scholarly journals Hypothalamic Microglial Heterogeneity and Signature under High Fat Diet–Induced Inflammation

2021 ◽  
Vol 22 (5) ◽  
pp. 2256
Author(s):  
Natália Ferreira Mendes ◽  
Carlos Poblete Jara ◽  
Ariane Maria Zanesco ◽  
Eliana Pereira de Araújo
Keyword(s):  
High Fat Diet ◽  
Ex Vivo ◽  
Experimental Models ◽  
High Fat ◽  
Inflammatory Stimuli ◽  
Hypothalamic Inflammation ◽  
Signaling Activation ◽  
New Research ◽  
Fat Feeding

Under high-fat feeding, the hypothalamus atypically undergoes pro-inflammatory signaling activation. Recent data from transcriptomic analysis of microglia from rodents and humans has allowed the identification of several microglial subpopulations throughout the brain. Numerous studies have clarified the roles of these cells in hypothalamic inflammation, but how each microglial subset plays its functions upon inflammatory stimuli remains unexplored. Fortunately, these data unveiling microglial heterogeneity have triggered the development of novel experimental models for studying the roles and characteristics of each microglial subtype. In this review, we explore microglial heterogeneity in the hypothalamus and their crosstalk with astrocytes under high fat diet–induced inflammation. We present novel currently available ex vivo and in vivo experimental models that can be useful when designing a new research project in this field of study. Last, we examine the transcriptomic data already published to identify how the hypothalamic microglial signature changes upon short-term and prolonged high-fat feeding.

scholarly journals Acute (24 h) activation of peroxisome proliferator-activated receptor-alpha (PPARalpha) reverses high-fat feeding-induced insulin hypersecretion in vivo and in perifused pancreatic islets

2003 ◽  
Vol 177 (2) ◽  
pp. 197-205 ◽  
Author(s):  
MJ Holness ◽  
ND Smith ◽  
GK Greenwood ◽  
MC Sugden
Keyword(s):  
Insulin Secretion ◽  
Ex Vivo ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Intravenous Glucose ◽  
Perifused Islets ◽  
Glucose Stimulated Insulin Secretion ◽  
Fat Feeding

Abnormal depletion or accumulation of islet lipid may be important for the development of pancreatic beta cell failure. Long-term lipid sensing by beta cells may be co-ordinated via peroxisome proliferator-activated receptors (PPARs). We investigated whether PPARalpha activation in vivo for 24 h affects basal and glucose-stimulated insulin secretion in vivo after intravenous glucose administration and ex vivo in isolated perifused islets. Insulin secretion after intravenous glucose challenge was greatly increased by high-fat feeding (4 weeks) but glucose tolerance was minimally perturbed, demonstrating insulin hypersecretion compensated for insulin resistance. The effect of high-fat feeding to enhance glucose-stimulated insulin secretion was retained in perifused islets demonstrating a stable, long-term effect of high-fat feeding to potentiate islet glucose stimulus-secretion coupling. Treatment of high-fat-fed rats with WY14,643 for 24 h reversed insulin hypersecretion in vivo without impairing glucose tolerance, suggesting improved insulin action, and ex vivo in perfused islets. PPARalpha activation only affected hypersecretion of insulin since glucose-stimulated insulin secretion was unaffected by WY14,643 treatment in vivo in control rats or in perifused islets from control rats. Our data demonstrate that activation of PPARalpha for 24 h can oppose insulin hypersecretion elicited by high-fat feeding via stable long-term effects exerted on islet function. PPARalpha could, therefore, participate in ameliorating abnormal glucose homeostasis and hyperinsulinaemia in dietary insulin resistance via modulation of islet function, extending the established requirement for PPARalpha for normal islet lipid homeostasis.

Effect of a high-fat diet on the incorporation of stored triacylglycerol into hepatic VLDL

1992 ◽  
Vol 263 (4) ◽  
pp. E615-E623 ◽  
Author(s):  
O. L. Francone ◽  
G. Griffaton ◽  
A. D. Kalopissis
Keyword(s):  
Endoplasmic Reticulum ◽  
High Fat Diet ◽  
Lipid Droplets ◽  
Control Diet ◽  
Oxidation Products ◽  
High Fat ◽  
Very Low Density Lipoproteins ◽  
Total Utilization ◽  
Fat Feeding

Triacylglycerol (TG) stored in cytoplasmic lipid droplets of hepatocytes was labeled by in vivo [1-(14)C]oleic acid injection to study the effect of a high-fat diet on its incorporation into very-low-density lipoproteins (VLDL). Compared with the control diet, hepatocytes of fat-fed rats 1) contained 7.6 times more cytoplasmic (floating fat) TG and 1.9 times more endoplasmic reticulum (microsomal) TG; 2) had 8 and 6 times lower TG specific activities in cytoplasm and endoplasmic reticulum, respectively; 3) incorporated 22% less 14C label into hepatocyte esterified lipids (TG, cholesterol, phospholipid); 4) secreted 48 and 33% less radioactive and total VLDL-TG, respectively; 5) oxidized more cytoplasmic TG-fatty acid (FA); and 6) showed a 50% decreased total utilization of stored TG-FA. With both diets, the lysosomal inhibitor chloroquine concomitantly decreased productions of labeled VLDL-TG, CO2, and acid-soluble oxidation products. The decreased incorporation of stored TG into VLDL-TG appreciably contributes to the overall inhibition of hepatic VLDL secretion by fat feeding. It appears to be related to the decreased mobilization rate of stored TG and its increased channelling toward oxidation.

scholarly journals Epiregulin induces leptin secretion and energy expenditure in high-fat diet-fed mice

2018 ◽  
Vol 239 (3) ◽  
pp. 377-388 ◽  
Author(s):  
Rumana Yasmeen ◽  
Qiwen Shen ◽  
Aejin Lee ◽  
Jacob H Leung ◽  
Devan Kowdley ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
High Fat Diet ◽  
Ex Vivo ◽  
Mapk Pathway ◽  
Treated Group ◽  
Dependent Manner ◽  
High Fat ◽  
Fat Depots ◽  
Expression Of Genes

Adipokine leptin regulates neuroendocrine circuits that control energy expenditure, thermogenesis and weight loss. However, canonic regulators of leptin secretion, such as insulin and malonyl CoA, do not support these processes. We hypothesize that epiregulin (EREG), a growth factor that is secreted from fibroblasts under thermogenic and cachexia conditions, induces leptin secretion associated with energy dissipation. The effects of EREG on leptin secretion were studied ex vivo, in the intra-abdominal white adipose tissue (iAb WAT) explants, as well as in vivo, in WT mice with diet-induced obesity (DIO) and in ob/ob mice. These mice were pair fed a high-fat diet and treated with intraperitoneal injections of EREG. EREG increased leptin production and secretion in a dose-dependent manner in iAb fat explants via the EGFR/MAPK pathway. After 2 weeks, the plasma leptin concentration was increased by 215% in the EREG-treated group compared to the control DIO group. EREG-treated DIO mice had an increased metabolic rate and core temperature during the active dark cycle and displayed cold-induced thermogenesis. EREG treatment reduced iAb fat mass, the major site of leptin protein production and secretion, but did not reduce the mass of the other fat depots. In the iAb fat, expression of genes supporting mitochondrial oxidation and thermogenesis was increased in EREG-treated mice vs control DIO mice. All metabolic and gene regulation effects of EREG treatment were abolished in leptin-deficient ob/ob mice. Our data revealed a new role of EREG in induction of leptin secretion leading to the energy expenditure state. EREG could be a potential target protein to regulate hypo- and hyperleptinemia, underlying metabolic and immune diseases.

Carnitine supplementation in high-fat diet-fed rats does not ameliorate lipid-induced skeletal muscle mitochondrial dysfunction in vivo

2015 ◽  
Vol 309 (7) ◽  
pp. E670-E678 ◽  
Author(s):  
Bart Wessels ◽  
Nicole M. A. van den Broek ◽  
Jolita Ciapaite ◽  
Sander M. Houten ◽  
Ronald J. A. Wanders ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
High Fat Diet ◽  
Ex Vivo ◽  
Carnitine Supplementation ◽  
High Fat ◽  
Muscle Lipid ◽  
Lipid Status

Muscle lipid overload and the associated accumulation of lipid intermediates play an important role in the development of insulin resistance. Carnitine insufficiency is a common feature of insulin-resistant states and might lead to incomplete fatty acid oxidation and impaired export of lipid intermediates out of the mitochondria. The aim of the present study was to test the hypothesis that carnitine supplementation reduces high-fat diet-induced lipotoxicity, improves muscle mitochondrial function, and ameliorates insulin resistance. Wistar rats were fed either normal chow or a high-fat diet for 15 wk. One group of high-fat diet-fed rats was supplemented with 300 mg·kg−1·day−1 l-carnitine during the last 8 wk. Muscle mitochondrial function was measured in vivo by 31P magnetic resonance spectroscopy (MRS) and ex vivo by high-resolution respirometry. Muscle lipid status was determined by 1H MRS (intramyocellular lipids) and tandem mass spectrometry (acylcarnitines). High-fat diet feeding induced insulin resistance and was associated with decreases in muscle and blood free carnitine, elevated levels of muscle lipids and acylcarnitines, and an increased number of muscle mitochondria that showed an improved capacity to oxidize fat-derived substrates when tested ex vivo. This was, however, not accompanied by an increase in muscle oxidative capacity in vivo, indicating that in vivo mitochondrial function was compromised. Despite partial normalization of muscle and blood free carnitine content, carnitine supplementation did not induce improvements in muscle lipid status, in vivo mitochondrial function, or insulin sensitivity. Carnitine insufficiency, therefore, does not play a major role in high-fat diet-induced muscle mitochondrial dysfunction in vivo.

Abstract 5383: The Circadian Clock within the Cardiomyocyte is a Novel Mechanism Regulating Myocardial Triglyceride Metabolism

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ju-Yun Tsai ◽  
Vijayalakshmi Nannegari ◽  
William C Heird ◽  
Martin E Young
Keyword(s):  
Circadian Clock ◽  
High Fat Diet ◽  
Myocardial Metabolism ◽  
Contractile Function ◽  
Ex Vivo ◽  
Diurnal Variations ◽  
High Fat ◽  
Triglyceride Metabolism ◽  
Myocardial Triglyceride ◽  
Fat Feeding

Virtually every mammalian cell, including the cardiomyocyte, has an intrinsic molecular circadian clock. The cardiomyocyte circadian clock has recently been shown to directly mediate diurnal variations in myocardial gene expression, metabolism, and contractile function. This includes modulation of the heart’s acute transcriptional response to increased circulating fatty acids, in a time-of-day-dependent manner. We therefore hypothesized that disruption of the cardiomyocyte circadian clock would impair metabolic adaptation of the heart to high fat feeding. Wild type (WT) and cardiomyocyte-specific circadian clock mutant (CCM) mice were fed either a control or high fat diet (10% and 45% calories from fat, respectively) for 16 weeks, after which myocardial adaptation was assessed at transcriptional, metabolic, and functional levels. Ex vivo mouse heart perfusions in the working mode revealed that high fat feeding induced alterations in myocardial metabolism ( e.g. reduced carbohydrate oxidation; p<0.01) and contractile function ( e.g. depressed cardiac power; p<0.01) in WT, but not CCM, hearts. Furthermore, the ability to decrease reliance on endogenous substrate utilization during an acute increase in fatty acid availability ex vivo was abolished in hearts from CCM mice fed the high fat diet (p<0.05), suggesting potential alterations in triglyceride metabolism. Consistent with the latter, microarray analysis revealed that the cardiomyocyte circadian clock regulates expression of several genes involved in triglyceride turnover. For example, diurnal variations in expression of diacylglycerol acyltransferase 2, which promotes lipogenesis, and rates of myocardial triglyceride synthesis both peak in the middle of the active phase (2- and 3- fold, trough-to-peak, respectively; p<0.05), which are abolished in CCM hearts. These data provide direct evidence that the cardiomyocyte circadian clock regulates myocardial triglyceride metabolism at multiple levels. We postulate that disruption of this intramyocellular mechanism may contribute to altered myocardial metabolism and contractile dysfunction observed during cardiac hypertrophy, diabetes mellitus, and/or shift work.

scholarly journals Dietary Lycium barbarum Polysaccharide Induces Nrf2/ARE Pathway and Ameliorates Insulin Resistance Induced by High-Fat via Activation of PI3K/AKT Signaling

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Yi Yang ◽  
Wang Li ◽  
Yan Li ◽  
Qing Wang ◽  
Ling Gao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Glycogen Synthase ◽  
Akt Signaling ◽  
Experimental Models ◽  
Related Factor ◽  
High Fat ◽  
Lycium Barbarum

Lycium barbarum polysaccharide (LBP), an antioxidant from wolfberry, displays the antioxidative and anti-inflammatory effects on experimental models of insulin resistance in vivo. However, the effective mechanism of LBP on high-fat diet-induced insulin resistance is still unknown. The objective of the study was to investigate the mechanism involved in LBP-mediated phosphatidylinositol 3-kinase (PI3K)/AKT/Nrf2 axis against high-fat-induced insulin resistance. HepG2 cells were incubated with LBP for 12 hrs in the presence of palmitate. C57BL/6J mice were fed a high-fat diet supplemented with LBP for 24 weeks. We analyzed the expression of nuclear factor-E2-related factor 2 (Nrf2), Jun N-terminal kinases (JNK), and glycogen synthase kinase 3β (GSK3β) involved in insulin signaling pathway in vivo and in vitro. First, LBP significantly induced phosphorylation of Nrf2 through PI3K/AKT signaling. Second, LBP obviously increased detoxification and antioxidant enzymes expression and reduced reactive oxygen species (ROS) levels via PI3K/AKT/Nrf2 axis. Third, LBP also regulated phosphorylation levels of GSK3β and JNK through PI3K/AKT signaling. Finally, LBP significantly reversed glycolytic and gluconeogenic genes expression via the activation of Nrf2-mediated cytoprotective effects. In summary, LBP is novel antioxidant against insulin resistance induced by high-fat diet via activation of PI3K/AKT/Nrf2 pathway.

scholarly journals High-fat diet increases autophagic flux in pancreatic beta cells in vivo and ex vivo in mice

Diabetologia ◽  
2015 ◽  
Vol 58 (9) ◽  
pp. 2074-2078 ◽  
Author(s):  
Kwan Yi Chu ◽  
Liam O’Reilly ◽  
Georg Ramm ◽  
Trevor J. Biden
Keyword(s):  
Beta Cells ◽  
High Fat Diet ◽  
Pancreatic Beta Cells ◽  
Ex Vivo ◽  
Autophagic Flux ◽  
High Fat

scholarly journals The Dopamine D2R Antagonist Trifluoperazine Suppresses High-Fat Diet-Induced Hyperglycemia and Hypothalamic Gliosis in Obese Mice

2021 ◽  
Author(s):  
Hui-Ting Huang ◽  
Pei-Chun Chen ◽  
Po-See Chen ◽  
Wen-Tai Chiu ◽  
Yu-Min Kuo ◽  
...  
Keyword(s):  
High Fat Diet ◽  
In Vivo Studies ◽  
Obese Mice ◽  
High Fat ◽  
Cns Inflammation ◽  
Hypothalamic Region ◽  
Hypothalamic Inflammation ◽  
Factor Α

Abstract Microglia, the resident macrophages of the central nervous system (CNS), as well as astrocytes, are CNS glia cells to support neurodevelopment and neuronal function. Yet, their activation-associated with CNS inflammation is involved in the initiation and progression of neurological disorders. Mild inflammation in the periphery and glial activation called gliosis in the hypothalamic region, arcuate nucleus (ARC), are generally observed in the obese individuals and animal models. Thus, reduction in peripheral and central inflammation is considered as a strategy to lessen the abnormality of obesity-associated metabolic indices. In this study, we reported that acute peripheral challenge by inflammagen lipopolysaccharide (LPS) triggered an upregulation of hypothalamic dopamine type 2 receptor (D2R) expression, and chronic feeding by high fat diet (HFD) caused an increased levels of D2R in the ARC. The in vitro and in vivo studies indicated that a D2R antagonist named trifluoperazine (TFP) was able to suppress LPS-stimulated activation of microglia and effectively inhibited LPS-induced peripheral inflammation, as well as hypothalamic inflammation. Further findings showed daily peripheral administration intraperitoneally (i.p.) by TFP for 4 weeks was able to reduce the levels of plasma and hypothalamic tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in obese mice receiving HFD for 16 weeks. Moreover, plasma glucose and insulin were effectively decreased by daily treatment with TFP for 4 weeks. In parallel, microglia and astrocytes in the ARC was also inhibited by peripheral administration by TFP. According to our results, TFP has the ability to suppress HFD-induced hyperglycemia, inflammation and gliosis in hypothalamus.

scholarly journals Sympathetic cardiac hyperinnervation and atrial autonomic imbalance in diet-induced obesity promote cardiac arrhythmias

2013 ◽  
Vol 305 (10) ◽  
pp. H1530-H1537 ◽  
Author(s):  
Belinda H. McCully ◽  
Wohaib Hasan ◽  
Cole T. Streiff ◽  
Jennifer C. Houle ◽  
William R. Woodward ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Parasympathetic Nervous System ◽  
Ex Vivo ◽  
System Control ◽  
Sprague Dawley ◽  
High Fat ◽  
Sprague Dawley Rats ◽  
Normal Chow

Obesity increases the risk of arrhythmias and sudden cardiac death, but the mechanisms are unknown. This study tested the hypothesis that obesity-induced cardiac sympathetic outgrowth and hyperinnervation promotes the development of arrhythmic events. Male Sprague-Dawley rats (250–275 g), fed a high-fat diet (33% kcal/fat), diverged into obesity-resistant (OR) and obesity-prone (OP) groups and were compared with rats fed normal chow (13% kcal/fat; CON). In vitro experiments showed that both OR and OP rats exhibited hyperinnervation of the heart and high sympathetic outgrowth compared with CON rats, even though OR rats are not obese. Despite the hyperinnervation and outgrowth, we showed that, in vivo, OR rats were less susceptible to arrhythmic events after an intravenous epinephrine challenge compared with OP rats. On examining total and stimulus-evoked neurotransmitter levels in an ex vivo system, we demonstrate that atrial acetylcholine content and release were attenuated in OP compared with OR and CON groups. OP rats also expressed elevated atrial norepinephrine content, while norepinephrine release was suppressed. These findings suggest that the consumption of a high-fat diet, even in the absence of overt obesity, stimulates sympathetic outgrowth and hyperinnervation of the heart. However, normalized cardiac parasympathetic nervous system control may protect the heart from arrhythmic events.

scholarly journals High fat diet induces microbiota-dependent silencing of enteroendocrine cells

2019 ◽  
Author(s):  
Lihua Ye ◽  
Olaf Mueller ◽  
Jennifer Bagwell ◽  
Michel Bagnat ◽  
Rodger A. Liddle ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Dietary Fat ◽  
High Fat Diet ◽  
Experimental System ◽  
Nutrient Sensing ◽  
Enteroendocrine Cells ◽  
Sensory Cells ◽  
High Fat ◽  
Fat Feeding

ABSTRACTEnteroendocrine cells (EECs) are specialized sensory cells in the intestinal epithelium that sense and transduce nutrient information. Consumption of dietary fat contributes to metabolic disorders, but EEC adaptations to high fat feeding were unknown. Here, we established a new experimental system to directly investigate EEC activity in vivo using a zebrafish reporter of EEC calcium signaling. Our results reveal that high fat feeding alters EEC morphology and converts them into a nutrient insensitive state that is coupled to endoplasmic reticulum (ER) stress. We called this novel adaptation “EEC silencing”. Gnotobiotic studies revealed that germ-free zebrafish are resistant to high fat diet induced EEC silencing. High fat feeding altered gut microbiota composition including enrichment ofAcinetobacterspecies, and we identified anAcinetobacterstrain sufficient to induce EEC silencing. These results establish a new mechanism by which dietary fat and gut microbiota modulate EEC nutrient sensing and signaling.

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