Uptake Of Fat Research Articles

ERICH4 is not involved in the assembly and secretion of intestinal lipoproteins

Background and AimsThe small intestine plays a central role in lipid metabolism, most notably the uptake of dietary fats that are packaged into chylomicrons and secreted into the circulation for utilisation by peripheral tissues. While microsomal triglyceride transfer protein (MTP) is known to play a key role in this pathway, the intracellular assembly, trafficking, and secretion of chylomicrons is incompletely understood. Methods and ResultsUsing human transcriptome datasets to find genes co-regulated with MTTP, we identified ERICH4 as a top hit. The gene encodes for glutamate-rich protein 4, a protein of unknown function. REACTOME gene-function prediction tools indicated that ERICH4 is involved in intestinal lipid metabolism. In addition, GWAS data point to a strong relationship between ERICH4 and plasma lipids. To validate ERICH4 as a lipid gene, we generated whole-body Erich4 knockout (Erich4-/-) mice. ERICH4 deficiency, however, did not result in changes in body weight and composition, food intake, circulating plasma lipids, energy absorption and excretion, and tissue weights compared to controls. Additionally, there were no morphological abnormalities seen in the small intestine. Challenging mice with a high-fat diet did not give rise to a phenotype either. ConclusionsDespite prediction tools indicating ERICH4 as a strong candidate gene in intestinal lipid metabolism, we here show that ERICH4 does not play a role in intestinal lipid metabolism in mice. It remains to be established whether ERICH4 plays a role in human lipid metabolism.

237 Disrupted insulin signaling due to an acute immune response in swine

Abstract Insulin is an anabolic hormone involved in glucose uptake and synthesis of fats, proteins, and glycogen. Altered insulin signaling can occur due to metabolic state, pathogen exposure, and autoimmune disorders. Lipopolysaccharide (LPS), an endotoxin secreted produced by gram-negative bacteria, can induce a severe, systemic immune response. In pigs, chronic LPS exposure has induced insulin resistance. However, the effects of acute exposure to LPS on insulin signaling and resistance have not been elucidated. Crossbred nursery pigs [n = 58, initial body weight (BW) = 12.1 kg ± 0.23 kg] were randomly assigned into two experimental subsets, where 10 animals were designated for repeated blood sampling and 48 animals underwent timed euthanasia for tissue collection. For repeated blood sampling, jugular catheters were placed under anesthesia and the animals were given 48 h to recover before being randomly assigned to treatments. These treatments were an intraperitoneal injection of either 15µg/kg BW LPS or an equal volume of 0.9% Saline (n = 5 pigs/treatment). Blood was collected for 48 h followed by euthanasia. The other 48 pigs were randomly assigned to the same treatments, and then randomly assigned to euthanasia timepoints of 0, 3, 6, 12, 24 or 48 h post injection for tissue collection. Among the catheterized pigs, 2-h post LPS challenge there was a decrease in serum insulin concentration (P < 0.05) and mild hyperglycemia (P < 0.05) post challenge. At 12- and 24-h post LPS challenge there was a decrease in insulin (P < 0.05) and a trend hyperglycemia was also apparent at 24 h (P = 0.063). In liver tissue, insulin related genes exhibited alterations post LPS injection. Phosphoinositide 3-kinase (pi3k) and insulin receptor substrate 1 (irs1) expression were decreased at 3 and 6 h (p< 0.05) and protein kinase b (akt) expression were decreased at 3 h (P < 0.05) post challenge. The expression of insulin inhibitor growth factor receptor bound protein 10 (grb10) was decreased at 6-, 12-, and 24-h after challenge (P < 0.05). Fructose-1-6-bisphosphatase (f16bp) expression was reduced at 3-, 6-, and 12-h (P < 0.05) in the liver while phosphoenolpyruvate carboxykinase (pepck) expression was decreased at 3- and 6-h (P < 0.01) post challenge. Other metabolic genes were decreased at 3-, 6-, and 12-h post LPS challenge, including fatty acid synthase (fas; P < 0.05), carbohydrate response element binding protein (chrebp; P < 0.05), and acetyl CoA carboxylase (acc; P < 0.05). Protein abundance of Akt 3 h after LPS injection was decreased in the liver (P < 0.05). In skeletal muscle 6 h post LPS injection, insulin receptor (insr), insulin-like growth factor receptor (igfr) and fas were all increased (P < 0.05) These results indicate disrupted insulin signaling at various levels after an acute immune response.

Disrupted Insulin Signaling Due to an Acute Immune Response in Swine

Insulin is an anabolic hormone involved in glucose uptake and synthesis of fats, proteins, and glycogen. Altered insulin signaling can occur due to metabolic state, pathogen exposure, and autoimmune disorders. Lipopolysaccharide (LPS), an endotoxin secreted produced by gram-negative bacteria, can induce a severe, systemic immune response. In pigs, chronic LPS exposure has induced insulin resistance. However, the effects of acute exposure to LPS on insulin signaling and resistance has not been elucidated. Crossbred nursery pigs (58, 12.1 kg ± 0.23kg BW) were randomly assigned into two experimental subsets, where 10 animals were designated for repeated blood sampling and 48 animals underwent timed euthanasia for tissue collection. For repeated blood sampling, jugular catheters were placed under anesthesia and the animals were given 48 hours to recover before being randomly assigned to treatments. These treatments were an intraperitoneal injection of either 15μg/kg BW LPS or an equal volume of 0.9% Saline (n=5 pigs/treatment). Blood was collected for 48 hours followed by euthanasia. The other 48 pigs were randomly assigned to the same treatments, and then randomly assigned to euthanasia timepoints of 0, 3, 6, 12, 24 or 48 hours post injection for tissue collection. Among the catheterized pigs, two hours post LPS challenge there was a decrease in serum insulin concentration (p<0.05) and mild hyperglycemia (p<0.05) post challenge. At 12 and 24 hours post LPS challenge there was a decrease in insulin (p<0.05) and a trend hyperglycemia was also apparent at 24 hours (p=0.063). In liver tissue, insulin related genes exhibited alterations post LPS injection. Phosphoinositide 3-kinase ( pi3k) and insulin receptor substrate 1 ( irs1) expression were decreased at 3 and 6 hours (p<0.05) and protein kinase b ( akt) expression were decreased at 3 hours (p<0.05) post challenge. The expression of insulin inhibitor growth factor receptor bound protein 10 ( grb10) was decreased at 6, 12, and 24 hours after challenge (p<0.05). Fructose-1-6-bisphosphatase ( f16bp) expression was reduced at 3, 6, and 12 hours (p<0.05) in the liver while phosphoenolpyruvate carboxykinase ( pepck) expression was decreased at 3 and 6 hours (p<0.01) post challenge. Other metabolic genes were decreased at 3, 6, and 12 hours post LPS challenge, including fatty acid synthase ( fas) (p<0.05), carbohydrate response element binding protein ( chrebp) (p<0.05), and acetyl CoA carboxylase ( acc)(p<0.05). Protein abundance of Akt 3 hours after LPS injection was decreased in the liver (p<0.05). In skeletal muscle 6 hours post LPS injection, insulin receptor ( insr), insulin-like growth factor receptor ( igfr) and fas were all increased (p<0.05) These results indicate disrupted insulin signaling at various levels after an acute immune response. Research reported in this abstract was supported by Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the National Institutes of Health under award number R01HD092304A. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Deletion of RAMP1 Signaling Enhances Diet-induced Obesity and Fat Absorption via Intestinal Lacteals in Mice.

Intestinal lymphatic vessels (lacteals) play a critical role in the absorption and transport of dietary lipids into the circulation. Calcitonin gene-related peptide and receptor activity-modifying protein 1 (RAMP1) are involved in lymphatic vessel growth. This study aimed to examine the role of RAMP1 signaling in lacteal morphology and function in response to a high-fat diet (HFD). RAMP1 deficient (RAMP1-/-) or wild-type (WT) mice were fed a normal diet (ND) or HFD for 8 weeks. RAMP1-/- mice fed a HFD had increased body weights compared to WT mice fed a HFD, which was associated with high levels of total cholesterol, triglycerides, and glucose. HFD-fed RAMP1-/- mice had shorter and wider lacteals than HFD-fed WT mice. HFD-fed RAMP1-/- mice had lower levels of lymphatic endothelial cell gene markers including vascular endothelial growth factor receptor 3 (VEGFR3) and lymphatic vascular growth factor VEGF-C than HFD-fed WT mice. The concentration of an absorbed lipid tracer in HFD-fed RAMP1-/- mice was higher than that in HFD-fed WT mice. The zipper-like continuous junctions were predominant in HFD-fed WT mice, while the button-like discontinuous junctions were predominant in HFD-fed RAMP1-/- mice. Deletion of RAMP1 signaling suppressed lacteal growth and VEGF-C/VEGFR3 expression but accelerated the uptake and transport of dietary fats through discontinuous junctions of lacteals, leading to excessive obesity. Specific activation of RAMP1 signaling may represent a target for the therapeutic management of diet-induced obesity.

Reversible expansion of tissue macrophages in response to macrophage colony-stimulating factor (CSF1) transforms systemic lipid and carbohydrate metabolism.

Macrophages regulate metabolic homeostasis in health and disease. Macrophage colony-stimulating factor (CSF1)-dependent macrophages contribute to homeostatic control of the size of the liver. This study aimed to determine the systemic metabolic consequences of elevating circulating CSF1. Acute administration of a CSF1-Fc fusion protein to mice led to monocytosis, increased resident tissue macrophages in the liver and all major organs, and liver growth. These effects were associated with increased hepatic glucose uptake and extensive mobilization of body fat. The impacts of CSF1 on macrophage abundance, liver size, and body composition were rapidly reversed to restore homeostasis. The effects of CSF1 on metabolism were independent of several known endocrine regulators and did not impact the physiological fasting response. Analysis using implantable telemetry in metabolic cages revealed progressively reduced body temperature and physical activity with no change in diurnal food intake. These results demonstrate the existence of a dynamic equilibrium between CSF1, the mononuclear phagocyte system, and control of liver-to-body weight ratio, which in turn controls systemic metabolic homeostasis. This novel macrophage regulatory axis has the potential to promote fat mobilization, without changes in appetence, which may have novel implications for managing metabolic syndrome.NEW & NOTEWORTHY CSF1 administration expands tissue macrophages, which transforms systemic metabolism. CSF1 drives fat mobilization and glucose uptake to support liver growth. The effects of CSF1 are independent of normal hormonal metabolic regulation. The effects of CSF1 are rapidly reversible, restoring homeostatic body composition. CSF1-dependent macrophages and liver size are coupled in a dynamic equilibrium.

Metabolic and mitochondrial dysregulation in CD4+ T cells from HIV-positive women on combination anti-retroviral therapy.

For optimal functionality, immune cells require a robust and adaptable metabolic program that is fueled by dynamic mitochondrial activity. In this study, we investigate the metabolic alterations occurring in immune cells during HIV infection and antiretroviral therapy by analyzing the uptake of metabolic substrates and mitochondrial phenotypes. By delineating changes in immune cell metabolic programming during HIV, we may identify novel potential therapeutic targets to improve anti-viral immune responses. After consent and voluntary participation was confirmed, whole blood was drawn from HIV uninfected women and women with chronic HIV infection on long-term combination antiretroviral therapy (HIV/cART). Peripheral blood mononuclear cells-derived immune cells were directly incubated with different fluorescently tagged metabolites and markers of mitochondrial activity: FITC-2-NBDG (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose), FITC-BODIPY (4,4-Difluoro-5,7-Dimethyl-4-Bora-3a,4a-Diaza-s-Indacene-3-Hexadecanoic Acid), FITC-MitoTracker Green and APC-MitoTracker Deep Red. The uptake of glucose and fats and the mitochondrial mass and potential were measured using flow cytometry. All values are reported quantitatively as geometric means of fluorescence intensity. During chronic HIV infection, cellular uptake of glucose increases in HIV+ dendritic cells in particular. CD4+ T cells had the lowest uptake of glucose and fats compared to all other cells regardless of HIV status, while CD8+ T cells took up more fatty acids. Interestingly, despite the lower utilization of glucose and fats in CD4+ T cells, mitochondrial mass increased in HIV+ CD4+ T cells compared to HIV negative CD4+ T-cells. HIV+ CD4+ T cells also had the highest mitochondrial potential. Significant disparities in the utilization of substrates by leukocytes during chronic HIV/cART exist. Innate immune cells increased utilization of sugars and fats while adaptive immune cells displayed lower glucose and fat utilization despite having a higher mitochondrial activity. Our findings suggest that cART treated HIV-infected CD4+ T cells be dysfunctional or may prefer alternative fuel sources not included in these studies. This underscores the importance of understanding the metabolic effects of HIV treatment on immune function.

Ability of high fat diet to induce liver pathology correlates with the level of linoleic acid and Vitamin E in the diet.

Increased uptake of fat, such as through the ingestion of high fat diet (HFD), can lead to fatty liver diseases and metabolic syndrome. It is not clear whether certain fatty acids may be more pathogenic than others to the liver. Linoleic acid (LA) is the most abundant polyunsaturated fatty acid in the Western diet and its excessive consumption can lead to increased lipid peroxidation. We hypothesized that a high level of LA in HFD will contribute significantly to the hepatic steatosis and injury, whereas vitamin E (VIT-E) may reverse the effects from LA by inhibiting lipid peroxidation. To test this hypothesis, we fed mice with the following diets for 20 weeks: a standard low-fat diet (CHOW), HFD with a low level of LA (LOW-LA, 1% of energy from LA), HFD with a high level of LA (HI-LA, 8% of energy from LA), or HI-LA diet with VIT-E supplement (HI-LA + VIT-E). We found that the HI-LA diet resulted in more body weight gain, larger adipocyte area, and higher serum levels of triglycerides (TG) and free fatty acids (FFA) relative to the CHOW and LOW-LA diets. In mice fed with the HI-LA diet, severer hepatic steatosis was seen with higher levels of hepatic TG and FFA. Expression of genes related to lipid metabolism was altered in the liver by HI-LA diet, including fibroblast growth factor 21 (Fgf21), cluster of differentiation 36 (Cd36), stearoyl-CoA desaturase 1 (Scd1), and acyl-CoA oxidase 1 (Acox1). Liver injury, inflammation and fibrotic response were all enhanced in mice fed with the HI-LA diet when compared with the LOW-LA diet. Notably, addition of VIT-E supplement, which restores the proper VIT-E/PUFA ratio, significantly reduced the detrimental effects of the high level of LA. Taken together, our results suggest that a high level of LA and a low ratio of VIT-E/PUFA in HFD can contribute significantly to metabolic abnormalities and hepatic injury.

Impact of polymorphism in oleogels of N-palmitoyl-L-phenylalanine.

Gels of edible oils, also called oleogels, are developed as alternative products of solid fats to limit the uptake of saturated and trans-unsaturated fats and lower the associated risk of coronary disease. The gelation of oils can be achieved with a low molecular weight organogelator (LMWO), a compound that self-assembles at low concentrations in a solid 3D network and provides the mixture its solid-like behavior. We have studied N-palmitoyl-L-phenylalanine (Palm-Phe), an endogenous compound (i.e. naturally present in the human body) as a model LMWO of rapeseed oil. Palm-Phe forms gels at a concentration of 1 wt% in rapeseed oil. We have studied the thermodynamic and mechanical behavior of the corresponding gels. As evidenced by DSC and rheology, this system exhibits two transitions upon heating, in addition to the sol-gel transition, a gel-gel transition between two polymorphic gels. The structural differences between both polymorphs were revealed using cryo-SEM, X-rays scattering, and FTIR experiments. The metastability of one of the polymorphs was proven by ageing and annealing experiments.

Mechanisms of drugs in the treatment of type 2 diabetes mellitus.

Mechanisms of drugs in the treatment of type 2 diabetes mellitus.

ODP011 Single Nuclei RNA-Sequencing of Frozen Human Adipose Tissue and PET/CT Imaging Coupled With Deep-Learning Reveals Single-Cell Landscape and Transcriptional Dynamics Related to Adipocyte Hypertrophy and in Vivo Dysmetabolism

Abstract Background Adipocyte hypertrophy is associated with glucose and lipid dysmetabolism, ectopic fat accumulation, and metabolic complications independently of the level of obesity [1]. In this study, we aimed to explore potential mechanisms driving the obesity-independent, hypertrophy-associated dysmetabolism at a single-cell resolution and to assess the applicability of single nuclei RNA-sequencing of flash-frozen human subcutaneous adipose tissue (AT) to probe for these metabolic differences. Methods In 40 healthy participants, peri-umbilical subcutaneous adipose tissue biopsies were collected by needle aspiration to determine adipocyte size. Tissue uptake of dietary fat was quantified via oral 18-fluoro-thiaheptadecanoic acid administration with positron emission tomography (PET) [2]. Rates of fatty acid oxidation and esterification were measured using intravenous [11C]-palmitate with PET and multi-compartmental modeling. PET/CT segmentation using deep convolutional neural networks was done with DeepImageTranslator [3,4]. Single nuclei RNA-sequencing was performed in two individuals with AT hypertrophy vs. hyperplasia but matched for the same sex, ethnicity, glucose-tolerance status, BMI, total and percent body fat, and waist circumference. Nuclei were extracted from frozen AT and purified by flow cytometry following a protocol that we have developed and validated. Capture of single nuclei and preparation of RNA libraries were done with 10X Genomics technology. Results Unsupervised clustering identified a number of cell-type markers identical to those previously reported in murine epididymal AT and human AT. We found reduced quantities of fibroadipogenic cells per volume of AT with fat cell hypertrophy. Furthermore, the fraction of DPP4+ fibroblasts is increased with AT hypertrophy. Analyses of RNA velocity shows decreased velocity of adipocyte transformation from a transcriptionally active (TADA) phenotype to mature adipocytes in AT hypertrophy. Furthermore, in AT hypertrophy, adipocytes from the early TADA stage are destined to become insulin-resistant adipocytes, whereas those in AT hyperplasia are developing into an insulin-sensitive phenotype. Metabolic imaging results show that hypertrophied subcutaneous AT is associated with lower subcutaneous and higher visceral AT volume and dietary fatty acid storage capacity. Conclusion We have documented, for the first time, the applicability and consistency of single-nuclei RNA-sequencing of frozen human subcutaneous AT. We uncovered changes in cell clusters and subclusters of adipocytes, fibroblasts, pericytes, endothelial and immune cells as well as differences in transcriptional dynamics and developmental trajectory. [1] Ye RZ, et al. Endocrine reviews. 2022 Feb;43(1): 35-60. [2] Montastier É, Ye RZ, et al. American Journal of Physiology-Endocrinology and Metabolism. 2021 Jun 1;320(6): E1093-106. [3] R. Z. Ye, et al., DeepImageTranslator: A free, user-friendly graphical interface for image translation using deep-learning and its applications in 3D CT image analysis, SLAS Technology, https://doi.org/10.1016/j.slast.2021.10. 014, [4] Ye EZ, Ye EH, Ye RZ. DeepImageTranslator V2: analysis of multimodal medical images using semantic segmentation maps generated through deep learning. bioRxiv. 2021 Jan 1. Presentation: No date and time listed

Lipid absorption and overall intestinal lymphatic transport are impaired following partial small bowel resection in mice

Short bowel syndrome (SBS) is associated with diminished levels of serum fats caused by unknown mechanisms. We have shown that mesenteric lymphatics remodel to a more primitive state one week after small bowel resection (SBR); therefore, this study focuses on the effect of chronic lymphatic remodeling and magnitude of resection on intestinal lipid uptake and transport. C57BL6 and Prox1 creER-Rosa26LSLTdTomato (lymphatic reporter) mice underwent 50% or 75% proximal SBR or sham operations. Functional transport of lipids and fecal fat content was measured and lymphatic vasculature was compared via imaging. There was a significant reduction in functional transport of cholesterol and triglyceride after SBR with increasing loss of bowel, mirrored by a progressive increase in fecal fat content. We also describe significant morphological changes in the lymphatic vasculature in both the lamina propria and mesentery. Intestinal lymphatic drainage assay in vivo demonstrated a marked reduction of systemic absorption after resection. Intestinal lymphatic vessels significantly remodel in the setting of chronic SBS. This remodeling may account at least in part for impaired intestinal uptake and transport of fat via the compromised lymphatic architecture. We believe that these changes may contribute to the development of intestinal failure associated liver disease (IFALD), a major morbidity in patients with SBS.

Revisiting the gut-liver axis: gut lymphatic system in liver cirrhosis and portal hypertension.

The lymphatic vascular system runs parallel to the blood vascular system, comprising a network of lymphatic vessels and secondary lymphoid organs. The intestinal lymphatic capillaries (lacteals) and the associated collecting vessels in the mesentery form the gut lymphatic system. The gut lymphatic vasculature comprises the longest-studied lymphatic vessel bed and plays a significant role in the uptake and transport of dietary fat, abdominal fluid balance, and gut immunosurveillance. Gut is closely connected to liver through the portal circulation. In several experimental and clinical studies, the "gut-liver-axis" has been demonstrated to contribute to the pathogenesis of portal hypertension, liver cirrhosis, and its complications. Given a significant impact of gut health on the liver, in the current review, we highlight "gut-liver axis" in context to the circulatory physiology of gut lymphatic vessels. Despite their paramount importance in maintaining fluid and immune homeostasis in the gut, gut lymphatic vessels remain one of the most understudied physiological systems in liver disease pathology. In the current review, we delineate the connections of gut lymphatics with abdominal fluid homeostasis and bacterial translocation in the pathogenesis of liver cirrhosis and portal hypertension. We describe mechanisms and factors that drive gut lymphangiogenesis and lymphatic vessel dysfunction during inflammation. The review also underscores the role of gut lymphatic endothelial cells in regulating gut and liver immunity. We finally discuss the prognostic and therapeutic prospects of studying gut lymphatic vessels in advanced liver cirrhosis.

Different prognostic impact of glucose uptake in visceral adipose tissue according to sex in patients with colorectal cancer

The purpose of this study was to investigate whether sex differences in visceral fat volume and glucose uptake measured by positron emission tomography/computed tomography (PET/CT) in abdominal visceral fat can stratify overall survival (OS) in patients with colorectal cancer (CRC). We retrospectively enrolled 293 patients diagnosed with CRC who underwent PET/CT before surgical resection. Fluorodeoxyglucose uptake of visceral adipose tissue (VAT-SUV) and subcutaneous adiposity tissue (SAT-SUV) were measured using PET/CT. The relative VAT (rVAT) was defined as the visceral fat volume normalized to the total volume of fat (VAT plus SAT). We defined sex-specific cutoff values for VAT-SUV, SAT-SUV, and rVAT. Univariate and multivariate analyses using Cox proportional hazard regression analysis were performed to identify the independent prognostic factors. The study population comprised 181 men and 112 women. The rVAT (0.40 vs. 0.29, p < 0.001) and VAT-SUV (0.55 vs. 0.48, p = 0.007) were significantly greater in men than in women. High rVAT (than low rVAT) and high VAT-SUV (than low VAT-SUV) showed a worse prognosis in male and female patients, respectively. Multivariate analysis indicated that the combination of rVAT and VAT-SUV was an independent prognostic factor for predicting OS in both male and female patients. The combination of rVAT and VAT-SUV could differentiate the patients with the best survival outcome from the other three individual groups in female patients, but not in males. Glucose uptake and relative volume of visceral fat may provide a new risk stratification for patients with CRC, especially female patients.

Analyses and Declarations of Omega-3 Fatty Acids in Canned Seafood May Help to Quantify Their Dietary Intake.

The American Heart Association (AHA) recently confirmed common recommendations of one to two fish dishes per week in order to prevent cardiovascular disease (CVD). Nevertheless, the natural fluctuations of lipids and fatty acids (FA) in processed seafood caught little public attention. Moreover, consumers of unprocessed seafood in general do not know how much omega-3 fatty acids (omega-3 FA) within servings they actually ingest. The few studies published until today considering this aspect have been re-evaluated in today’s context. They included four observational studies with canned fatty coldwater fish (mackerel and herring from the same region, season, producer and research group). Their outcomes were similar to those conducted in the following years using supplements. Cans containing seafood (especially fatty coldwater fish) with declared content of omega-3 FA are ready-to-use products. Human studies have shown a higher bioavailability of omega-3 FA by joint uptake of fat. Canned fatty coldwater fish contain omega-3 FA plus plenty of fat in one and the same foodstuff. That suggests a new dietary paradigm with mixed concepts including several sources with declared content of omega-3 FA for reducing the cardiovascular risk and other acknowledged indications.

The Roles of Cytoplasmic Lipid Droplets in Modulating Intestinal Uptake of Dietary Fat.

Dietary fat absorption is required for health but also contributes to hyperlipidemia and metabolic disease when dysregulated. One step in the process of dietary fat absorption is the formation of cytoplasmic lipid droplets (CLDs) in small intestinal enterocytes; these CLDs serve as dynamic triacylglycerol storage organelles that influence the rate at which dietary fat is absorbed. Recent studies have uncovered novel factors regulating enterocyte CLD metabolism that in turn influence the absorption of dietary fat. These include peroxisome proliferator-activated receptor α activation, compartmentalization of different lipid pools, the gut microbiome, liver X receptor and farnesoid X receptor activation, obesity, and physiological factors stimulating CLD mobilization. Understanding how enterocyte CLD metabolism is regulated is key in modulating the absorption of dietary fat in the prevention of hyperlipidemia and its associated metabolic disorders.

Cells with Many Talents: Lymphatic Endothelial Cells in the Brain Meninges.

The lymphatic system serves key functions in maintaining fluid homeostasis, the uptake of dietary fats in the small intestine, and the trafficking of immune cells. Almost all vascularized peripheral tissues and organs contain lymphatic vessels. The brain parenchyma, however, is considered immune privileged and devoid of lymphatic structures. This contrasts with the notion that the brain is metabolically extremely active, produces large amounts of waste and metabolites that need to be cleared, and is especially sensitive to edema formation. Recently, meningeal lymphatic vessels in mammals and zebrafish have been (re-)discovered, but how they contribute to fluid drainage is still not fully understood. Here, we discuss these meningeal vessel systems as well as a newly described cell population in the zebrafish and mouse meninges. These cells, termed brain lymphatic endothelial cells/Fluorescent Granular Perithelial cells/meningeal mural lymphatic endothelial cells in fish, and Leptomeningeal Lymphatic Endothelial Cells in mice, exhibit remarkable features. They have a typical lymphatic endothelial gene expression signature but do not form vessels and rather constitute a meshwork of single cells, covering the brain surface.

Effect of Paraplegia on the Time Course of Exogenous Fatty Acid Incorporation Into the Plasma Triacylglycerol Pool in the Postprandial State.

Spinal cord injury (SCI) results in disordered fat metabolism. Autonomic decentralization might contribute to dyslipidemia in SCI, in part by influencing the uptake of dietary fats through the gut-lymph complex. However, the neurogenic contributions to dietary fat metabolism are unknown in this population. We present a subset of results from an ongoing registered clinical trial (NCT03691532) related to dietary fat absorption. We fed a standardized (20 kcal⋅kgFFM–1) liquid meal tolerance test (50% carb, 35% fat, and 15% protein) that contained stable isotope lipid tracer (5 mg⋅kgFFM–1 [U-13C]palmitate) to persons with and without motor complete thoracic SCI. Blood samples were collected at six postprandial time points over 400 min. Changes in dietary fatty acid incorporated into the triacylglycerol (TAG) pool (“exogenous TAG”) were used as a marker of dietary fat absorption. This biomarker showed that those with paraplegia had a lower amplitude than non-injured participants at Post240 (52.4 ± 11.0 vs. 77.5 ± 16.0 μM), although this failed to reach statistical significance (p = 0.328). However, group differences in the time course of absorption were notable. The injury level was also strongly correlated with time-to-peak exogenous TAG concentration (r = −0.806, p = 0.012), with higher injuries resulting in a slower rise in exogenous TAG. This time course documenting exogenous TAG change is the first to show a potential neurogenic alteration in SCI dietary fat absorption.

Increased myocardial fat supply improves cardiac energetics and function in heart failure

Abstract Introduction The failing heart is starved of energy, in part accounting for its contractile dysfunction. Reduced uptake of fat and sugar required for energy production has frequently been demonstrated in heart failure, therefore altering metabolism of glucose and/or fat is therefore attractive as a therapy. We hypothesized increasing glucose supply would be beneficial over increasing fat supply so measured ATP usage (via PCr/ATP ratio and flux through creatine kinase) and cardiac function during fat emulsion infusion or euglycaemic hyperinsulinaemic clamp. Methods 11 patients with a diagnosis of heart failure and nonischaemic cardiomyopathy were recruited, mean age 66 (range 49–80), mean BMI 27.7 (range 21.3–37.5), F:M 3:8, 3 diabetic and 8 non-diabetic. On the first visit they had a baseline cardiac magnetic resonance (CMR), collecting cardiac volumes and function, then were randomised to receive either fat infusion or euglycaemic clamp. Following an hour of infusion, CMR was repeated followed by 31P cardiac magnetic resonance spectroscopy, then a dobutamine stress sequence at 65% maximum heart rate. They received the alternate infusion at the next visit. Results Data was normally distributed. Baseline ejection fraction was 37±9%. PCr/ATP ratio was greater with the fat infusion compared to euglycaemic clamp (1.82±0.26 vs 1.68±0.24, p=0.04). Fat emulsion infusion also brought about a greater ejection fraction increase over the baseline, compared to the euglycaemic clamp in which there was little difference (+5.3±5.3% vs −0.6±3.1%, p=0.004). Calculated cardiac work was greater in the fat infusion group than the Insulin/glucose group (682±156 L.mmHg/min vs 581±85 L.mmHg/min, p=0.009). There was no significant difference in creatine kinase first order rate constant (fat infusion 0.2±0.09/s vs euglycaemic clamp 0.16±0.07/s, p=0.32) nor creatine kinase flux (fat infusion 1.85±0.92 μmol/g/s vs euglycaemic clamp 1.46±0.58 μmol/g/s, p=0.22). The increment in cardiac output on stress over baseline was not significantly different between arms (fat infusion +3.39±3.07 L/min vs euglycaemic clamp +3.08±2.57 L/min, p=0.42). The PCr/ATP ratio showed positive correlation with the stress ejection fraction (R2=0.656, p=0.001), but not with resting ejection fraction. Conclusions Increased supply of fat to the myocardium brought about improved contractility and cardiac energetics compared to an increased glucose supply. The increase in PCr/ATP ratio would imply (given ATP concentrations are kept constant in the myocardium) there is a greater availability of phosphocreatine, suggesting increased mitochondrial ATP synthesis. These results were unexpected as it has traditionally been thought that increased glucose metabolism would yield greater cardiac function in the failing heart. These data suggest targeting myocardial fat metabolism may provide novel treatments for cardiac dysfunction. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation

Association of glucose uptake of visceral fat and acute myocardial infarction: a pilot 18F-FDG PET/CT study

BackgroundInflamed visceral adipose tissue (VAT) facilitates chronic inflammation in atherosclerotic lesions thereby leading to increased risk of coronary artery disease (CAD). In this study, we evaluated the glucose uptake of VAT and the carotid artery with 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) and their association with CAD, including acute myocardial infarction (AMI).MethodsA total of 90 participants were enrolled (32 with AMI, 33 with chronic stable angina; CSA, and 25 control participants) and undertook 18F-FDG PET/CT. VAT glucose uptake was measured by using maximum standardized uptake value (SUVmax) of VAT region. The target-to-background ratio (TBR) of carotid artery was defined as the SUVmax of carotid artery divided by the SUVmax of jugular vein. The SUVmax of spleen, bone-marrow (BM), and high-sensitivity C-reactive protein (hsCRP) were used for the assessment of systemic inflammatory activity.ResultsVAT SUVmax was highest in participants with AMI, intermediate in participants with CSA, and lowest in control participants. Carotid artery TBR and systemic inflammatory surrogate markers including spleen SUVmax, BM SUVmax, and hsCRP were also higher in the AMI group than in the CSA or control group. Furthermore, VAT SUVmax showed significant positive correlation with carotid artery TBR, spleen SUVmax, BM SUVmax, and hsCRP. In multivariate linear regression and logistic regression analyses, VAT SUVmax was independently associated with carotid artery TBR and AMI.ConclusionsGlucose uptake of VAT assessed by 18F-FDG PET/CT was associated with the severity of CAD and synchronized with the carotid artery inflammation in participants with CAD.

The effects of high-oleic peanuts as an alternative feed ingredient on broiler performance, ileal digestibility, apparent metabolizable energy, and histology of the intestine.

Locally grown feed ingredients of high energy and protein content, such as peanuts, maybe economically feasible alternatives to corn and soybean meal in broiler diets. Even though normal-oleic peanuts have been demonstrated to be a viable feed ingredient for poultry, few studies to date have examined the use of high-oleic peanuts (HO PN) as an alternative feed ingredient for broiler chickens. Thus, we aimed to determine the effect of feeding HO PN on broiler performance, nutrient digestibility, and intestinal morphology. Three isocaloric, isonitrogenous experimental diets were formulated with 1) dietary inclusion of ~10% coarse-ground whole HO PN; 2) a corn-soybean meal control diet with 5.5% added poultry fat; and 3) a control diet supplemented with 5.5% oleic fatty acid oil. Three-hundred Ross 708 broilers were randomly placed in 10 replicate pens per treatment with 10 chicks per pen and raised until 42 d. Body weights (BW) and feed intake were determined weekly, and feed conversion ratio (FCR) was calculated. Jejunum samples were collected at 42 d for histomorphometric analysis. Analysis of variance was performed on all variables using a general linear mixed model in JMP Pro14. Broilers in the HO PN group had lower (P < 0.05) BW and higher FCR than other treatment groups at weeks 2 and 6. There were no significant differences in the jejunum villi surface area between the treatment groups. However, broilers fed the HO PN diet had greater (P = 0.019) apparent metabolizable energy relative to the other treatment groups, suggesting improved nutrient uptake of dietary fats and/or carbohydrates in the HO PN treatment group. However, additional studies are warranted to further define the nutritional value of HO PN as an alternative poultry feed ingredient.