Effects of saturated versus unsaturated fatty acids on metabolism, gliosis, and hypothalamic leptin sensitivity in male mice.

BACKGROUND: Development of obesity and its comorbidities is not only the result of excess energy intake, but also of dietary composition. Understanding how hypothalamic metabolic circuits interpret nutritional signals is fundamental to advance towards effective dietary interventions. OBJECTIVE: We aimed to determine the metabolic response to diets enriched in specific fatty acids. METHODS: Male mice received a diet enriched in unsaturated fatty acids (UOLF) or saturated fatty acids (SOLF) for 8 weeks. RESULTS: UOLF and SOLF mice gained more weight and adiposity, but with no difference between these two groups. Circulating leptin levels increased on both fatty acid-enriched diet, but were higher in UOLF mice, as were leptin mRNA levels in visceral adipose tissue. In contrast, serum non-esterified fatty acid levels only rose in SOLF mice. Hypothalamic mRNA levels of NPY decreased and of POMC increased in both UOLF and SOLF mice, but only SOLF mice showed signs of hypothalamic astrogliosis and affectation of central fatty acid metabolism. Exogenous leptin activated STAT3 in the hypothalamus of all groups, but the activation of AKT and mTOR and the decrease in AMPK activation in observed in controls and UOLF mice was not found in SOLF mice. CONCLUSIONS: Diets rich in fatty acids increase body weight and adiposity even if energy intake is not increased, while increased intake of saturated and unsaturated fatty acids differentially modify metabolic parameters that could underlie more long-term comorbidities. Thus, more understanding of how specific nutrients affect metabolism, weight gain, and obesity associated complications is necessary.

Butyric Acid Precursor Tributyrin Modulates Hippocampal Synaptic Plasticity and Prevents Spatial Memory Deficits: Role of PPARγ and AMPK.

BACKGROUND: Short chain fatty acids (SCFA), such as butyric acid (BA), derived from the intestinal fermentation of dietary fiber and contained in dairy products, are gaining interest in relation to their possible beneficial effects on neuropsychological disorders. METHODS: C57BL/6J male mice were used to investigate the effect of tributyrin (TB), a prodrug of BA, on hippocampus (HIP)-dependent spatial memory, HIP synaptic transmission and plasticity mechanisms, and the expression of genes and proteins relevant to HIP glutamatergic transmission. RESULTS: Ex vivo studies, carried out in HIP slices, revealed that TB can transform early-LTP into late-LTP (l-LTP) and to rescue LTP-inhibition induced by scopolamine. The facilitation of l-LTP induced by TB was blocked both by GW9662 (a PPARγ antagonist) and C-Compound (an AMPK inhibitor), suggesting the involvement of both PPARγ and AMPK on TB effects. Moreover, 48-hour intake of a diet containing 1% TB prevented, in adolescent but not in adult mice, scopolamine-induced impairment of HIP-dependent spatial memory. In the adolescent HIP, TB upregulated gene expression levels of Pparg, leptin, and adiponectin receptors, and that of the glutamate receptor subunits AMPA-2, NMDA-1, NMDA-2A, and NMDA-2B. CONCLUSIONS: Our study shows that TB has a positive influence on LTP and HIP-dependent spatial memory, which suggests that BA may have beneficial effects on memory.

Free-choice high-fat diet alters circadian oscillation of energy intake in adolescent mice: role of prefrontal cortex.

PURPOSE: Our aim was to characterize the effect of an unfamiliar high-fat diet (HFD) on circadian feeding behaviour, plasma parameters, body weight (BW), and gene expression in the prefrontal cortex (PFC) of adolescent male mice. To this end, mice were allowed to consume a HFD during 48 h, but one group was allowed a free choice of HFD or normal chow (FC-HFD), while the other was restricted to a non-optional unfamiliar HFD feeding (NOP-HFD). METHODS: Energy intake was monitored at 6-h intervals during 48 h. Mice cohorts were killed at 6-h intervals after 48-h dietary treatment, and PFC samples dissected for RT-PCR analysis. RESULTS: Mice on the FC-HFD protocol avoided eating the standard chow, showed lower energy intake and lower BW increase than NOP-HFD mice. All animals with access to HFD exhibited nocturnal overeating, but diurnal hyperphagia was more prominent in the FC-HFD cohort. A robust increase in tyrosine hydroxylase (Th) gene expression was detected specifically during the light period of the circadian cycle in FC-HFD mice. In contrast, both protocols similarly up-regulated the expression of cytosolic malic enzyme (Me1), which is very sensitive to HFD. CONCLUSION: Our data show that the PFC participates in driving motivational feeding during HFD-evoked hyperphagia and also suggest that sensory neural pathways might be relevant for the onset of eating disorders and overweight. Moreover, we have observed that animals that had the possibility of choosing between standard chow and HFD were more hyperphagic and specifically displayed an overexpression of the tyrosine hydroxylase gene.

Decreased rates of operant food self-administration are associated with reward deficits in high-fat feeding mice.

PURPOSE: Highly palatable foods behave as appetitive reinforcers and tend to be consumed compulsively. Nevertheless, the motivation for this kind of diets in experimental diet-induced obesity models has not been well established. Our hypothesis is that obesity caused by a regular consumption of high-fat diet (HFD) occurs concomitantly with the inhibition of food reward. The ultimate goal of our study was to further analyze the extent to which the perception of food as an appetitive reinforcer is a necessary condition for obesity. METHODS: We have evaluated the influence of HFD on operant food self-administration (FSA) during a whole light-dark (12-12-h) cycle in mice that consumed HFD either during 1, 4 or 8 weeks. The study has been complemented by a two-bottle free-choice assay between tap water and sweetened drinks. RESULTS: These data show that both 4- and 8-week HFD treatments induced a significant decrease in operant FSA rate. Moreover, HFD impaired the sweetened-conditioned flavor preference in the two-bottle choice assay. CONCLUSION: Our results, showing a reduction in how hard an animal is willing to work for food reinforcers, provide evidence that chronic consumption of HFD negatively contributes to the incentive motivation to acquire food/drink reinforcers. We demonstrate that energy homeostasis imbalance triggered by HFD is associated with the inhibition of hedonic feeding.

NOD1 receptor is up-regulated in diabetic human and murine myocardium.

Type 2 diabetes has a complex pathology that involves a chronic inflammatory state. Emerging evidence suggests a link between the innate immune system receptor NOD1 (nucleotide-binding and oligomerization domain 1) and the pathogenesis of diabetes, in monocytes and hepatic and adipose tissues. The aim of the present study was to assess the role of NOD1 in the progression of diabetic cardiomyopathy. We have measured NOD1 protein in cardiac tissue from Type 2 diabetic (db) mice. Heart and isolated cardiomyocytes from db mice revealed a significant increase in NOD1, together with an up-regulation of nuclear factor κB (NF-κB) and increased apoptosis. Heart tissue also exhibited an enhanced expression of pro-inflammatory cytokines. Selective NOD1 activation with C12-γ-D-glutamyl-m-diaminopimelic acid (iEDAP) resulted in an increased NF-κB activation and apoptosis, demonstrating the involvement of NOD1 both in wild-type and db mice. Moreover, HL-1 cardiomyocytes exposed to elevated concentrations of glucose plus palmitate displayed an enhanced NF-κB activity and apoptotic profile, which was prevented by silencing of NOD1 expression. To address this issue in human pathology, NOD1 expression was evaluated in myocardium obtained from patients with Type 2 diabetes (T2DMH) and from normoglycaemic individuals without cardiovascular histories (NH). We have found that NOD1 was expressed in both NH and T2DMH; however, NOD1 expression was significantly pronounced in T2DMH. Furthermore, both the pro-inflammatory cytokine tumour necrosis factor α (TNF-α) and the apoptosis mediator caspase-3 were up-regulated in T2DMH samples. Taken together, our results define an active role for NOD1 in the heightened inflammatory environment associated with both experimental and human diabetic cardiac disease.

Tributyrin reverses the deleterious effect of saturated fat on working memory and synaptic plasticity in juvenile mice: differential effects in males and females.

Short-chain fatty acids, such as butyric acid, derived from the intestinal fermentation of dietary fiber, have been proposed as a treatment for certain pathologies of the central nervous system. Our research group has shown that tributyrin (TB), a butyric acid prodrug, reverses deficits in spatial memory and modulates hippocampal synaptic plasticity. In the present work, diets enriched in either saturated (SOLF; Saturated OiL-enriched Food) or unsaturated (UOLF; Unsaturated OiL-enriched Food) fat were supplied during either 2 h or 8 weeks to 5-week-old male and female mice undergoing a treatment schedule with TB. After the dietary treatment, spatial learning and memory (SLM) was assessed in both the Y-maze and the eight-arm radial maze (RAM). Hippocampal expression of genes involved in glutamatergic transmission as well as synaptic plasticity (long-term potentiation -LTP- and long-term depression -LTD-) were also analyzed. Our results show that 2 h of SOLF intake impaired LTP as well as the performance in the Y-Maze in juvenile male mice whereas no effect was found in females. Moreover, TB reversed both effects in SLM and LTP in males. In the case of chronic intake, both SOLF and UOLF deteriorated SLM measured in the RAM in both sexes whereas TB only reversed LTP impairment induced by SOLF in male mice. These results suggest that TB may have a potentially beneficial influence on learning and memory processes, contingent upon the type of diet and the sex of the individuals.

Spatial memory impairment and changes in hippocampal morphology are triggered by high-fat diets in adolescent mice. Is there a role of leptin?

Recent evidence has established that consumption of high-fat diets (HFD) is associated with deficits in hippocampus-dependent memory. Adolescence is an important period for shaping learning and memory acquisition that could be particularly sensitive to the detrimental effects of HFD. In the current study we have administered this kind of diets to both adolescent (5-week old) and young adult (8-week old) male C57BL mice during 8 weeks and we have evaluated its effect on (i) spatial memory performance in the novel location recognition (NLR) paradigm, and (ii) spine density and neural cell adhesion molecule (NCAM) expression in hippocampal CA1 pyramidal neurons. In order to characterize the eventual involvement of central leptin receptors we have also investigated the functionality of leptin receptors within the hippocampus. Here we report that animals that started to consume HFD during the adolescence were less efficient than their control counterparts in performing spatial memory tasks. In contrast to that, mice that were submitted to HFD during the young adult period displayed intact performance in the NLR test. In mice receiving HFD from the adolescence, the behavioral impairment was accompanied by an increase of dendritic spine density in CA1 pyramidal neurons that correlated with the up-regulation of neural cell adhesion molecule (NCAM) in this area. Deficits in spatial memory occurred concomitantly with a desensitization of the proteinkinase B (Akt) pathway coupled to hippocampal leptin receptors. In contrast, the STAT3 pathway remained unaffected by HFD. All effects of HFD were long-lasting because they remained intact even after 5 weeks of food restriction. Our results provide further evidence of the susceptibility of the hippocampus to HFD in adolescent individuals and suggest that leptin signaling integrity in this brain area is pivotal for memory performance.

Saturated and unsaturated triglyceride-enriched diets modify amino acid content in the mice hippocampus.

Elevated intake of fat modulates l-glutamate (l-Glu) turnover within the hippocampus (HIP). Our aim has been to investigate the effect of saturated vs unsaturated fat on the content of l-Glu and other amino acids involved in synaptic transmission within the HIP. The study was carried out in male mice fed (2 h or 8 weeks) with standard chow or with diets enriched either with saturated (SOLF) or unsaturated triglycerides (UOLF). An in vitro assay was performed in HIP slices incubated with palmitic (PA), oleic (OA), or lauric acid (LA). Amino acids were quantified by capillary electrophoresis. While both diets increased the amount of l-Glu and l-aspartate and decreased l-glutamine levels, only UOLF affected d-serine and taurine levels. γ-Aminobutyric acid was specifically decreased by SOLF. In vitro assays revealed that PA and OA modified l-Glu, glycine, l-serine and d-serine concentration. Our results suggest that fatty acids contained in SOLF and UOLF have an impact on HIP amino acid turnover that may account, at least partially, for the functional changes evoked by these diets.

Regional specific effect of saturated vs unsaturated fat on leptin receptor signalling in mice brain areas regulating feeding.

Leptin receptors (LepR) are expressed in brain areas controlling food intake homeostasis, such as the hypothalamus, the hippocampus and the prefrontal cortex. In a previous study we reported that long-term intake of saturated and monounsaturated fat alters hypothalamic LepR signalling. The current study aims at investigating the effect of foods high in either saturated (SOLF) or monounsaturated fat (UOLF) on LepR functionality in the hippocampus and the prefrontal cortex. Male mice were placed on SOLF/UOLF (eight weeks), then treated with recombinant murine leptin (1 mg/kg). After 60 min, brain regions were dissected and processed for western blot of phosphorylated STAT3 (pSTAT3), Akt (pAkt) and AMPK (pAMPK). Levels of SOCS3 were also quantified. SOLF itself increased basal levels of pSTAT3, while UOLF impaired leptin-induced phosphorylation of both Akt and AMPK. SOCS3 levels were specifically increased by UOLF within the prefrontal cortex. Our results show that SOLF and UOLF differently affect LepR signalling within the hippocampus and the prefrontal cortex, which points to the complex effect of saturated and unsaturated fat on brain function, particularly in areas regulating food intake.

High-fat diets induce changes in hippocampal glutamate metabolism and neurotransmission.

Obesity and high-fat (HF) diets have a deleterious impact on hippocampal function and lead to impaired synaptic plasticity and learning deficits. Because all of these processes need an adequate glutamatergic transmission, we have hypothesized that nutritional imbalance triggered by these diets might eventually concern glutamate (Glu) neural pathways within the hippocampus. Glu is withdrawn from excitatory synapses by specific uptake mechanisms involving neuronal (EAAT-3) and glial (GLT-1, GLAST) transporters, which regulate the time that synaptically released Glu remains in the extracellular space and, consequently, the duration and location of postsynaptic receptor activation. The goal of the present study was to evaluate in mouse hippocampus the effect of a short-term high-fat dietary treatment on 1) Glu uptake kinetics, 2) the density of Glu carriers and Glu-degrading enzymes, 3) the density of Glu receptor subunits, and 4) synaptic transmission and plasticity. Here, we show that HF diet triggers a 50% decrease of the Michaelis-Menten constant together with a 300% increase of the maximal velocity of the uptake process. Glial Glu carriers GLT-1 and GLAST were upregulated in HF mice (32 and 27%, respectively), whereas Glu-degrading enzymes glutamine synthase and GABA-decarboxilase appeared to be downregulated in these animals. In addition, HF diet hippocampus displayed diminished basal synaptic transmission and hindered NMDA-induced long-term depression (NMDA-LTD). This was coincident with a reduced density of the NR2B subunit of NMDA receptors. All of these results are compatible with the development of leptin resistance within the hippocampus. Our data show that HF diets upregulate mechanisms involved in Glu clearance and simultaneously impair Glu metabolism. Neurochemical changes occur concomitantly with impaired basal synaptic transmission and reduced NMDA-LTD. Taken together, our results suggest that HF diets trigger neurochemical changes, leading to a desensitization of NMDA receptors within the hippocampus, which might account for cognitive deficits.

Cholecystokinin promotes functional expression of the aquaglycerol channel aquaporin 7 in adipocytes.

BACKGROUND AND PURPOSE: Cholecystokinin (CCK) promotes triglyceride storage and adiponectin production in white adipose tissue (WAT), suggesting that CCK modulates WAT homeostasis. Our goal was to investigate the role of CCK in regulating the expression and function of the aquaglycerol channel aquaporin 7 (AQP7), a protein that is pivotal for maintaining adipocyte homeostasis and preserving insulin responsiveness. EXPERIMENTAL APPROACH: The effect of the bioactive fragment of CCK, CCK-8, in regulating adipose AQP7 expression and glycerol efflux was assessed in rats as well as in preadipocytes. Moreover, the involvement of insulin receptors in the effects of CCK-8 was characterized in preadipocytes lacking insulin receptors. KEY RESULTS: CCK-8 induced AQP7 gene expression in rat WAT, concomitantly increasing plasma glycerol concentration. In isolated preadipocytes, CCK-8 also enhanced both AQP7 expression and glycerol leakage. The effects of CCK-8 were independent of the lipolysis rate, as CCK-8 failed to promote fatty acid release by adipocytes. In addition, CCK-8 did not enhance hormone sensitive lipase phosphorylation, which is the rate-limiting step of lipolysis. Moreover, the effects of CCK-8 were dependent on the activation of protein kinase B and PPARγ. Silencing insulin receptor expression inhibited CCK-8-induced Aqp7 expression in preadipocytes. Furthermore, insulin enhanced the effect of CCK-8. CONCLUSIONS AND IMPLICATIONS: CCK regulates AQP7 expression and function, and this effect is dependent on insulin. Accordingly, CCK receptor agonists could be suitable for preserving and improving insulin responsiveness in WAT.

Effect of Lauric vs. Oleic Acid-Enriched Diets on Leptin Autoparacrine Signalling in Male Mice.

High-fat diets enriched with lauric acid (SOLF) do not enhance leptin production despite expanding white adipose tissue (WAT). Our study aimed at identifying the influence of SOLF vs. oleic acid-enriched diets (UOLF) on the autoparacrine effect of leptin and was carried out on eight-week-old mice consuming control chow, UOLF or SOLF. Phosphorylation of kinases integral to leptin receptor (LepR) signalling pathways (705Tyr-STAT3, 473Ser-Akt, 172Thr-AMPK), adipocyte-size distribution, fatty acid content, and gene expression were analyzed in WAT. SOLF enhanced basal levels of phosphorylated proteins but reduced the ability of leptin to enhance kinase phosphorylation. In contrast, UOLF failed to increase basal levels of phosphorylated proteins and did not modify the effect of leptin. Both SOLF and UOLF similarly affected adipocyte-size distribution, and the expression of genes related with adipogenesis and inflammation. WAT composition was different between groups, with SOLF samples mostly containing palmitic, myristic and lauric acids (>48% w/w) and UOLF WAT containing more than 80% (w/w) of oleic acid. In conclusion, SOLF appears to be more detrimental than UOLF to the autoparacrine leptin actions, which may have an impact on WAT inflammation. The effect of SOLF and UOLF on WAT composition may affect WAT biophysical properties, which are able to condition LepR signaling.

Differential Deleterious Impact of Highly Saturated Versus Monounsaturated Fat Intake on Vascular Function, Structure, and Mechanics in Mice.

Vegetable oils such as palm oil (enriched in saturated fatty acids, SFA) and high-oleic-acid sunflower oil (HOSO, containing mainly monounsaturated fatty acids, MUFA) have emerged as the most common replacements for trans-fats in the food industry. The aim of this study is to analyze the impact of SFA and MUFA-enriched high-fat (HF) diets on endothelial function, vascular remodeling, and arterial stiffness compared to commercial HF diets. Five-week-old male C57BL6J mice were fed a standard (SD), a HF diet enriched with SFA (saturated oil-enriched Food, SOLF), a HF diet enriched with MUFA (unsaturated oil-enriched Food, UOLF), or a commercial HF diet for 8 weeks. Vascular function was analyzed in the thoracic aorta. Structural and mechanical parameters were assessed in mesenteric arteries by pressure myography. SOLF, UOLF, and HF diet reduced contractile responses to phenylephrine and induced endothelial dysfunction in the thoracic aorta. A significant increase in the ß-index, and thus in arterial stiffness, was also detected in mesenteric arteries from the three HF groups, due to enhanced deposition of collagen in the vascular wall. SOLF also induced hypotrophic inward remodeling. In conclusion, these data demonstrate a deleterious effect of HF feeding on obesity-related vascular alterations that is exacerbated by SFA.

Interaction Between Circadian Rhythms, Energy Metabolism, and Cognitive Function.

The interaction between meal timing and light regulates circadian rhythms in mammals and not only determines the sleep-wake pattern but also the activity of the endocrine system. Related with that, the necessity to fulfill energy needs is a driving force that requires the participation of cognitive skills whose performance has been shown to undergo circadian variations. These facts have led to the concept that cognition and feeding behaviour can be analysed from a chronobiological perspective. In this context, research carried out during the last two decades has evidenced the link between feeding behaviour/nutritional habits and cognitive processes, and has highlighted the impact of circadian disorders on cognitive decline. All that has allowed hypothesizing a tight relationship between nutritional factors, chronobiology, and cognition. In this connection, experimental diets containing elevated amounts of fat and sugar (high-fat diets; HFDs) have been shown to alter in rodents the circadian distribution of meals, and to have a negative impact on cognition and motivational aspects of behaviour that disappear when animals are forced to adhere to a standard temporal eating pattern. In this review, we will present relevant studies focussing on the effect of HFDs on cognitive aspects of behaviour, paying particular attention to the influence that chronobiological alterations caused by these diets may have on hippocampaldependent cognition.

Specific Deletion of the Astrocyte Leptin Receptor Induces Changes in Hippocampus Glutamate Metabolism, Synaptic Transmission and Plasticity.

The aim of this study was to indentify the involvement of leptin receptors (LepR) in astrocytes in hippocampal synaptic transmission and plasticity and metabolism. To this end we used a genetic mouse model (GFAP-LepR-/-) of specific LepR ablation in GFAP positive cells and recorded excitatory postsynaptic potentials (fEPSPs) within the CA1 area. Glutamate (Glu) uptake and the expression of Glu transporters (EEAT3, GLT-1 and GLAST) and enzymes involved in Glu metabolism (glutamine synthase, GABA decarboxylase 65 and 67) were quantified. Modifications in the expression of GFAP, the glucose transporter (GLUT)-1, and the monocarboxylate transporters MCT-2 and MCT-4, were also analyzed. The results show that depletion of LepR in GFAP positive cells reduced basal synaptic transmission within the CA1 area and impaired N-methyl-d-aspartate (NMDA)-evoked long-term depression (NMDA-LTD). Hippocampal slices from GFAP-LepR-/- mice displayed lower Glu uptake efficacy together with up-regulation of GLT-1, glutamine synthase, GFAP and GLUT-1. In conclusion, astrocyte LepRs are involved in the maintenance of Glu homeostasis and Glu neurotransmission within the hippocampus. Our findings support a role of hippocampal LepRs in synaptic plasticity, which could have an impact on memory and learning processes.

The cholecystokinin receptor agonist, CCK-8, induces adiponectin production in rat white adipose tissue.

BACKGROUND AND PURPOSE: A cholecystokinin (CCK) system has been identified in white adipose tissue (WAT). Nevertheless, the endocrine actions of CCK on WAT remain unknown. Our goal was to investigate the role of CCK in regulating the production of adiponectin, an adipokine expressed in WAT, which is pivotal in preserving energy homeostasis. EXPERIMENTAL APPROACH: The effect of the bioactive CCK fragment CCK-8 on adiponectin production was studied both in vivo and in vitro. CCK-8 effects were characterized in rats treated with selective CCK1 and CCK2 receptor antagonists as well as in pre-adipocytes carrying the selective silencing of either CCK1 or CCK2 receptors. The influence of insulin on CCK-8 responses was also analysed. KEY RESULTS: In WAT, CCK-8 increased plasma adiponectin levels and the expression of the adiponectin gene (Adipoq). In pre-adipocytes, CCK-8 up-regulated adiponectin production. CCK-8 effects were abolished by L-365,260, a selective CCK2 receptor antagonist. CCK2 receptor knockdown also abolished the effects of CCK-8 in pre-adipocytes. Moreover, in vitro CCK-8 effects were blocked by triciribine, a specific inhibitor of protein kinase B (Akt) and by the PPARγ antagonist T0070907. Silencing the expression of the insulin receptor inhibited CCK-8-induced Adipoq expression in pre-adipocytes. Furthermore, insulin potentiated the effect of CCK-8. CONCLUSION AND IMPLICATIONS: CCK-8 stimulates adiponectin production in WAT by acting on CCK2 receptors, through a mechanism involving both Akt and PPARγ. Moreover, CCK-8 actions are only observed in the presence of insulin. Our results could have translational value in the design of new insulin-sensitizing therapies.

Potential Role of Leptin in Cardiac Steatosis Induced by Highly Saturated Fat Intake during Adolescence.

SCOPE: To identify the age-dependent effect of diets containing elevated amounts of either saturated or unsaturated fatty acids on cardiac steatosis in mice. METHODS AND RESULTS: Five- and eight-week-old C57BL/6J mice cohorts are given free access to either a saturated or an unsaturated fatty-acid-enriched diet during 8 weeks. Body weight (BW) and food intake are monitored during this period. Cardiac lipid content, carnitine palmitoyltransferase-I (CPT-I) activity, and the amount of uncoupling proteins 2 and 3 (UCP2 and UCP3) are analyzed and correlated with blood leptin concentration. Leptin and PPARγ gene expression is quantified in white adipose tissue (WAT). Both diets have a similar effect on food intake, BW, and adiposity, independently of the age. Nevertheless, cardiac steatosis is specifically identified in adolescent mice consuming the saturated diet. These animals also display lower activity of cardiac CPT-I, a down-regulation of cardiac UCP2, together with lower concentration of plasma leptin. Accordingly, leptin gene expression is reduced in the visceral WAT. CONCLUSION: Consumption of diets containing elevated amounts of saturated fat during adolescence and early adult life promotes cardiac steatosis in mice. An insufficient endocrine activity of WAT, in terms of leptin production, may account for such an effect.

Intermittent-Excessive and Chronic-Moderate Ethanol Intake during Adolescence Impair Spatial Learning, Memory and Cognitive Flexibility in the Adulthood.

Intermittent and excessive ethanol consumption over very short periods of time, known as binge drinking, is common in the adolescence, considered a vulnerable period to the effects of alcohol in terms of cognitive performance. One of the brain functions most drastically affected by ethanol in adolescent individuals seems to be spatial learning and memory dependent on the hippocampus. In the current study we have focused on the long-lasting effects on spatial learning and memory of intermittent and excessive alcohol consumption compared to chronic and moderate alcohol exposure during adolescence. Five-week old male Wistar rats consumed ethanol for 24 days following two different self-administration protocols that differed in the intake pattern. Spatial learning and memory were evaluated in the radial arm maze. Hippocampal synaptic plasticity was assessed by measuring field excitatory postsynaptic potentials. Hippocampal expression of AMPA and NMDA receptor subunits as well as levels of phosphorylated Ser9-GSK3ß (the inactive form of GSK3ß) were also quantified. Our results show that both patterns of ethanol intake during adolescence impair spatial learning, memory and cognitive flexibility in the adulthood in a dose-dependent way. Nevertheless, changes in synaptic plasticity, gene expression and levels of inactive GSK3ß depended on the pattern of ethanol intake.

Inflammatory stress and altered angiogenesis evoked by very high-fat diets in mouse liver.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), a condition that leads to fibrosis, is caused by intake of very high-fat diets (HFDs). However, while the negative impact on the liver of these diets has been an issue of interest, systematic research on the effect of HFDs are lacking. OBJECTIVE: To characterize the overall impact of HFDs on both molecular and morphological signs of liver remodeling. METHODS: A study was conducted on male C57BL/6J mice to assess the effect of 4- and 8-week HFDs (60% kcal from fat) on (i) liver steatosis and fibrosis, and (ii) expression of factors involved in inflammation and angiogenesis. RESULTS: After an 8-week HFD, vascular endothelial growth factor type-2 receptor (VEGF-R2) and fatty acid translocase/trombospondin-1 receptor (CD36) were overexpressed in liver tissue of mice given HFDs. These changes suggest impaired liver angiogenesis and occurred together with (i) increased GPR78-BiP and EIF2α phosphorylation, suggesting endoplasmic reticulum stress, (ii) induction of Col1a1 gene expression, a marker of fibrosis, and (iii) increased CD31 immunolabeling, consistent with active angiogenesis and fibrosis. CONCLUSION: Our data show that very HFDs promote a rapid inflammatory response, as well as deregulation of angiogenesis, both consistent with development of liver fibrosis.

Differential Impact of Ad Libitum or Intermittent High-Fat Diets on Bingeing Ethanol-Mediated Behaviors.

BACKGROUND: Dietary factors have significant effects on the brain, modulating mood, anxiety, motivation and cognition. To date, no attention has been paid to the consequences that the combination of ethanol (EtOH) and a high-fat diet (HFD) have on learning and mood disorders during adolescence. The aim of the present work was to evaluate the biochemical and behavioral consequences of ethanol binge drinking and an HFD consumption in adolescent mice. METHODS: Animals received either a standard diet or an HFD (ad libitum vs. binge pattern) in combination with ethanol binge drinking and were evaluated in anxiety and memory. The metabolic profile and gene expression of leptin receptors and clock genes were also evaluated. RESULTS: Excessive white adipose tissue and an increase in plasma insulin and leptin levels were mainly observed in ad libitum HFD + EtOH mice. An upregulation of the Lepr gene expression in the prefrontal cortex and the hippocampus was also observed in ad libitum HFD groups. EtOH-induced impairment on spatial memory retrieval was absent in mice exposed to an HFD, although the aversive memory deficits persisted. Mice bingeing on an HFD only showed an anxiolytic profile, without other alterations. We also observed a mismatch between Clock and Bmal1 expression in ad libitum HFD animals, which were mostly independent of EtOH bingeing. CONCLUSIONS: Our results confirm the bidirectional influence that occurs between the composition and intake pattern of a HFD and ethanol consumption during adolescence, even when the metabolic, behavioral and chronobiological effects of this interaction are dissociated.