Eicosapentaenoic Acid Protects against Metabolic Impairments in the APPswe/PS1dE9 Alzheimer's Disease Mouse Model.

BACKGROUND: Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by amyloid-ß (Aß) plaques. Systemic inflammation and obesity may exacerbate AD pathogenesis. We previously reported anti-inflammatory and anti-obesity effects of EPA in mice. OBJECTIVES: We aimed to determine whether EPA reduces obesity-associated metabolic dysfunctions and Aß accumulation in AD amyloidogenic mice. METHODS: Two-mo-old APPswe/PS1dE9 transgenic (TG) mice and non-TG littermates were randomly assigned to low fat (LF; 10% kcal fat), high fat (HF; 45% kcal fat), or EPA (36 g/kg)-supplemented HF diets. Body composition, glucose tolerance, and energy expenditure were measured, and serum and brain metabolic markers were tested 38 wk postintervention. Outcomes were statistically analyzed via 3-factor ANOVA, modeling genotype, sex, and diet interactions. RESULTS: HF-fed males gained more weight than females (Δ = 61 mg; P < 0.001). Compared with LF, HF increased body weights of wild-type (WT) males (Δ = 31 mg; P < 0.001). EPA reduced HF-induced weight gain in WT males (Δ = 24 mg; P = 0.054) but not in females. HF mice showed decreased glucose clearance and respiratory energy compared with LF-fed groups (Δ = -1.31 g/dL; P < 0.001), with no significant effects of EPA. However, EPA conferred metabolic improvements by decreasing serum leptin and insulin (Δ = -2.51 g/mL and Δ = -0.694 ng/mL, respectively compared with HF, P ≤ 0.05) and increasing adiponectin (Δ = 21.6 ng/mL; P < 0.001). As we expected, TG mice expressed higher serum and brain Aß than WT mice (Δ = 0.131 ng/mL; P < 0.001 and Δ = 0.56%; P < 0.01, respectively), and EPA reduced serum Aß1-40 in TG males compared with HF (Δ = 0.053 ng/mL; P ≤ 0.05). CONCLUSIONS: To our knowledge, this is the first report that EPA reduces serum Aß1-40 in obese AD male mice, warranting further investigations into tissue-specific mechanisms of EPA in AD.

Effects of 3-week total meal replacement vs. typical food-based diet on human brain functional magnetic resonance imaging food-cue reactivity and functional connectivity in people with obesity.

OBJECTIVES: Calorie restriction via total meal replacement (TMR) results in greater reduction of food cravings compared to reduced-calorie typical diet (TD). Direct evidence of the impact of these interventions on human brain fMRI food-cue reactivity (fMRI-FCR) and functional connectivity is absent. We examined the effects of a 3-week 1120 kcal/d TMR intervention as compared to an iso-caloric TD intervention using an fMRI-FCR paradigm. METHODS: Thirty-two male and female subjects with obesity (19-60 years; 30-39.9 kg/m2) participated in a randomized two-group repeated measures dietary intervention study consisting of 1120 kcal/d from either 1) TMR (shakes), 2) TD (portion control). Pre-intervention and following the 3-week diet fMRI-FCR, functional connectivity, food cravings (Food Craving Inventory) and weight were considered. RESULTS: Compared to TD, TMR showed increased fMRI-FCR of the bilateral dorsolateral prefrontal (dlPFC), orbitofrontal, anterior cingulate, primary motor and left insular cortices and bilateral nucleus accumbens regions in the post-intervention state relative to the pre-intervention state. Compared to TD, TMR was also associated with negative modulation of fMRI-FCR of the nucleus accumbens, orbitofrontal cortex and amygdala by dlPFC. Reduced body weight (4.87 kg, P < 0.001), body fat (2.19 kg, P = 0.004) and overall food cravings (0.41, P = 0.047) were seen in the TMR group. In the TD group reduced body weight (2.37 kg, P = 0.004) and body fat (1.64 kg, P = 0.002) were noted. Weight loss was significantly greater in TMR versus TD (2.50 kg, P = 0.007). CONCLUSIONS: Greater weight loss and reduced cravings, coupled with stronger activations and potential negative modulation of the food reward related regions by the dlPFC during exposure to visual food cues is consistent with increased executive control in TMR vs. TD.

Do scores on the Food Craving Inventory and Three-Factor Eating Questionnaire correlate with expected brain regions of interest in people with obesity?

OBJECTIVE: To examine whether subscales of Food Craving Inventory (FCI) and Three-factor Eating Questionnaire (TFEQ) correlate with brain functional magnetic resonance imaging food-cue reactivity (fMRI-FCR) in the brain. METHODS: Thirty-two male and female adults with obesity (19-60years; 30-39.9kg/m2) participated in a 3-week dietary intervention (1120kcal/day from either 1) total meal replacement shakes, 2) portion-controlled typical food. FCI, TFEQ and fMRI-FCR were measured pre- and post-intervention. Correlations between pre-intervention fMRI-FCR and standardized pre-intervention FCI and TFEQ subscales; and also post- versus pre-intervention change in fMRI-FCR (ΔfMRI-FCR) and standardized changes in FCI and TFEQ subscales were examined at the whole brain level using tools in FMRIB Software Library. RESULTS: Twenty-eight subjects completed the intervention. Pre-intervention high-fat food cravings (P=0.041) and fast-food cravings (P=0.017) were negatively correlated with fMRI-FCR of several brain regions that regulate executive control over ingestion (i.e. bilateral lateral frontal pole, dorsolateral prefrontal cortex and dorsal anterior cingulate cortex). Post- vs. pre-intervention change in sweet (P=0.012) and fast food cravings (P=0.004) were negatively correlated with ΔfMRI-FCR of bilateral lateral frontal pole, dorsolateral prefrontal cortex, inferior frontal gyrus (pars opercularis) and dorsal anterior cingulate cortex (i.e. brain regions that regulate executive control over ingestion). Negative correlations were also observed between the changes in sweet and fast food cravings and ΔfMRI-FCR of brain regions that regulate food reward (i.e. bilateral mid-anterior insula, right nucleus accumbens), motor readiness to ingest (i.e. bilateral precentral gyrus), internally focused attention (i.e. bilateral precuneus and posterior cingulate cortex) and visual object recognition (i.e. occipital pole, lateral occipital cortex and middle and inferior temporal cortices). Changes in cravings for starchy food (P=0.032) and overall food cravings (P=0.027) were also negatively correlated with ΔfMRI-FCR of brain regions involved in regulating internally focused attention and visual object recognition. CONCLUSIONS: In individuals with obesity, decreased food cravings seem to be reflective of increased fMRI-FCR of brain regions that regulate executive control over ingestion. Taken together, constructs measured by FCI seem to be reflective of neurophysiological processes underlying ingestive behavior and the changes in neurophysiological processes occurring during calorie restriction. CLINICAL TRIALS REGISTRY NUMBER: NCT02637271; the protocol is available at https://clinicaltrials.gov/ct2/show/NCT02637271.