Non-adipose Tissues Research Articles

Adipocyte-Specific GH Receptor-Null (AdGHRKO) Mice Have Enhanced Insulin Sensitivity With Reduced Liver Triglycerides.

Global GH receptor-null or knockout (GHRKO) mice have been extensively studied owing to their unique phenotype (dwarf and obese but remarkably insulin sensitive and long-lived). To better understand the influence of adipose tissue (AT) on the GHRKO phenotype, we previously generated fat-specific GHRKO (FaGHRKO) mice using the adipocyte protein-2 (aP2) promoter driving Cre expression. Unlike global GHRKO mice, FaGHRKO mice are larger than control mice and have an increase in white AT (WAT) mass and adipocyte size as well as an increase in brown AT mass. FaGHRKO mice also have an unexpected increase in IGF-1, decrease in adiponectin, no change in insulin sensitivity or liver triglyceride content, and a decreased lifespan. Extensive analysis of the aP2 promoter/enhancer by multiple laboratories has revealed expression in nonadipose tissues, confounding interpretation of results. In the current study, we used the adiponectin promoter/enhancer to drive Cre expression, which better targets mature adipocytes, and generated a new line of adipocyte-specific GHRKO (AdGHRKO) mice. AdGHRKO mice have an increase in adipocyte size and WAT depot mass in all depots except male perigonadal, a WAT accumulation pattern similar to FaGHRKO mice. Likewise, adiponectin levels and WAT fibrosis are decreased in both tissue-specific mouse lines. However, unlike FaGHRKO mice, AdGHRKO mice have no change in IGF-1 levels, improved glucose homeostasis, and reduced liver triglycerides. Thus, AdGHRKO mice should be valuable for future studies assessing the contribution of adipocyte GHR signaling in long-term health and lifespan.

Fitness versus adiposity in cardiovascular disease risk.

Obesity and low cardiorespiratory fitness are both established predictors of cardiovascular disease morbidity and mortality. Whether the protective effects of fitness outweigh the deleterious effects of obesity, however, remains a topic of debate. To extend knowledge of the relative influence of fitness and fatness on cardiovascular disease outcomes, however, attention must be paid to measurement quality. Eliminating inherent bias of self-report and including the highest quality assessments of cardiorespiratory fitness and fatness simultaneously are imperative for head-to-head comparisons. Studies must move beyond body mass index and total body fat percentage to differentiate the heterogenous effects of various adipose tissue depots on cardiovascular risk. Imaging techniques that measure visceral adiposity and other risk-laden ectopic adipose depots while also quantifying cardioprotective adipose depots such as lower body subcutaneous fat and even non-adipose tissues such as skeletal muscle may further illuminate the influence of body composition on cardiovascular health. This review underscores key studies within a large body of literature that provide the foundation for the fit-vs.-fat debate in the context of cardiovascular disease risk, and identifies important considerations for future research.

Cotton rat (Sigmodon hispidus) develops metabolic disorders associated with visceral adipose inflammation and fatty pancreas without obesity.

Obesity induces metabolic disorders such as type 2 diabetes, hypertension, and cardiovascular diseases and has become a global health concern. Recent studies imply that fat accumulation in nonadipose tissue correlates with metabolic disorders. However, there are no suitable animal models to evaluate this phenomenon. This study investigated the characteristics of metabolic disorders found in cotton rat (Sigmodon hispidus). Blood biochemical examinations revealed that cotton rats, predominantly males, developed hyperinsulinemia, hyperglycemia, and dyslipidemia when fed a normal diet. The islets increased in size through β-cell hyperplasia, which was associated with serum insulin level in both sexes, strongly indicating insulin resistance. In male cotton rats, oxidative stress was observed in β cells, and macrophage infiltration into the visceral white adipose tissue was reported, both of which were associated with serum insulin level without visceral obesity. In contrast, female cotton rats developed hyperinsulinemia without histopathological changes that were reported in males. Adipocytes were found to be accumulated in the pancreas but not in the liver of both sexes during aging. Pancreatic fat accumulation was associated with the serum insulin level only in females. Taken together, cotton rats developed metabolic disorders associated with visceral fat inflammation in the absence of obesity. In addition, pancreatic ectopic fat may also be related to the early stages of these conditions. Thus, the cotton rat may serve as a novel and useful model for metabolic disorders characterized by visceral adipose inflammation and ectopic fat accumulation in the pancreas without obesity.

Adipocytes and Abdominal Aortic Aneurysm: Putative Potential Role of Adipocytes in the Process of AAA Development

Adipose tissue plays a role in the storage of excess energy as triglycerides (TGs). Excess fat accumulation causes various metabolic and cardiovascular diseases. It has been reported that ectopic fat deposition and excess TG accumulation in non-adipose tissue might be important predictors of cardiometabolic and vascular risk. For example, ectopic fat in perivascular tissue promotes atherosclerotic plaque formation in the arterial wall. Recently, it has been reported that ectopic fat (adipocyte) in the vascular wall of an abdominal aortic aneurysm (AAA) is present in both human and experimental animal models. The pathological significance of adipocytes in the AAA wall has not been fully understood. In this review, we summarized the functions of adipocytes and discussed potential new drugs that target vascular adipocytes for AAA treatment. Previous studies suggest that adipocytes in vascular wall play an important role in the development of AAA. Adipocytes in the vascular wall could be novel targets for the development of AAA therapeutic drugs.

Mechanisms of triacylglycerides oxidation in artificial lipid droplets

Lipid droplets (LDs) are inducible cellular organelles that have a pivotal role in physiological processes. Depending on their size and host cell type they serve functions ranging from lipid storage (e.g. in adipocytes), cytoprotection (in non-adipose tissue) and inflammation (in macrophages and leukocytes).[1] LD are micelles consisting of a neutral lipid core (triglycerides - TAG, cholesteryl esters - CE and fatty acids - FA) surrounded by a monolayer of phospholipids (PL). Under conditions of oxidative stress (e.g. cancer) lipid droplets have been found to contain increased levels of oxidized TAG (oxTAG). [2] Oxidized lipid species have been shown to be involved in the disturbance of cellular processes by various mechanisms but are also known to serve regulatory functions [3]. Non-enzymatic lipid oxidation is based on an oxygen dependent radical-propagation mechanism. Due to the highly unpolar milieu in the LDs core, polar oxygen-centered radicals (e.g. hydroxyl radical) cannot penetrate through the outer LDs phospholipid monolayer indicating that other mechanisms of radical reactions might govern generation of oxidized lipids in LDs, either involving longer lived, hydrophobic organic radicals or radical propagation from PL monolayer into the LD core. LDs of specific composition (molar ratio: PC/PE 3:1; PL/TAG 1:20) and defined size (140 nm) were prepared by differential ultracentrifugation steps. Size and composition of generated micellar structures was elucidated by nanotracking light scattering microscopy and fluorescence spectrophotometry. Generated micelles were oxidized by either Fenton chemistry (hydroxyl radicals) or by AAPH (organic radicals) and further analyzed by LC-MS using RPC-ESI-QTOF or ESI-LTQ-Orbitrap.

Inhibition of PPAR Gamma, Adipogenesis, and Insulin Sensitivity by MAGED1

Adipocytes serve as critical integrators of energy balance and glucose homeostasis by storing excess energy to prevent ectopic fat accumulation in non-adipose tissues and by secreting various adipokines to modulate whole-body metabolism. Peroxisome proliferator-activated receptor-γ (PPARγ) is a master regulator of adipogenesis and a target of the thiazolidinedione (TZD) class of antidiabetic drugs; therefore, identifying novel regulators of PPARγ action in adipocytes is essential for the future development of therapeutics for diabetes. MAGE Family Member D1 (MAGED1), by acting as an adaptor for ubiquitin-dependent degradation pathways and a co-factor for transcription, plays an important role in neural development, cell differentiation, and circadian rhythm. Here, we showed that MAGED1 expression was downregulated during adipogenesis and MAGED1 inhibited preadipocyte proliferation and adipogenesis in vitro. Mechanistically, MAGED1 bound to PPARγ and suppressed the stability and transcriptional activity of PPARγ. Compared to wild type littermates, MAGED1-deficient mice showed increased levels of PPARγ protein and its target genes, more CD29+CD34+Sca-1+ adipocyte precursors, and hyperplasia of white adipose tissues (WATs) at young ages. Moreover, MAGED1-deficient mice developed late-onset obesity as a result of decreased energy expenditure and physical activity. However, these mice were metabolically healthy as shown by improved glucose clearance and insulin sensitivity. Lipid profiling showed that obesity in MAGED1 knockout (KO) mice did not cause increased levels of serum lipids. On the other hand, expression and secretion of adipokines such as leptin and adiponectin were upregulated in KO mice. Taken together, our data identify MAGED1 as a novel negative regulator of PPARγ activity, adipogenesis, and insulin sensitivity in mice. MAGED1 might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance. Disclosure Q. Wang: None. J. Tang: None. X. Gao: None. H. Ruan: None.

Effect of puerarin in promoting fatty acid oxidation by increasing mitochondrial oxidative capacity and biogenesis in skeletal muscle in diabetic rats

BackgroundType 2 diabetes is characterized by dyslipidemia and the accumulation of lipids in non-adipose tissue, including skeletal muscle. Puerarin, which is a natural isoflavonoid isolated from the root of the plant Pueraria lobata, has been shown to have antidiabetic activity. However, the lipid-reducing effect of puerarin, in particular in skeletal muscle, has not yet been addressed.MethodsWe examined the effect of puerarin on mitochondrial function and the oxidation of fatty acids in the skeletal muscle of high-fat diet/streptozotocin-induced diabetic rats.ResultsPuerarin effectively alleviated dyslipidemia and decreased the accumulation of intramyocellular lipids by upregulating the expression of a range of genes involved in mitochondrial biogenesis, oxidative phosphorylation, the detoxification of reactive oxygen species, and the oxidation of fatty acids in the muscle of diabetic rats. Also, the effect of puerarin on mitochondrial biogenesis might partially involve the function of the μ-opioid receptor. In addition, puerarin decreased the trafficking of fatty acid translocase/CD36 to the plasma membrane to reduce the uptake of fatty acids by myocytes. In vitro studies confirmed that puerarin acted directly on muscle cells to promote the oxidation of fatty acids in insulin-resistant myotubes treated with palmitate.ConclusionsPuerarin improved the performance of mitochondria in muscle and promoted the oxidation of fatty acids, which thus prevented the accumulation of intramyocellular lipids in diabetic rats. Our findings will be beneficial both for elucidating the mechanism of the antidiabetic activity of puerarin and for promoting the therapeutic potential of puerarin in the treatment of diabetes.

STK25 regulates oxidative capacity and metabolic efficiency in adipose tissue.

Whole-body energy homeostasis at over-nutrition critically depends on how well adipose tissue remodels in response to excess calories. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of ectopic lipid storage in non-adipose tissue and systemic insulin resistance in the context of nutritional stress. Here, we investigated the role of STK25 in regulation of adipose tissue dysfunction in mice challenged with a high-fat diet. We found that overexpression of STK25 in high-fat-fed mice resulted in impaired mitochondrial function and aggravated hypertrophy, inflammatory infiltration and fibrosis in adipose depots. Reciprocally, Stk25-knockout mice displayed improved mitochondrial function and were protected against diet-induced excessive fat storage, meta-inflammation and fibrosis in brown and white adipose tissues. Furthermore, in rodent HIB-1B cell line, STK25 depletion resulted in enhanced mitochondrial activity and consequently, reduced lipid droplet size, demonstrating an autonomous action for STK25 within adipocytes. In summary, we provide the first evidence for a key function of STK25 in controlling the metabolic balance of lipid utilization vs lipid storage in brown and white adipose depots, suggesting that repression of STK25 activity offers a potential strategy for establishing healthier adipose tissue in the context of chronic exposure to dietary lipids.

Acute loss of iron–sulfur clusters results in metabolic reprogramming and generation of lipid droplets in mammalian cells

Iron-sulfur (Fe-S) clusters are ancient cofactors in cells and participate in diverse biochemical functions, including electron transfer and enzymatic catalysis. Although cell lines derived from individuals carrying mutations in the Fe-S cluster biogenesis pathway or siRNA-mediated knockdown of the Fe-S assembly components provide excellent models for investigating Fe-S cluster formation in mammalian cells, these experimental strategies focus on the consequences of prolonged impairment of Fe-S assembly. Here, we constructed and expressed dominant-negative variants of the primary Fe-S biogenesis scaffold protein iron-sulfur cluster assembly enzyme 2 (ISCU2) in human HEK293 cells. This approach enabled us to study the early metabolic reprogramming associated with loss of Fe-S-containing proteins in several major cellular compartments. Using multiple metabolomics platforms, we observed a ∼12-fold increase in intracellular citrate content in Fe-S-deficient cells, a surge that was due to loss of aconitase activity. The excess citrate was generated from glucose-derived acetyl-CoA, and global analysis of cellular lipids revealed that fatty acid biosynthesis increased markedly relative to cellular proliferation rates in Fe-S-deficient cells. We also observed intracellular lipid droplet accumulation in both acutely Fe-S-deficient cells and iron-starved cells. We conclude that deficient Fe-S biogenesis and acute iron deficiency rapidly increase cellular citrate concentrations, leading to fatty acid synthesis and cytosolic lipid droplet formation. Our findings uncover a potential cause of cellular steatosis in nonadipose tissues.

Aberrant fatty acid metabolism in skeletal muscle contributes to insulin resistance in zinc transporter 7 (znt7)-knockout mice

ZnT7 (Slc30a7) is a widely expressed zinc transporter involved in sequestration of zinc into the Golgi apparatus and vesicular compartments. znt7-knockout (KO) mice are mildly zinc-deficient and lean. Despite their lean phenotype, adult male znt7-KO mice are prone to insulin resistance. We hypothesized that fat partitioning from adipose to nonadipose tissues causes insulin resistance in znt7-KO mice. Here, we used biological and biochemical methods, including fatty acid and oxylipin profiling, EM, immunohistochemistry, quantitative RT-PCR, and Western blot analysis, to identify the underlying mechanism of insulin resistance in znt7-KO mice. We found that insulin resistance in this model was primarily associated with increased intracellular fatty acid levels in the skeletal muscle, which promoted intracellular lipid accumulation and production of bioactive lipid mediators, such as 12,13-dihydroxyoctadecanoic acid (12,13-DiHOME) and 12-hydroxyeicosatetraenoic acid (12-HETE). The expression of fatty acid-binding protein 3 (Fabp3) was dramatically up-regulated in the znt7-KO muscle cells accompanied by increased expression of Cd36, Slc27a1, and Slc27a4, the three major fatty acid transporters in the skeletal muscle. We also demonstrated that znt7-KO muscle cells had increased fatty acid oxidative capacity, indicated by enlarged mitochondria and increased mRNA or protein expression of key enzymes involved in the fatty acid mitochondrial shuttle and β-oxidation. We conclude that increased fatty acid uptake in the znt7-KO skeletal muscle is a key factor that contributes to the excessive intracellular lipid deposit and elevated production of bioactive lipid mediators. These mediators may play pivotal roles in oxidative stress and inflammation, leading to insulin resistance.

Kill two birds with one stone: making multi-transgenic pre-diabetes mouse models through insulin resistance and pancreatic apoptosis pathogenesis.

BackgroundType 2 diabetes is characterized by insulin resistance accompanied by defective insulin secretion. Transgenic mouse models play an important role in medical research. However, single transgenic mouse models may not mimic the complex phenotypes of most cases of type 2 diabetes.MethodsFocusing on genes related to pancreatic islet damage, peripheral insulin resistance and related environmental inducing factors, we generated single-transgenic (C/EBP homology protein, CHOP) mice (CHOP mice), dual-transgenic (human islet amyloid polypeptide, hIAPP; CHOP) mice (hIAPP-CHOP mice) and triple-transgenic (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1; hIAPP; CHOP) mice (11β-HSD1-hIAPP- CHOP mice). The latter two types of transgenic (Tg) animals were induced with high-fat high-sucrose diets (HFHSD). We analyzed the diabetes-related symptoms and histology features of the transgenic animals.ResultsComparing symptoms on the spot-checked points, we determined that the triple-transgene mice were more suitable for systematic study. The results of intraperitoneal glucose tolerance tests (IPGTT) of triple-transgene animals began to change 60 days after induction (p < 0.001). After 190 days of induction, the body weights (p < 0.01) and plasma glucose of the animals in Tg were higher than those of the animals in Negative Control (Nc). After sacrificed, large amounts of lipid were found deposited in adipose (p < 0.01) and ectopically deposited in the non-adipose tissues (p < 0.05 or 0.01) of the animals in the Tg HFHSD group. The weights of kidneys and hearts of Tg animals were significantly increased (p < 0.01). Serum C peptide (C-P) was decreased due to Tg effects, and insulin levels were increased due to the effects of the HFHSD in the Tg HFHSD group, indicating that damaged insulin secretion and insulin resistance hyperinsulinemia existed simultaneously in these animals. The serum corticosterone of Tg was slightly higher than those of Nc due to the effects of the 11βHSD-1 transgene and obesity. In Tg HFHSD, hepatic adipose deposition was more severe and the pancreatic islet area was enlarged under compensation, accompanying apoptosis. In the transgenic control diet (Tg ControlD) group, hepatic adipose deposition was also severe, pancreatic islets were damaged, and their areas were decreased (p < 0.05), and apoptosis of pancreatic cells occurred. Taken together, these data show the transgenes led to early-stage pathological changes characteristic of type 2 diabetes in the triple-transgene HFHSD group. The disease of triple-transgenic mice was more severe than that of dual or single-transgenic mice.ConclusionThe use of multi-transgenes involved in insulin resistance and pancreatic apoptosis is a better way to generate polygene-related early-stage diabetes models.

Characterization of Ageing- and Diet-Related Swine Models of Sarcopenia and Sarcopenic Obesity.

Sarcopenia and sarcopenic obesity are currently considered major global threats for health and well-being. However, there is a lack of adequate preclinical models for their study. The present trial evaluated the suitability of aged swine by determining changes in adiposity, fatty acids composition, antioxidant status and lipid peroxidation, development of metabolic disturbances and structural changes in tissues and organs. Iberian sows with clinical evidence of aging-related sarcopenia were fed a standard diet fulfilling their maintenance requirements or an obesogenic diet for 100 days. Aging and sarcopenia were related to increased lipid accumulation and cellular dysfunction at both adipose tissue and non-adipose ectopic tissues (liver and pancreas). Obesity concomitant to sarcopenia aggravates the condition by increasing visceral adiposity and causing dyslipidemia, insulin resistance and lipotoxicity in non-adipose tissues. These results support that the Iberian swine model represents certain features of sarcopenia and sarcopenic obesity in humans, paving the way for future research on physiopathology of these conditions and possible therapeutic targets.

The effect of diet and exercise on lipid droplet dynamics in human muscle tissue.

The majority of fat in the human body is stored as triacylglycerols in white adipose tissue. In the obese state, adipose tissue mass expands and excess lipids are stored in non-adipose tissues, such as skeletal muscle. Lipids are stored in skeletal muscle in the form of small lipid droplets. Although originally viewed as dull organelles that simply store lipids as a consequence of lipid overflow from adipose tissue, lipid droplets are now recognized as key components in the cell that exert a variety of relevant functions in multiple tissues (including muscle). Here, we review the effect of diet and exercise interventions on myocellular lipid droplets and their putative role in insulin sensitivity from a human perspective. We also provide an overview of lipid droplet biology and identify gaps for future research.

Plasma ceramide levels are altered in low and normal birth weight men in response to short-term high-fat overfeeding

Low birth weight (LBW) individuals have an increased risk of developing insulin resistance and type 2 diabetes compared with normal birth weight (NBW) individuals. We hypothesised that LBW individuals exhibit an increased fatty acid flux into lipogenesis in non-adipose tissue with a resulting accumulation of lipotoxic lipids, including ceramides, in the blood. Therefore, we measured fasting plasma levels of 27 ceramides in 18 young, healthy, LBW men and 25 NBW controls after an isocaloric control diet and a 5-day high-fat, high-calorie diet by HPLC-HRMS. LBW men did not show elevated plasma ceramide levels after the control or high-fat, high-calorie diet. An increased fatty acid oxidation rate in these individuals during both diets may limit ceramide synthesis and thereby compensate for a likely increased fatty acid load to non-adipose tissue. Interestingly, LBW and NBW men decreased d18:0–18:1/d18:1–18:0 and d18:1–24:2/d18:2–24:1 levels and increased the d18:0–24:1a level in response to overfeeding. Plasma d18:0–24:1a and total ceramide levels were positively associated with the fasting blood glucose level and endogenous glucose production after the control diet, and the total ceramide level was in addition positively associated with hepatic insulin resistance. Further studies are needed to determine if lipotoxicity contributes to insulin resistance in LBW individuals.

Comparison of Fatty Acid and Gene Profiles in Skeletal Muscle in Normal and Obese C57BL/6J Mice before and after Blunt Muscle Injury.

Injury and obesity are two major health burdens affecting millions of people worldwide. Obesity is recognized as a state of chronic inflammation accompanied by various co-morbidities like T2D or cardiovascular diseases. There is increasing evidence that obesity impairs muscle regeneration, which is mainly due to chronic inflammation and to excessive accumulation of lipids in adipose and non-adipose tissue. To compare fatty acid profiles and changes in gene expression at different time points after muscle injury, we used an established drop tower-based model with a defined force input to damage the extensor iliotibialis anticus on the left hind limb of female C57BL/6J mice of normal weight and obese mice. Although most changes in fatty acid content in muscle tissue are diet related, levels of eicosaenoic (normal weight) and DHG-linolenic acid (obese) in the phospholipid and docosahexaenoic acid (normal weight) in the triglyceride fraction are altered after injury. Furthermore, changes in gene transcription were detected in 3829 genes in muscles of normal weight mice, whereas only 287 genes were altered in muscles of obese mice after trauma. Alterations were found within several pathways, among them notch-signaling, insulin-signaling, sonic hedgehog-signaling, apoptosis related pathways, fat metabolism related cholesterol homeostasis, fatty acid biosynthetic process, fatty acid elongation, and acyl-CoA metabolic process. We could show that genes involved in fat metabolism are affected 3 days after trauma induction mostly in normal weight but not in obese mice. The strongest effects were observed in normal weight mice for Alox5ap, the activating protein for leukotriene synthesis, and Apobec1, an enzyme substantial for LDL synthesis. In summary, we show that obesity changes the fat content of skeletal muscle and generally shows a negative impact upon blunt muscle injury on various cellular processes, among them fatty acid related metabolism, notch-, insulin-, sonic hedgehog-signaling, and apoptosis.

Body Composition following Necrotising Enterocolitis in Preterm Infants

Background: The optimal nutritional regimen for preterm infants, including those that develop necrotising enterocolitis (NEC), is unknown. Objective: The objective here was to evaluate body composition at term in infants following NEC, in comparison with healthy infants. The primary outcome measure was non-adipose tissue mass (non-ATM). Methods: We compared body composition assessed by magnetic resonance imaging at term in infants born <31 weeks of gestational age that participated in NEON, a trial comparing incremental versus immediate delivery of parenteral amino acids on non-ATM, and SMOF versus intralipid on intrahepatocellular lipid content. There were no differences in the primary outcomes. We compared infants that received surgery for NEC (NEC-surgical), infants with medically managed NEC (NEC-medical), and infants without NEC (reference). Results: A total of 133 infants were included (8 NEC-surgical; 15 NEC-medical; 110 reference). In comparison with the reference group, infants in the NEC-surgical and NEC-medical groups were significantly lighter [adjusted mean difference (95% CI) NEC-surgical: –630 g (–1,010, –210), p = 0.003; NEC-medical: –440 g (–760, –110), p = 0.009] and the total adipose tissue volume (ATV) was significantly lower [NEC-surgical: –360 cm³ (–516, –204), p < 0.001; NEC-medical: –127 cm³ (–251, –4); p = 0.043]. There were no significant differences in non-ATM [adjusted mean difference (95% CI) NEC-surgical: –46 g (–281, 189), p = 0.70; NEC-medical: –122 g (–308, 63), p = 0.20]. Conclusion: The lower weight at term in preterm infants following surgically and medically managed NEC, in comparison to preterm infants that did not develop the disease, was secondary to a reduction in ATV. This suggests that the nutritional regimen received was adequate to preserve non-ATM but not to support the normal third-trimester deposition of adipose tissue in preterm infants.

Effect of sex and age on fatty acid composition of Iberian swine foetuses exposed to maternal malnutrition

Intrauterine growth restriction (IUGR) is the consequence of inadequate placental supply of oxygen and/or nutrients during prenatal development. The adaptive response of the offspring is time-dependent, but there is also increasing evidence of a strong modulation by sex. The present study aimed to determine time-related changes and sex-related differences in fatty acid composition at non-adipose tissues involved in metabolism regulation during the development of IUGR fetuses. For that, we analyzed the liver and muscle (longissimus dorsi) fatty acids composition of IUGRs foetuses (obtained as consequence of maternal malnutrition) throughout pregnancy (Day 70 vs. 90) and sex-related effects (male vs. female). The final distribution of sampled foetuses was: 33 foetuses at Day 70 of pregnancy (13 females and 20 males), and 23 foetuses at Day 90, (10 females and 13 males). Both in liver and muscle a higher concentration of saturated fatty acids (SFA; P

Side‐effects related to adjuvant CAPOX treatment for colorectal cancer are associated with intermuscular fat area, not with total skeletal muscle or fat, a retrospective observational study

AbstractAimsChemotherapeutic treatment is regularly accompanied by side‐effects. Hydrophilic chemotherapeutics such as capecitabine and oxaliplatin (CAPOX), often used in colorectal cancer treatment, predominantly accumulate in non‐adipose tissues. Therefore the aim of this paper was to investigate whether body composition and fat infiltration in the muscle (muscle attenuation and intermuscular‐adipose‐tissue [IMAT] content) are associated with chemotherapy‐induced toxicities.MethodsIn this retrospective observational study, we collected data from 115 colorectal cancer patients receiving adjuvant CAPOX chemotherapy between 2006 and 2015. Information on cancer characteristics were obtained from the Netherlands Cancer Registry. Diagnostic CT scans were retrieved to assess cross‐sectional areas of skeletal muscle and adipose tissue at the third lumbar vertebrae. Information on dose‐limiting toxicity [DLT] and relative administered dose (as % of BSA‐based‐planned‐dose) were retrieved from medical charts. Associations between body composition, muscle quality and chemotherapy‐induced toxicities were determined using Cox‐regression and linear‐regression analyses.ResultsWe found that DLT incidence was 90% in our cohort: 50% had their dose reduced, 30% their next cycle postponed, 4% a full treatment stop and 6% was hospitalized at their first DLT. Most common were reductions in oxaliplatin dose whilst keeping the capecitabine dose constant. Cox regression analysis indicated no association between body composition or muscle quality and DLT during the first treatment cycle or time to the first DLT. Multiple linear regression showed that higher IMAT‐index and IMAT muscle percentage were associated with a lower relative administered dose of oxaliplatin.ConclusionsIn conclusion; only IMAT, not skeletal or fat area was associated with dose‐limiting toxicities among these CRC patients who received CAPOX treatment.

Cumulus cells protect the oocyte against saturated free fatty acids.

In the cow a major characteristic of metabolic stress is an elevated level of plasma free fatty acid, due to increased lipid mobilization from adipose tissue. Elevated levels of free fatty acids in blood (complexed to albumin) are associated with increased lipotoxicity in non-adipose tissue. An overview is provided on the negative impact of free fatty acids and the metabolic stress imposed on the oocyte and early embryo and thus on bovine fertility. There is increasing evidence that in vitro as well as in vivo the elevated levels of free fatty acids in blood during metabolic stress can severely hamper oocyte and embryo development. However, fatty acids do also form an essential nutrient source for the oocyte and embryo, which indicates that these good and bad effects of fatty acids should be in subtle balance to optimize the developmental competence of the oocyte and embryo.

Caveolin-1 regulates lipid droplet metabolism in endothelial cells via autocrine prostacyclin–stimulated, cAMP-mediated lipolysis

Lipid droplets (LD) are dynamic organelles involved in intracellular lipid metabolism in almost all eukaryotic cells, and LD-associated proteins tightly regulate their dynamics. One LD coat protein is caveolin-1 (Cav-1), an essential component for caveola assembly in highly differentiated cells, including adipocytes, smooth muscle cells, and endothelial cells (EC). However, the role of Cav-1 in LD dynamics is unclear. Here we report that EC lacking Cav-1 exhibit impaired LD formation. The decreased LD formation is due to enhanced lipolysis and not caused by reduced triglyceride synthesis or fatty acid uptake. Mechanistically, the absence of Cav-1 increased cAMP/PKA signaling in EC, as indicated by elevated phosphorylation of hormone-sensitive lipase and increased lipolysis. Unexpectedly, we also observed enhanced autocrine production of prostaglandin I2 (PGI2, also called prostacyclin) in Cav-1 KO EC, and this PGI2 increase appeared to stimulate cAMP/PKA pathways, contributing to the enhanced lipolysis in Cav-1 KO cells. Our results reveal an unanticipated role of Cav-1 in regulating lipolysis in non-adipose tissue, indicating that Cav-1 is required for LD metabolism in EC and that it regulates cAMP-dependent lipolysis in part via the autocrine production of PGI2.