Triglyceride Storage Research Articles

Identification of lipid synthesis genes in Schizochytrium sp. and their application in improving eicosapentaenoic acid synthesis in Yarrowia lipolytica

BackgroundEicosapentaenoic acid (EPA) is widely used in the functional food and nutraceutical industries due to its important benefits to human health. Oleaginous microorganisms are considered a promising alternative resource for the production of EPA lipids. However, the storage of EPA in triglyceride (TG) becomes a key factor limiting its level.ResultsThis study aimed to incorporate more EPA into TG storage through metabolic engineering. Firstly, key enzymes for TG synthesis, the diacylglycerol acyltransferase (DGAT) and glycerol-3-phosphate acyltransferase (GPAT) genes from Schizochytrium sp. HX-308 were expressed in Yarrowia lipolytica to enhance lipid and EPA accumulation. In addition, engineering the enzyme activity of DGATs through protein engineering was found to be effective in enhancing lipid synthesis by replacing the conserved motifs “HFS” in ScDGAT2A and “FFG” in ScDGAT2B with the motif “YFP”. Notably, combined with lipidomic analysis, the expression of ScDGAT2C and GPAT2 enhanced the storage of EPA in TG. Finally, the accumulation of lipid and EPA was further promoted by identifying and continuing to introduce the ScACC, ScACS, ScPDC, and ScG6PD genes from Schizochytrium sp., and the lipid and EPA titer of the final engineered strain reached 2.25 ± 0.03 g/L and 266.44 ± 5.74 mg/L, respectively, which increased by 174.39% (0.82 ± 0.02 g/L) and 282.27% (69.70 ± 0.80 mg/L) compared to the initial strain, respectively.ConclusionThis study shows that the expression of lipid synthesis genes from Schizochytrium sp. in Y. lipolytica effectively improves the synthesis of lipids and EPA, which provided a promising target for EPA-enriched microbial oil production.

Changes in Cells Associated with Insulin Resistance.

Insulin is a polypeptide hormone synthesized and secreted by pancreatic β-cells. It plays an important role as a metabolic hormone. Insulin influences the metabolism of glucose, regulating plasma glucose levels and stimulating glucose storage in organs such as the liver, muscles and adipose tissue. It is involved in fat metabolism, increasing the storage of triglycerides and decreasing lipolysis. Ketone body metabolism also depends on insulin action, as insulin reduces ketone body concentrations and influences protein metabolism. It increases nitrogen retention, facilitates the transport of amino acids into cells and increases the synthesis of proteins. Insulin also inhibits protein breakdown and is involved in cellular growth and proliferation. On the other hand, defects in the intracellular signaling pathways of insulin may cause several disturbances in human metabolism, resulting in several chronic diseases. Insulin resistance, also known as impaired insulin sensitivity, is due to the decreased reaction of insulin signaling for glucose levels, seen when glucose use in response to an adequate concentration of insulin is impaired. Insulin resistance may cause, for example, increased plasma insulin levels. That state, called hyperinsulinemia, impairs metabolic processes and is observed in patients with type 2 diabetes mellitus and obesity. Hyperinsulinemia may increase the risk of initiation, progression and metastasis of several cancers and may cause poor cancer outcomes. Insulin resistance is a health problem worldwide; therefore, mechanisms of insulin resistance, causes and types of insulin resistance and strategies against insulin resistance are described in this review. Attention is also paid to factors that are associated with the development of insulin resistance, the main and characteristic symptoms of particular syndromes, plus other aspects of severe insulin resistance. This review mainly focuses on the description and analysis of changes in cells due to insulin resistance.

Mechanisms of lipotoxicity-induced dysfunction and death of human pancreatic beta cells under obesity and type 2 diabetes conditions.

The term "pancreatic beta-cell lipotoxicity" refers to the detrimental effects of free fatty acids (FFAs) on a wide variety of cellular functions. Basic research in the field has primarily analyzed the effects of palmitic acid and oleic acid. The focus on these two physiological FFAs, however, ignores differences in chain length and degree of saturation. In order to gain a comprehensive understanding of the lipotoxic mechanisms, a wide range of structurally related FFAs should be investigated. Structure-activity relationship analyses of FFAs in the human EndoC-βH1 beta-cell line have provided a deep insight into the mechanisms of beta-cell lipotoxicity. This review focuses on the effects of a wide range of FFAs with crucial structural determinants for the development of lipotoxicity in human beta cells and documents an association between increased triglyceride stores in obesity and in type 2 diabetes.

The regulation of triglyceride and glycogen storage by Glucose transporter 1 ( Glut1 ) in Drosophila fat tissue.

Obesity reflects an imbalance in nutrient storage resulting in excess fat accumulation. The molecules that tissues use to regulate nutrient storage are not well understood. A previously published genetic screen using Drosophila melanogaster larvae identified Glut1 , a transmembrane glucose transporter, as a potential obesity gene. To identify the adipose-specific functions of this gene, Glut1 levels were decreased using RNAi targeted to fly fat tissue. Adult Glut1 RNAi flies have lower glycogen and triglyceride levels, as well as decreased FASN1 RNA expression. This suggests that Glut1 functions to promote glycogen and triglyceride storage and fatty acid synthesis in Drosophila adipose tissue.

The Unrestrained Overeating Behavior and Clinical Perspective.

Obesity-related co-morbidities decrease life quality, reduce working ability, and lead to early death. In the adult population, eating addiction manifests with excessive food consumption and the unrestrained overeating behavior, which is associated with increased risk of morbidity and mortality and defined as the binge eating disorder (BED). This hedonic intake is correlated with fat preference and the total amount of dietary fat consumption is the most potent risk factor for weight gain. Long-term BED leads to greater sensitivity to the rewarding effects of palatable foods and results in obesity fatefully. Increased plasma concentrations of non-esterified free fatty acids and lipid-overloaded hypertrophic adipocytes may cause insulin resistance. In addition to dietary intake of high-fat diet, sedentary lifestyle leads to increased storage of triglycerides not only in adipose tissue but also ectopically in other tissues. Lipid-induced apoptosis, ceramide accumulation, reactive oxygen species overproduction, endoplasmic reticulum stress, and mitochondrial dysfunction play role in the pathogenesis of lipotoxicity. Food addiction and BED originate from complex action of dopaminergic, opioid, and cannabinoid systems. BED may also be associated with both obesity and major depressive disorder. For preventing morbidity and mortality, as well as decreasing the impact of obesity-related comorbidities in appropriately selected patients, opiate receptor antagonists and antidepressant combination are recommended. Pharmacotherapy alongside behavioral management improves quality of life and reduces the obesity risk; however, the number of licensed drugs is very few. Thus, stereotactic treatment is recommended to break down the refractory obesity and binge eating in obese patient. As recent applications in the field of non-invasive neuromodulation, transcranial magnetic stimulation and transcranial direct current stimulation are thought to be important in image-guided deep brain stimulation in humans. Chronic overnutrition most likely provides repetitive and persistent signals that up-regulate inhibitor of nuclear factor kappa B (NF-κB) kinase beta subunit/NF-κB (IKKβ/NF-κB) in the hypothalamus before the onset of obesity. However, how the mechanisms of high-fat diet-induced peripheral signals affect the hypothalamic arcuate nucleus remain largely unknown.

Lipolysis products from triglyceride-rich lipoproteins induce stress protein ATF3 in osteoblasts.

High fat diets overwhelm the physiological mechanisms for absorption, storage, and utilization of triglycerides (TG); consequently TG, TG-rich lipoproteins (TGRL), and TGRL remnants accumulate, circulate systemically, producing dyslipidemia. This associates with, or is causative for increased atherosclerotic cardiovascular risk, ischemic stroke, fatty liver disease, and pancreatitis. TGRL hydrolysis by endothelial surface-bound lipoprotein lipase (LPL) generates metabolites like free fatty acids which have proinflammatory properties. While osteoblasts utilize fatty acids as an energy source, dyslipidemia is associated with negative effects on the skeleton. In this study we investigated the effects of TGRL lipolysis products (TGRL-LP) on expression of a stress responsive transcription factor, termed activating transcription factor 3 (ATF3), reactive oxygen species (ROS), ATF3 target genes, and angiopoietin-like 4 (Angptl4) in osteoblasts. As ATF3 negatively associates with osteoblast differentiation, we also investigated the skeletal effects of global ATF3 deletion in mice. TGRL-LPincreased expression of Atf3, proinflammatory proteins Ptgs2 and IL-6, and induced ROS in MC3T3-E1 osteoblastic cells. Angptl4 is an endogenous inhibitor of LPL which was transcriptionally induced by TGRL-LP, while recombinant Angptl4 prevented TG-driven Atf3 induction. Atf3 global knockout male mice demonstrated increased trabecular and cortical microarchitectural parameters. In summary, we find that TGRL-LP induce osteoblastic cell stress as evidenced by expression of ATF3, which may contribute to the negative impact of dyslipidemia in the skeleton. Further, concomitant induction of Angptl4 in osteoblasts might play a protective role by reducing local lipolysis.

Leptin-dependent differential remodeling of visceral and pericardial adipose tissue following chronic exercise and psychosocial stress.

Obesity is driven by an imbalance between caloric intake and energy expenditure, causing excessive storage of triglycerides in adipose tissue at different sites around the body. Increased visceral adipose tissue (VAT) is associated with diabetes, while pericardial adipose tissue (PAT) is associated with cardiac pathology. Adipose tissue can expand either through cellular hypertrophy or hyperplasia, with the former correlating with decreased metabolic health in obesity. The aim of this study was to determine how VAT and PAT remodel in response to obesity, stress, and exercise. Here we have used the male obese Zucker rats, which carries two recessive fa alleles that result in the development of hyperphagia with reduced energy expenditure, resulting in morbid obesity and leptin resistance. At 9 weeks of age, a group of lean (Fa/Fa or Fa/fa) Zucker rats (LZR) and obese (fa/fa) Zucker rats (OZR) were treated with unpredictable chronic mild stress or exercise for 8 weeks. To determine the phenotype for PAT and VAT, tissue cellularity and gene expression were analyzed. Finally, leptin signaling was investigated further using cultured 3T3-derived adipocytes. Tissue cellularity was determined following hematoxylin and eosin (H&E) staining, while qPCR was used to examine gene expression. PAT adipocytes were significantly smaller than those from VAT and had a more beige-like appearance in both LZR and OZR. In the OZR group, VAT adipocyte cell size increased significantly compared with LZR, while PAT showed no difference. Exercise and stress resulted in a significant reduction in VAT cellularity in OZR, while PAT showed no change. This suggests that PAT cellularity does not remodel significantly compared with VAT. These data indicate that the extracellular matrix of PAT is able to remodel more readily than in VAT. In the LZR group, exercise increased insulin receptor substrate 1 (IRS1) in PAT but was decreased in the OZR group. In VAT, exercise decreased IRS1 in LZR, while increasing it in OZR. This suggests that in obesity, VAT is more responsive to exercise and subsequently becomes less insulin resistant compared with PAT. Stress increased PPAR-γ expression in the VAT but decreased it in the PAT in the OZR group. This suggests that in obesity, stress increases adipogenesis more significantly in the VAT compared with PAT. To understand the role of leptin signaling in adipose tissue remodeling mechanistically, JAK2 autophosphorylation was inhibited using 5 μM 1,2,3,4,5,6-hexabromocyclohexane (Hex) in cultured 3T3-derived adipocytes. Palmitate treatment was used to induce cellular hypertrophy. Hex blocked adipocyte hypertrophy in response to palmitate treatment but not the increase in lipid droplet size. These data suggest that leptin signaling is necessary for adipocyte cell remodeling, and its absence induces whitening. Taken together, our data suggest that leptin signaling is necessary for adipocyte remodeling in response to obesity, exercise, and psychosocial stress.

Multi‐omic profiling of isogenic ApoE3/3 and ApoE4/4 iPSC‐derived astrocytes uncovers altered lipid metabolism and mitochondrial function of ApoE4 astrocytes

AbstractBackgroundAs the main genetic risk factor for AD, glial ApoE4 has been implicated in a number of early disease relevant processes, such as lipid dyshomeostasis, mitochondrial dysfunction and altered immune function. This ApoE4 glial phenotype is not yet well characterized and this hampers the rationale design of ApoE4‐targeting interventions.MethodWe characterize the phenotypes of ApoE3/3 and ApoE4/4 iPSC‐derived astrocytes by multi‐omic profiling. In addition, we use lipidomic and metabolic profiling of interventions in ApoE4 astrocytes to define compounds that normalize lipid counts and metabolic function.ResultIn the ApoE4 astrocytes we observe strong accumulation of cholesterol esters (storage product of cholesterol) and triglycerides (storage products of fatty acids), in comparison to the ApoE3 astrocytes. Interestingly, our proteomic and transcriptomic profiling of these cells reveal an increase in cholesterol synthesis, despite the already high levels of cholesterol esters in the cell. Moreover, our proteomic and transcriptomic results display an increase in mitochondrial pathways, such as beta‐oxidation, TCA cycle and oxidative phosphorylation and a decrease in glycolysis. Not only mitochondrial function is altered but also mitochondrial organization, as we see an upregulation of the most relevant proteins for mitochondrial fusion, MFN1, MFN2 and OPA1. Our lipidomic and metabolic profiling of ApoE4 astrocytes after treatment with a number of different interventions reveals new insights into these altered lipid metabolic pathways.ConclusionOur multi‐omic profiling of iPSC‐derived ApoE3/3 and ApoE4/4 astrocytes uncovers that ApoE4 astrocytes have altered lipid metabolism, mitochondrial function and mitochondrial organization. Treatment with interventions reveals new insights into these altered pathways.

Characterization of Biodiesel and Diesel Combustion Particles: Chemical Composition, Lipid Metabolism, and Implications for Health and Environment.

Biodiesel, derived from alkyl esters of vegetable oils or animal fats, has gained prominence as a greener alternative to diesel due to its reduced particle mass. However, it remains debatable whether biodiesel exposure has more severe health issues than diesel. This study performed high-resolution mass spectrometry to examine the detailed particle chemical compositions and lipidomics analysis of human lung epithelial cells treated with emissions from biodiesel and diesel fuels. Results show the presence of the peak substances of CHO compounds in biodiesel combustion that contain a phthalate ester (PAEs) structure (e.g., n-amyl isoamyl phthalate and diisobutyl phthalate). PAEs have emerged as persistent organic pollutants across various environmental media and are known to possess endocrine-disrupting properties in the environment. We further observed that biodiesel prevents triglyceride storage compared to diesel and inhibits triglycerides from becoming phospholipids, particularly with increased phosphatidylglycerols (PGs) and phosphatidylethanolamines (PEs), which potentially could lead to a higher probability of cancer metastasis.

Irisin and Energy Metabolism and the Role of Irisin on Metabolic Syndrome.

Irisin is a thermogenic hormone that leads to causes energy expenditure by increasing brown adipose tissue (BAT). This protein hormone that enables the conversion of white adipose tissue (WAT) to BAT is the irisin protein. This causes energy expenditure during conversion. WAT stores triglycerides and fatty acids and contains very few mitochondria. They also involve in the development of insulin resistance (IR). WAT, which contains a very small amount of mitochondria, contributes to the formation of IR by storing triglycerides and fatty acids. WAT functions as endocrine tissue in the body, synthesizing various molecules such as leptin, ghrelin, NUCB2/nesfatin-1, and irisin along with fat storage. BAT is quite effective in energy expenditure, unlike WAT. The number of mitochondria and lipid droplets composed of multicellular cells in BAT is much higher when compared to WAT. BAT contains a protein called uncoupling protein-1 (UCP1) in the mitochondrial membranes. This protein pumps protons from the intermembrane space toward the mitochondrial matrix. When UCP1 is activated, heat dissipation occurs while ATP synthesis does not occur, because UCP1 is a division protein. At the same time, BAT regulates body temperature in infants. Its effectiveness in adults became clear after the discovery of irisin. The molecular mechanism of exercise, which increases calorie expenditure, became clear with the discovery of irisin. Thus, the isolation of irisin led to the clarification of metabolic events and fat metabolism. In this review, literature information will be given on the effect of irisin hormone on energy metabolism and metabolic syndrome (MetS).

The pseudokinase TRIB3 controls adipocyte lipid homeostasis and proliferation in vitro and in vivo

ObjectiveIn vivo studies in humans and mice have implicated the pseudokinase Tribbles 3 (TRIB3) in various aspects of energy metabolism. Whilst cell-based studies indicate a role for TRIB3 in adipocyte differentiation and function, it is unclear if and how these cellular functions may contribute to overall metabolic health. MethodsWe investigated the metabolic phenotype of whole-body Trib3 knockout (Trib3KO) mice, focusing on adipocyte and adipose tissue functions. In addition, we combined lipidomics, transcriptomics, interactomics and phosphoproteomics analyses to elucidate cell-intrinsic functions of TRIB3 in pre- and mature adipocytes. ResultsTrib3KO mice display increased adiposity, but their insulin sensitivity remains unaltered. Trib3KO adipocytes are smaller and display higher Proliferating Cell Nuclear Antigen (PCNA) levels, indicating potential alterations in either i) proliferation-differentiation balance, ii) impaired expansion after cell division, or iii) an altered balance between lipid storage and release, or a combination thereof. Lipidome analyses suggest TRIB3 involvement in the latter two processes, as triglyceride storage is reduced and membrane composition, which can restrain cellular expansion, is altered. Integrated interactome, phosphoproteome and transcriptome analyses support a role for TRIB3 in all three cellular processes through multiple cellular pathways, including Mitogen Activated Protein Kinase- (MAPK/ERK), Protein Kinase A (PKA)-mediated signaling and Transcription Factor 7 like 2 (TCF7L2) and Beta Catenin-mediated gene expression. ConclusionsOur findings support TRIB3 playing multiple distinct regulatory roles in the cytoplasm, nucleus and mitochondria, ultimately controlling adipose tissue homeostasis, rather than affecting a single cellular pathway.

Comparative and Predictive Analysis of Clinical and Metabolic Features of Anorexia Nervosa and Bulimia Nervosa.

Eating disorders have become increasingly prevalent over the years; the age at which they appear has decreased, and they can lead to serious illness or death. Therefore, the number of studies on the matter has increased. Eating disorders like anorexia nervosa (AN) and bulimia nervosa (BN) are affected by many factors including mental illnesses that can have serious physical and psychological consequences. Accordingly, the present study aimed to compare the clinical and metabolic features of patients with AN and BN and identify potential biomarkers for distinguishing between the two disorders. Clinical data of 41 participants who sought treatment for eating disorders between 2012 and 2022, including 29 AN patients and 12 BN patients, were obtained from NPIstanbul Brain Hospital in Istanbul, Turkey. The study included the clinical variables of both outpatient and inpatient treatments. Principal component analysis (PCA) was utilized to gain insights into differentiating AN and BN patients based on clinical characteristics, while machine learning techniques were applied to identify eating disorders. The study found that thyroid hormone levels in patients with AN and BN were influenced by non-thyroidal illness syndrome (NTIS), which could be attributed to various factors, including psychiatric disorders, substance abuse, and medication use. Lipid profile comparisons revealed higher triglyceride levels in the BN group (P<0.05), indicating increased triglyceride synthesis and storage as an energy source. Liver function tests showed lower levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in BN patients (P<0.05), while higher prolactin levels (P<0.05) suggested an altered hypothalamic-pituitary-gonadal axis. Imbalances in minerals such as calcium and magnesium (P<0.05) were observed in individuals with eating disorders. PCA effectively differentiated AN and BN patients based on clinical features, and the Naïve Bayes (NB) model showed promising results in identifying eating disorders. The findings of the study provide important insights into AN and BN patients' clinical features and may help guide future research and treatment strategies for these conditions.

Mice lacking triglyceride synthesis enzymes in adipose tissue are resistant to diet-induced obesity.

Triglycerides (TGs) in adipocytes provide the major stores of metabolic energy in the body. Optimal amounts of TG stores are desirable as insufficient capacity to store TG, as in lipodystrophy, or exceeding the capacity for storage, as in obesity, results in metabolic disease. We hypothesized that mice lacking TG storage in adipocytes would result in excess TG storage in cell types other than adipocytes and severe lipotoxicity accompanied by metabolic disease. To test this hypothesis, we selectively deleted both TG synthesis enzymes, DGAT1 and DGAT2, in adipocytes (ADGAT DKO mice). As expected with depleted energy stores, ADGAT DKO mice did not tolerate fasting well and, with prolonged fasting, entered torpor. However, ADGAT DKO mice were unexpectedly otherwise metabolically healthy and did not accumulate TGs ectopically or develop associated metabolic perturbations, even when fed a high-fat diet. The favorable metabolic phenotype resulted from activation of energy expenditure, in part via BAT (brown adipose tissue) activation and beiging of white adipose tissue. Thus, the ADGAT DKO mice provide a fascinating new model to study the coupling of metabolic energy storage to energy expenditure.

Mice lacking triglyceride synthesis enzymes in adipose tissue are resistant to diet-induced obesity

Triglycerides (TGs) in adipocytes provide the major stores of metabolic energy in the body. Optimal amounts of TG stores are desirable as insufficient capacity to store TG, as in lipodystrophy, or exceeding the capacity for storage, as in obesity, results in metabolic disease. We hypothesized that mice lacking TG storage in adipocytes would result in excess TG storage in cell types other than adipocytes and severe lipotoxicity accompanied by metabolic disease. To test this hypothesis, we selectively deleted both TG synthesis enzymes, DGAT1 and DGAT2, in adipocytes (ADGAT DKO mice). As expected with depleted energy stores, ADGAT DKO mice did not tolerate fasting well and, with prolonged fasting, entered torpor. However, ADGAT DKO mice were unexpectedly otherwise metabolically healthy and did not accumulate TGs ectopically or develop associated metabolic perturbations, even when fed a high-fat diet. The favorable metabolic phenotype resulted from activation of energy expenditure, in part via BAT (brown adipose tissue) activation and beiging of white adipose tissue. Thus, the ADGAT DKO mice provide a fascinating new model to study the coupling of metabolic energy storage to energy expenditure.

Salacia reticulata Extract Suppresses Fat Accumulation by Regulating Lipid Metabolism.

The excessive storage of triglycerides in adipose tissue is a characteristic feature of obesity, which arises from an imbalance between energy intake and expenditure. In this study, we aimed to explore the potential anti-obesity effects of Salacia reticulata extracts (SC) in a high-fat diet (HFD)-induced in obese mice and 3T3-L1 adipocytes, with a specific focus on understanding the underlying lipid mechanisms. Mice were fed with a normal diet (NC; normal control), HFD (60% high-fat diet), Met (HFD containing metformin 250 mg/kg b.w.), SC25 (HFD containing SC 25 mg/kg b.w.), SC50 (HFD containing SC 50 mg/kg b.w.), or SC 100 (HFD containing SC 100 mg/kg b.w.) for 12 weeks. Notably, SC supplementation led to significant reductions in body weight gain, adipose tissue weight, adipose tissue mass, and adipocyte size in HFD-fed mice. Furthermore, SC supplementation exerted inhibitory effects on the adipogenesis and lipogenesis pathways while promoting lipolysis and thermogenesis pathways in the adipose tissues of HFD-fed mice. In vitro experiments using 3T3-L1 cells demonstrated that SC treatment during the differentiation phase suppressed adipogenesis and lipogenesis, whereas SC treatment after differentiation, activated lipolysis and thermogenesis. Collectively, these findings indicate that SC exhibits a direct influence on the lipid metabolism of adipocytes, making it an effective candidate for weight loss interventions.

Differential digestive and metabolic profile of juveniles and adults of the estuarine-dependent marine fish Mugil liza (Mugilidae) cohabiting inside a southwestern Atlantic coastal lagoon

Integrative studies on intraspecific differences of digestive enzymes, energy reserves, and morphological/somatic traits in juveniles and adults of estuarine-dependent marine fish while inhabiting inside a coastal lagoon are lacking. This study was carried on juveniles and adults of Mugil liza Valenciennes, 1836 inhabiting inside Mar Chiquita Coastal Lagoon (Argentina). Both stages exhibited amylase, maltase, sucrase, lipase, trypsin, and aminopeptidase-N activities in the intestine, which were active over a wide range of pH and temperatures and exhibited Michaelis–Menten kinetics. Adults exhibited higher intestinal coefficient (31%), higher amylase (32%), and lower maltase (82%) and lipase activities (38%). Glycogen concentration in liver and muscle was similar, while free glucose concentration was higher in adults (772% and 400%, respectively). In adults, retroperitoneal fat (absent in juveniles) constituted the main triglycerides (TAG) storage site, while TAG concentration in liver and muscle was lower (86% and 80%, respectively) than that in juveniles. No differences were found in protein concentration in any storage organ. The results show that juveniles and adults exhibit a digestive and metabolic profile at the biochemical level and intraspecific differences in key components of carbohydrate and lipid metabolism that could support preparation for reproductive migration of adults outside the coastal lagoon.

HILPDA is a lipotoxic marker in adipocytes that mediates the autocrine negative feedback regulation of triglyceride hydrolysis by fatty acids and alleviates cellular lipotoxic stress

BackgroundLipolysis is a key metabolic pathway in adipocytes that renders stored triglycerides available for use by other cells and tissues. Non-esterified fatty acids (NEFAs) are known to exert feedback inhibition on adipocyte lipolysis, but the underlying mechanisms have only partly been elucidated. An essential enzyme in adipocyte lipolysis is ATGL. Here, we examined the role of the ATGL inhibitor HILPDA in the negative feedback regulation of adipocyte lipolysis by fatty acids. MethodsWe exposed wild-type, HILPDA-deficient and HILPDA-overexpressing adipocytes and mice to various treatments. HILPDA and ATGL protein levels were determined by Western blot. ER stress was assessed by measuring the expression of marker genes and proteins. Lipolysis was studied in vitro and in vivo by measuring NEFA and glycerol levels. ResultsWe show that HILPDA mediates a fatty acid-induced autocrine feedback loop in which elevated intra- or extracellular fatty acids levels upregulate HILPDA by activation of the ER stress response and the fatty acid receptor 4 (FFAR4). The increased HILPDA levels in turn downregulate ATGL protein levels to suppress intracellular lipolysis, thereby maintaining lipid homeostasis. The deficiency of HILPDA under conditions of excessive fatty acid load disrupts this chain of events, leading to elevated lipotoxic stress in adipocytes. ConclusionOur data indicate that HILPDA is a lipotoxic marker in adipocytes that mediates a negative feedback regulation of lipolysis by fatty acids via ATGL and alleviates cellular lipotoxic stress.

Antiobesity effect of Kaempferia parviflora accompanied by inhibition of lipogenesis and stimulation of lipolysis.

Obesity occurs when energy intake is excessive compared to energy expenditure, resulting in the excessive storage of triglyceride in adipose tissue. The present study aimed to investigate the antiobesity effects of Kaempferia parviflora extracts (PF) in high-fat diet (HFD)-induced obese mice and 3T3-L1 adipocytes to demonstrate the lipid mechanisms underlying these effects. Mice were fed with a normal diet (AIN93G normal diet), HFD (60% HFD), Met (HFD containing metformin 250 mg/kg b.w.), PF50 (HFD containing PF 50 mg/kg b.w.), and PF100 (HFD containing PF 100 mg/kg b.w.) for 12 weeks. Body weight gain, adipose tissue weight, adipose tissue mass, and size of adipocytes were significantly decreased by PF supplementation in HFD-fed mice. Moreover, PF supplementation suppressed the adipogenesis and lipogenesis pathways and activated the lipolysis and thermogenesis pathways in the adipose tissues of HFD-fed mice. PF treatment during the differentiation of 3T3-L1 cells suppressed adipogenesis and lipogenesis and PF treatment after differentiation activated lipolysis and thermogenesis. Thus, we suggest that PF is effective for weight loss by directly affecting the lipid metabolism of adipocytes.

Aptamer-modified atomically precise gold nanoclusters as targeted nanozymes to scavenge reactive oxygen species in white adipocytes

Oxidative stress caused by excessive reactive oxygen species (ROS) leads to the dysfunction of white adipocytes and white fat, and also promotes triglyceride storage by inhibiting the respiration of adipocytes directly. Nanozymes, as a new generation of artificial enzymes, have exhibited attractive potential in scavenging ROS and treatment of ROS-related diseases. Herein, aptamer-modified atomically precise gold Au25 nanoclusters (Apt-Au25 NCs), are employed as targeted nanozymes to scavenge ROS in white adipocytes. Our results show that Apt-Au25 NCs have high targeting capability toward white adipocytes with low cytotoxicity. Furthermore, Apt-Au25 NCs show high superoxide dismutase (SOD)-like and catalase (CAT)-like activity in a concentration-dependent manner, and also good thermal and pH stability compared with natural SOD and CAT. Finally, the efficiency of ROS scavenging by Apt-Au25 NCs in white adipocytes is evaluated. This work demonstrates that Apt-Au25 NCs, as targeted nanozymes, are efficient in scavenging ROS in white adipocytes, exhibiting promising potential for the treatment of obesity and related diseases.

Maternal hypothyroidism in rats impairs placental nutrient transporter expression, increases labyrinth zone size, and impairs fetal growth

IntroductionHypothyroidism during pregnancy is associated with fetal growth restriction (FGR). FGR is commonly caused by placental insufficiency and yet the role of hypothyroidism in placental regulation of fetal growth is unknown. This study aimed to investigate the effects of maternal hypothyroidism on placental nutrient transporter expression, placental morphology, and placental metabolism. MethodsHypothyroidism was induced in female Sprague-Dawley rats by adding methimazole (MMI) to drinking water at moderate (MOD, MMI at 0.005% w/v) and severe (SEV, MMI at 0.02% w/v) doses from one week prior to pregnancy and throughout gestation. Maternal and fetal tissues were collected on embryonic day 20 (E20). ResultsHypothyroidism reduced fetal weight (PTrt<0.001) despite causing fetal hyperglycaemia (PTrt = 0.016). Placental weight was not affected by hypothyroidism however placental efficiency was reduced (PTrt<0.001), as was the junctional zone (JZ):labyrinth zone (LZ) weight ratio (PTrt = 0.005). LZ glycogen content was increased (PTrt = 0.029) and while mRNA expression of glucose transporters was reduced by hypothyroidism, only GLUT1 protein expression was reduced in male LZs. Maternal hypothyroidism reduced mitochondrial content (PTrt = 0.031), particularly in SEV males relative to CON males (P = 0.004). Protein expression of Complex V (P < 0.001) and Complex III (P = 0.002) of the electron transport chain were also reduced in males. Maternal hypothyroidism reduced LZ (PTrt<0.001) and fetal plasma triglycerides (P = 0.019) while fetal free fatty acids and the expression of LZ lipid transporters was not affected. DiscussionOverall, maternal hypothyroidism may lead to FGR through reduced maternal T4 availability, changes to placental morphology, altered nutrient transporter expression and sex-specific effects on placental metabolism. Changes to LZ glycogen and triglyceride stores as well as mitochondrial content suggest a metabolic shift from oxidative phosphorylation to anaerobic glycolysis in males. These changes also likely impact fetal substrate availability and therefore fetal growth.