Impact of Long-Term Dietary High Fat and Eicosapentaenoic Acid on Behavior and Hypothalamic-Pituitary-Adrenal Axis Activity in Amyloidogenic APPswe/PSEN1dE9 Mice.

INTRODUCTION: Alzheimer's disease (AD) alters neurocognitive and emotional function and causes dysregulation of multiple homeostatic processes. The leading AD framework pins amyloid beta plaques and tau tangles as primary drivers of dysfunction. However, many additional variables, including diet, stress, sex, age, and pain tolerance, interact in ways that are not fully understood to impact the onset and progression of AD pathophysiology. We asked: (1) does high-fat diet, compared to low-fat diet, exacerbate AD pathophysiology and behavioral decline? And, (2) can supplementation with eicosapentaenoic (EPA)-enriched fish oil prevent high-fat-diet-induced changes? METHODS: Male and female APPswePSdE9 mice, and their non-transgenic littermates, were randomly assigned to a diet condition (low-fat, high-fat, high-fat with EPA) and followed from 2 to 10 months of age. We assessed baseline corticosterone concentration during aging, pain tolerance, cognitive function, stress coping, and corticosterone response to a stressor. RESULTS: Transgenic mice were consistently more active than non-transgenic mice but did not perform worse on either cognitive task, even though we recently reported that these same transgenic mice exhibited metabolic changes and had increased amyloid beta. Mice fed high-fat diet had higher baseline and post-stressor corticosterone, but diet did not impact cognition or pain tolerance. Sex had the biggest influence, as female mice were consistently more active and had higher corticosterone than males. CONCLUSION: Overall, diet, genotype, and sex did not have consistent impacts on outcomes. We found little support for predicted interactions and correlations, suggesting diet impacts metabolic function and amyloid beta levels, but these outcomes do not translate to changes in behaviors measured here.

Mechanisms linking endoplasmic reticulum (ER) stress and microRNAs to adipose tissue dysfunction in obesity.

Over accumulation of lipids in adipose tissue disrupts metabolic homeostasis by affecting cellular processes. Endoplasmic reticulum (ER) stress is one such process affected by obesity. Biochemical and physiological alterations in adipose tissue due to obesity interfere with adipose ER functions causing ER stress. This is in line with increased irregularities in other cellular processes such as inflammation and autophagy, affecting overall metabolic integrity within adipocytes. Additionally, microRNAs (miRNAs), which can post-transcriptionally regulate genes, are differentially modulated in obesity. A better understanding and identification of such miRNAs could be used as novel therapeutic targets to fight against diseases. In this review, we discuss ways in which ER stress participates as a common molecular process in the pathogenesis of obesity-associated metabolic disorders. Moreover, our review discusses detailed underlying mechanisms through which ER stress and miRNAs contribute to metabolic alteration in adipose tissue in obesity. Hence, identifying mechanistic involvement of miRNAs-ER stress cross-talk in regulating adipose function during obesity could be used as a potential therapeutic approach to combat chronic diseases, including obesity.

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.

Temperature-Dependent Effects of Eicosapentaenoic Acid (EPA) on Browning of Subcutaneous Adipose Tissue in UCP1 Knockout Male Mice.

Uncoupling protein 1 (UCP1) plays a central role in thermogenic tissues by uncoupling cellular respiration to dissipate energy. Beige adipocytes, an inducible form of thermogenic cells in subcutaneous adipose tissue (SAT), have become a major focus in obesity research. We have previously shown that eicosapentaenoic acid (EPA) ameliorated high-fat diet (HFD)-induced obesity by activating brown fat in C57BL/6J (B6) mice at thermoneutrality (30 °C), independently of UCP1. Here, we investigated whether ambient temperature (22 °C) impacts EPA effects on SAT browning in wild-type (WT) and UCP1 knockout (KO) male mice and dissected underlying mechanisms using a cell model. We observed resistance to diet-induced obesity in UCP1 KO mice fed HFD at ambient temperature, with significantly higher expression of UCP1-independent thermogenic markers, compared to WT mice. These markers included the fibroblast growth factor 21 (FGF21) and sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b), suggesting the indispensable role of temperature in beige fat reprogramming. Surprisingly, although EPA induced thermogenic effects in SAT-derived adipocytes harvested from both KO and WT mice, EPA only increased thermogenic gene and protein expression in the SAT of UCP1 KO mice housed at ambient temperature. Collectively, our findings indicate that the thermogenic effects of EPA, which are independent of UCP1, occur in a temperature-dependent manner.

Effect of Dietary Geranylgeraniol and Green Tea Polyphenols on Glucose Homeostasis, Bone Turnover Biomarkers, and Bone Microstructure in Obese Mice.

Previously, we demonstrated that the administration of either geranylgeraniol (GGOH) or green tea polyphenols (GTP) improved bone health. This study examined the combined effects of GGOH and GTP on glucose homeostasis in addition to bone remodeling in obese mice. We hypothesized that GGOH and GTP would have an additive or synergistic effect on improving glucose homeostasis and bone remodeling possibly in part via suppression of proinflammatory cytokines. Forty-eight male C57BL/6J mice were assigned to a high-fat diet (control), HFD + 400 mg GGOH/kg diet (GG), HFD + 0.5% GTP water (TP), or HFD + GGOH + GTP (GGTP) diet for 14 weeks. Results demonstrated that GTP supplementation improved glucose tolerance in obese mice. Neither GGOH nor GTP affected pancreas insulin or bone formation procollagen type I intact N-terminal, bone volume at the lumbar vertebrae, or bone parameters at the trabecular bone and cortical bone of the femur. There was an interactive effect for serum bone resorption collagen type 1 cross-linked C-telopeptide concentrations, resulting in no-GGOH and no-GTP groups having the highest values. GGOH increased trabecular number and decreased trabecular separation at the lumbar vertebrae. GTP increased trabecular thickness at lumbar vertebrae. The GG group produced the greatest connectivity density and the lowest structure model index. Only GTP, not GGOH, decreased adipokines concentrations (resistin, leptin, monocyte chemoattractant protein-1, and interleukin-6). In an obese male mouse model, individual GGOH and GTP supplementation improved glucose homeostasis, serum CTX, and trabecular microstructure of LV-4. However, the combined GGOH and GTP supplementation compromises such osteoprotective effects on serum CTX and trabecular bone of obese mice.

Engineering and Characterization of a Biomimetic Microchip for Differentiating Mouse Adipocytes in a 3D Microenvironment.

Although two-dimensional (2D) cell cultures are the standard in cell research, one pivotal disadvantage is the lack of cell-cell and cell-extracellular matrix (ECM) signaling in the culture milieu. However, such signals occur in three-dimensional (3D) in vivo environments and are essential for cell differentiation, proliferation, and a range of cellular functions. In this study, we developed a microfluidic device to proliferate and differentiate functional adipose tissue and adipocytes by utilizing 3D cell culture technology. This device was used to generate a tissue-specific 3D microenvironment to differentiate 3T3-L1 preadipocytes into either visceral white adipocytes using visceral adipose tissue (VAT) or subcutaneous white adipose tissue (SAT). The microchip has been tested and validated by functional assessments including cell morphology, inflammatory response to a lipopolysaccharide (LPS) challenge, GLUT4 tracking, and gene expression analyses. The biomimetic microfluidic chip is expected to mimic functional adipose tissues that can replace 2D cell cultures and allow for more accurate analysis of adipose tissue physiology.

Renin angiotensin system inhibition attenuates adipocyte-breast cancer cell interactions.

Obesity is a significant breast cancer (BC) risk factor and is associated with 20-40% increased risk in obese post-menopausal women compared to their lean counterparts. Several obesity-related metabolic dysregulations have been linked to BC risk, including overactivation of the renin-angiotensin system (RAS). Currently, RAS inhibitors including angiotensin converting enzyme inhibitor (ACEi) and AT1 receptor blockers (ARBs), are used as safe and effective anti-hypertensive therapies in BC patients. However, it is uncertain how inhibition of RAS in adipose tissue impacts obesity-BC crosstalk. We hypothesized that adipose RAS inhibition will reduce BC cell motility and inflammation. We determined (1) the direct effects of Ang II, ACEi (captopril; Cap) or ARB (telmisartan; Tel) on receptor positive MCF-7 and receptor triple negative MDA-MB-231 cells; and (2) the effects of conditioned media (CM) from human mesenchymal stem cells differentiated into adipocytes, which were pretreated with RAS inhibitors, on BC cells. We demonstrated that direct treatments of BC cells with Ang II, Cap or Tel did not alter inflammatory cytokines in either BC cell line. However, CM from Ang II-pretreated adipocytes significantly increased secretion of pro-inflammatory markers at protein level. RAS inhibitors reduced their secretion in MDA-MB-231, but not in MCF-7 cells. Additionally, CM from adipocytes treated with RAS inhibitors significantly reduced markers of inflammation, fat synthesis, and angiogenesis in both BC cell lines. Furthermore, CM from ACEi pretreated adipocytes reduced cell motility in both BC cell lines. Findings from our study indicate an important role of adipose RAS inhibition in adipocyte and BC cell crosstalk.

The renin angiotensin system, oxidative stress and mitochondrial function in obesity and insulin resistance.

Obesity is a complex disease characterized by excessive expansion of adipose tissue and is an important risk factor for chronic diseases such as cardiovascular disorders, hypertension and type 2 diabetes. Moreover, obesity is a major contributor to inflammation and oxidative stress, all of which are key underlying causes for diabetes and insulin resistance. Specifically, adipose tissue secretes bioactives molecules such as inflammatory hormone angiotensin II, generated in the Renin Angiotensin System (RAS) from its precursor angiotensinogen. Accumulated evidence suggests that RAS may serve as a strong link between obesity and insulin resistance. Dysregulation of RAS also occurs in several other tissues including those involved in regulation of glucose and whole body homeostasis as well as insulin sensitivity such as muscle, liver and pancreas and heart. Here we review the scientific evidence for these interactions and potential roles for oxidative stress, inflammation and mitochondrial dysfunction in these target tissues which may mediate effects of RAS in metabolic diseases. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.

The p21-activated kinase (PAK1) is involved in diet-induced beta cell mass expansion and survival in mice and human islets.

AIMS/HYPOTHESIS: Human islets from type 2 diabetic donors are reportedly 80% deficient in the p21 (Cdc42/Rac)-activated kinase, PAK1. PAK1 is implicated in beta cell function and maintenance of beta cell mass. We questioned the mechanism(s) by which PAK1 deficiency potentially contributes to increased susceptibility to type 2 diabetes. METHODS: Non-diabetic human islets and INS 832/13 beta cells cultured under diabetogenic conditions (i.e. with specific cytokines or under glucolipotoxic [GLT] conditions) were evaluated for changes to PAK1 signalling. Combined effects of PAK1 deficiency with GLT stress were assessed using classic knockout (Pak1 (-/-) ) mice fed a 45% energy from fat/palmitate-based, 'western' diet (WD). INS 832/13 cells overexpressing or depleted of PAK1 were also assessed for apoptosis and signalling changes. RESULTS: Exposure of non-diabetic human islets to diabetic stressors attenuated PAK1 protein levels, concurrent with increased caspase 3 cleavage. WD-fed Pak1 knockout mice exhibited fasting hyperglycaemia and severe glucose intolerance. These mice also failed to mount an insulin secretory response following acute glucose challenge, coinciding with a 43% loss of beta cell mass when compared with WD-fed wild-type mice. Pak1 knockout mice had fewer total beta cells per islet, coincident with decreased beta cell proliferation. In INS 832/13 beta cells, PAK1 deficiency combined with GLT exposure heightened beta cell death relative to either condition alone; PAK1 deficiency resulted in decreased extracellular signal-related kinase (ERK) and B cell lymphoma 2 (Bcl2) phosphorylation levels. Conversely, PAK1 overexpression prevented GLT-induced cell death. CONCLUSIONS/INTERPRETATION: These findings suggest that PAK1 deficiency may underlie an increased diabetic susceptibility. Discovery of ways to remediate glycaemic dysregulation via altering PAK1 or its downstream effectors offers promising opportunities for disease intervention.

Doc2b serves as a scaffolding platform for concurrent binding of multiple Munc18 isoforms in pancreatic islet ß-cells.

Biphasic glucose-stimulated insulin secretion (GSIS) from pancreatic ß-cells involves soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor (SNARE) protein-regulated exocytosis. SNARE complex assembly further requires the regulatory proteins Munc18c, Munc18-1 and Doc2b. Munc18-1 and Munc18c are required for first- and second-phase GSIS respectively. These distinct Munc18-1 and Munc18c roles are related to their transient high-affinity binding with their cognate target (t-)SNAREs, Syntaxin 1A and Syntaxin 4 respectively. Doc2b is essential for both phases of GSIS, yet the molecular basis for this remains unresolved. Because Doc2b binds to Munc18-1 and Munc18c via its distinct C2A and C2B domains respectively, we hypothesized that Doc2b may provide a plasma membrane-localized scaffold/platform for transient docking of these Munc18 isoforms during GSIS. Towards this, macromolecular complexes composed of Munc18c, Doc2b and Munc18-1 were detected in ß-cells. In vitro interaction assays indicated that Doc2b is required to bridge the interaction between Munc18c and Munc18-1 in the macromolecular complex; Munc18c and Munc18-1 failed to associate in the absence of Doc2b. Competition-based GST-Doc2b interaction assays revealed that Doc2b could simultaneously bind both Munc18-1 and Munc18c. Hence these data support a working model wherein Doc2b functions as a docking platform/scaffold for transient interactions with the multiple Munc18 isoforms operative in insulin release, promoting SNARE assembly.

Doc2b enrichment enhances glucose homeostasis in mice via potentiation of insulin secretion and peripheral insulin sensitivity.

AIMS/HYPOTHESIS: Insulin secretion from pancreatic beta cells and insulin-stimulated glucose uptake into skeletal muscle are processes regulated by similar isoforms of the soluble N-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE) and mammalian homologue of unc-18 (Munc18) protein families. Double C2 domain ß (Doc2b), a SNARE- and Munc18-interacting protein, is implicated as a crucial effector of glycaemic control. However, whether Doc2b is naturally limiting for these processes, and whether Doc2b enrichment might exert a beneficial effect upon glycaemia in vivo, remains undetermined. METHODS: Tetracycline-repressible transgenic (Tg) mice engineered to overexpress Doc2b simultaneously in the pancreas, skeletal muscle and adipose tissues were compared with wild-type (Wt) littermate mice regarding glucose and insulin tolerance, islet function in vivo and ex vivo, and skeletal muscle GLUT4 accumulation in transverse tubule/sarcolemmal surface membranes. SNARE complex formation was further assessed using Doc2b overexpressing L6-GLUT4-myc myoblasts to derive mechanisms relatable to physiological in vivo analyses. RESULTS: Doc2b Tg mice cleared glucose substantially faster than Wt mice, correlated with enhancements in both phases of insulin secretion and peripheral insulin sensitivity. Heightened peripheral insulin sensitivity correlated with elevated insulin-stimulated GLUT4 vesicle accumulation in cell surface membranes of Doc2b Tg mouse skeletal muscle. Mechanistic studies demonstrated Doc2b enrichment to enhance syntaxin-4-SNARE complex formation in skeletal muscle cells. CONCLUSIONS/INTERPRETATION: Doc2b is a limiting factor in SNARE exocytosis events pertinent to glycaemic regulation in vivo. Doc2b enrichment may provide a novel means to simultaneously boost islet and skeletal muscle function in vivo in the treatment and/or prevention of diabetes.

Novel roles for insulin receptor (IR) in adipocytes and skeletal muscle cells via new and unexpected substrates.

The insulin signaling pathway regulates whole-body glucose homeostasis by transducing extracellular signals from the insulin receptor (IR) to downstream intracellular targets, thus coordinating a multitude of biological functions. Dysregulation of IR or its signal transduction is associated with insulin resistance, which may culminate in type 2 diabetes. Following initial stimulation of IR, insulin signaling diverges into different pathways, activating multiple substrates that have roles in various metabolic and cellular processes. The integration of multiple pathways arising from IR activation continues to expand as new IR substrates are identified and characterized. Accordingly, our review will focus on roles for IR substrates as they pertain to three primary areas: metabolism/glucose uptake, mitogenesis/growth, and aging/longevity. While IR functions in a seemingly pleiotropic manner in many cell types, through these three main roles in fat and skeletal muscle cells, IR multi-tasks to regulate whole-body glucose homeostasis to impact healthspan and lifespan.

Fish Oil Improves Offspring Metabolic Health of Paternal Obese Mice by Targeting Adipose Tissue.

Obesity is a fast-growing epidemic affecting more than 40% of the US population and leads to co-morbidities such as type 2 diabetes and cancer. More importantly, there is a rapid increase in childhood obesity associated with obesity in parents. Further, offspring are encoded with approximately half of their genetic information from the paternal side. Obesity in fathers at the preconceptional period likely influences the intergenerational development of obesity. This study focuses on the role of fish oil supplementation as a non-pharmacological intervention in fathers and its impact on childhood obesity using animal models. Male mice were fed a low-fat diet or high-fat diet with or without fish oil for 10 weeks and mated with female mice on a chow diet. Offspring were then continued on a chow diet until 8 or 16 weeks. In vivo insulin tolerance was tested to assess the metabolic health of offspring. Further, adipose tissue was harvested upon sacrifice, and genetic markers of inflammation and lipid metabolism in the tissue were analyzed. Offspring of males supplemented with fish oil showed lower body weight, improved insulin tolerance, and altered inflammatory markers. Markers of fatty acid oxidation were higher, while markers of fatty acid synthesis were lower in offspring of fathers fed fish oil. This supports fish oil as an accessible intervention to improve offspring metabolic health.

Enhanced Metabolic Effects of Fish Oil When Combined with Vitamin D in Diet-Induced Obese Male Mice.

Vitamin D (vit D) and fish oil (FO) both offer unique health benefits, however, their combined effects have not been evaluated in obesity and nonalcoholic fatty liver disease (NAFLD). Hence, we hypothesized that vit D and FO supplementation would have additive effects in reducing obesity-associated inflammation and NAFLD. Male C57BL6 mice were split into four groups and fed a high fat (HF) diet supplemented with a low (HF; +200 IU vit D) or high dose of vitamin D (HF + D; +1000 IU vit D); combination of vit D and FO (HF-FO; +1000 IU vit D); or only FO (HF-FO; +200 IU vit D) for 12 weeks. We measured body weight, food intake, glucose tolerance, and harvested epididymal fat pad and liver for gene expression analyses. Adiposity was reduced in groups supplemented with both FO and vit D. Glucose clearance was higher in FO-supplemented groups compared to mice fed HF. In adipose tissue, markers of fatty acid synthesis and oxidation were comparable in groups that received vit D and FO individually in comparison to HF. However, the vit D and FO group had significantly lower fatty acid synthesis and higher oxidation compared to the other groups. Vit D and FO also significantly improved fatty acid oxidation, despite similar fatty acid synthesis among the four groups in liver. Even though we did not find additive effects of vit D and FO, our data provide evidence that FO reduces markers of obesity in the presence of adequate levels of vit D.

Role of Fish Oil in Preventing Paternal Obesity and Improving Offspring Skeletal Muscle Health.

This study investigates the effects of fish oil supplementation during the periconceptional period in male mice. Specifically, it examines the impact of fish oil on intergenerational health, as determined by skeletal muscle markers. To mimic paternal obesity, thirty mice were separated into three groups with distinct dietary regimes for 10 weeks: a high-fat diet (HF), a high-fat diet supplemented with fish oil (FO), and a low-fat diet (LF). Then, these mice mated with control female mice. Dams and offspring consumed a chow diet during gestation and lactation, and the offspring continued on a chow diet. To study short-term (8 weeks) and long-term (16 weeks) effects of FO, skeletal muscle was isolated at the time of sacrifice, and gene analyses were performed. Results suggest that offspring born to FO-supplemented sires exhibited a significant, short-term upregulation of genes associated with insulin signaling, fatty acid oxidation, and skeletal muscle growth with significant downregulation of genes involved in fatty acid synthesis at 8 weeks. Prominent differences in the above markers were observed at 8 weeks compared to 16 weeks. These findings suggest the potential benefits of FO supplementation for fathers during the periconceptional period in reducing the health risks of offspring due to paternal obesity.

Effects of Fish Oil Supplementation on Reducing the Effects of Paternal Obesity and Preventing Fatty Liver in Offspring.

Nonalcoholic fatty liver disease (NAFLD) is a serious public health concern, which calls for appropriate diet/nutrition intervention. Fish oil (FO) has several benefits in reducing obesity, but its intergenerational role in reducing the effects of paternal obesity has not been established. Hence, we hypothesized that FO supplementation to an obese father during the pre-conceptional period could improve the metabolic health of the offspring, specifically in the liver. Three groups of male mice were fed with a low-fat (LF), high-fat (HF), or high-fat diet supplemented with FO (HF-FO) for 10 weeks and were then allowed to mate with female mice fed a chow diet. Offspring were sacrificed at 16 weeks. The liver tissue was harvested for genomic and histological analyses. The offspring of HF and HF-FO fathers were heavier compared to that of the LF mice during 9-16 weeks. The glucose tolerance of the offspring of HF-FO fathers were significantly improved as compared to the offspring of HF fathers. Paternal FO supplementation significantly lowered inflammation and fatty acid synthesis biomarkers and increased fatty acid oxidation biomarkers in the offspring liver. In summary, FO supplementation in fathers shows the potential to reduce metabolic and cardiovascular diseases through genetic means in offspring.

Anti-inflammatory mechanisms of polyphenols in adipose tissue: role of gut microbiota, intestinal barrier integrity and zinc homeostasis.

Obesity is associated with an imbalance of micro-and macro-nutrients, gut dysbiosis, and a "leaky" gut phenomenon. Polyphenols, such as curcumin, resveratrol, and anthocyanins may alleviate the systemic effects of obesity, potentially by improving gut microbiota, intestinal barrier integrity (IBI), and zinc homeostasis. The essential micronutrient zinc plays a crucial role in the regulation of enzymatic processes, including inflammation, maintenance of the microbial ecology, and intestinal barrier integrity. In this review, we focus on IBI- which prevents intestinal lipopolysaccharide (LPS) leakage - as a critical player in polyphenol-mediated protective effects against obesity-associated white adipose tissue (WAT) inflammation. This occurs through mechanisms that block the movement of the bacterial endotoxin LPS across the gut barrier. Available research suggests that polyphenols reduce WAT and systemic inflammation via crosstalk with inflammatory NF-κB, the mammalian target of rapamycin (mTOR) signaling and zinc homeostasis.

Long-term effects of adolescent exposure to olanzapine in C57BL/6 J mice and the impact of dietary fish oil supplementation.

RATIONALE: Second-generation antipsychotic (SGA) medications can produce abnormal weight gain and metabolic dysfunction in children, but little is known about the post-treatment consequences of adolescent SGA exposure. OBJECTIVES: The objective of this study was to determine the long-term, post-treatment effects of adolescent olanzapine exposure on weight and metabolic function and whether dietary fish oil (FO) modulated any observed effects of olanzapine. METHODS: Male and female mice were fed a high-fat, high-sugar (HF-HS) diet or an HF-HS diet supplemented with fish oil (HF-HS-FO) and were treated with olanzapine or vehicle for 29 days beginning on postnatal day 37. RESULTS: In male mice, adolescent olanzapine treatment suppressed weight gain during and after treatment and improved metabolic function in adulthood; dietary fish oil reduced weight gain, increased expression of fatty acid oxidation genes, and decreased expression of genes associated with fatty acid synthesis and inflammation. In contrast, few effects were observed in female mice. CONCLUSIONS: The current results suggest that adolescent olanzapine exposure can produce long-term alterations in weight and metabolic function in male mice and that dietary fish oil can reduce adverse effects of lifelong consumption of an HF-HS diet. Because expected adverse effects of adolescent olanzapine treatment were not observed, the potential beneficial effects of dietary fish oil for SGA-induced weight gain and metabolic dysfunction could not be evaluated.