose and insulin. Notably, stress promotes weight regain (Elfhag and Rössner, 2005) by elevating cortisol levels, which in turn leads to increases in the serum levels of glucose and insulin (Rosmond et al, 1998).…”

“…Similarly, administration of high doses of insulin to adults with type 1 diabetes resulted in excessive weight gain compared with that observed with conventional therapy (The Diabetes Control and Complications Trial Research Group, 2001). Moreover, long-term high-fat dieting can lead to elevated levels of serum corticosterone (Shen et al, 2017;Lizarbe et al, 2019).…”

Brain Metabolism Alterations in Type 2 Diabetes: What Did We Learn From Diet-Induced Diabetes Models?

“…Glucose intolerance develops promptly in rodents exposed to HFD, followed by a progressive increase of fasting insulin levels and metabolic derangements such as hepatic lipid accumulation (Soares et al, 2018). We have also recently reported that increasing the dietary amount of lard-based fat from 10 to 45 or 60% leads to slightly different diabetic phenotypes: compared to controls that were exposed to the low-fat diet, increased fed glycemia and plasma corticosterone were observed in mice fed a 60%-but not 45%-fat diet (Lizarbe et al, 2019b).…”

“…Brain insulin signaling deficits have been proposed to impact the brain through mechanisms that include the modulation of energy metabolism, synaptic plasticity, learning and memory, as well as interacting with Aβ and tau, the building blocks of amyloid plaques and neurofibrillary tangles (Craft et al, 1998;Steen et al, 2005;Zhao and Townsend, 2009). In addition, a plethora of studies in rodent models of diabetes suggest that both glucose neurotoxicity and deficient insulin signaling impair brain structure and function leading to behavioral and cognitive alterations (e.g., Duarte et al, 2012aDuarte et al, , 2019Calvo-Ochoa et al, 2014;Girault et al, 2019;Lizarbe et al, 2019b).…”

A glucose-stimulated BOLD fMRI study of hypothalamic dysfunction in mice fed a high-fat and high-sucrose diet

“…Western blot analysis was carried out as previously detailed (Lizarbe, Soares et al, 2019) using antibodies against cAMP response element-binding protein (CREB; clone LB9, produced in mouse, #ab178322, AbCam, Cambridge, UK; RRID:AB_2827810), phospho-CREB (Ser133) conjugated with AlexaFluor488 (produced in rabbit, #06-519-AF488, Milipore, Temecula, CA, USA; RRID:AB_310153), c-fos (produced in rabbit, #SAB2100833, Sigma-Aldrich; RRID:AB_10600287), and β -actin conjugated with horseradish peroxidase (produced in mouse, #A3854, Sigma-Aldrich; RRID:AB_262011). Secondary antibodies were conjugated with horseradish peroxidase: goat anti-rabbit IgG (#ab6721, AbCam; RRID:AB_955447); goat antimouse IgG, #ab6789, AbCam; RRID:AB_955439).…”