Lipid Accumulation In Obesity Research Articles

Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity

ObjectiveLipotoxic injury from renal lipid accumulation in obesity and type 2 diabetes (T2D) is implicated in associated kidney damage. However, models examining effects of renal ectopic lipid accumulation independent of obesity or T2D are lacking. We generated renal tubule-specific adipose triglyceride lipase knockout (RT-SAKO) mice to determine if this targeted triacylglycerol (TAG) over-storage affects glycemic control and kidney health. MethodsMale and female RT-SAKO mice and their control littermates were tested for changes in glycemic control at 10–12 and 16–18 weeks of age. Markers of kidney health and blood lipid and hormone concentrations were analyzed. Kidney and blood lysophosphatidic acid (LPA) levels were measured, and a role for LPA in mediating impaired glycemic control was evaluated using the LPA receptor 1/3 inhibitor Ki-16425. ResultsAll groups remained insulin sensitive, but 16- to 18-week-old male RT-SAKO mice became glucose intolerant, without developing kidney inflammation or fibrosis. Rather, these mice displayed lower circulating insulin and glucagon-like peptide 1 (GLP-1) levels. Impaired first-phase glucose-stimulated insulin secretion was detected and restored by Exendin-4. Kidney and blood LPA levels were elevated in older male but not female RT-SAKO mice, associated with increased kidney diacylglycerol kinase epsilon. Inhibition of LPA-mediated signaling restored serum GLP-1 levels, first-phase insulin secretion, and glucose tolerance. ConclusionsTAG over-storage alone is insufficient to cause renal tubule lipotoxicity. This work is the first to show that endogenously derived LPA modulates GLP-1 levels in vivo, demonstrating a new mechanism of kidney-gut-pancreas crosstalk to regulate insulin secretion and glucose homeostasis.

Let-7a-5p Regulates Animal Lipid Accumulation by Targeting Srebf2 and Thbs1 Signaling.

Recently, the trend of obesity is becoming increasingly prevalent, and the underlying pathogenesis of obesity is complex and needs to be researched further. In this study, we report a decreased expression of let-7a-5p in the white adipose tissue (WAT) of animals with obesity. Using the RNA oligo, let-7a-5p over-expression or suppression-expression is achieved, impacting the proliferation and differentiation of preadipocytes in vitro. Srebf2 mechanistically interacts with the metabolic effect of let-7a-5p and participates in lipid accumulation by regulating Srebf2 downstream signaling. Moreover, let-7a-5p binds to Thbs1 to interact with the PI3K-AKT-mTOR pathway, down-regulating the phosphorylation levels of AKT, mTOR, and S6K1 to decrease lipid accumulation. In conclusion, our study highlights the physiological significance of let-7a-5p in lipid accumulation and suggests that the let-7a-5p/Srebf2 and let-7a-5p/Thbs1/PI3K-AKT-mTOR axes may represent potential mechanisms for controlling lipid accumulation in obesity.

MiR-383-5p Regulates Preadipocyte Proliferation and Differentiation by Targeting RAD51AP1.

Obesity has become a major health problem worldwide, and increasing evidence supports the importance of microRNAs (miRNAs) in its pathogenesis. Recently, we found that miR-383-5p_1 is highly expressed in the perirenal fat of high-fat-fed rabbits, but it is not yet known whether miR-383-5p is involved in lipid metabolism. Here, we used transcriptome sequencing technology to screen 1642 known differentially expressed genes between miR-383-5p mimic groups and miR-383-5p negative control groups. Gene Ontology Resource (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were enriched in the pathway related to lipid metabolism, and glycine biosynthesis, the NOD receptor signal pathway and nonalcoholic fatty liver were significantly enriched. Afterwards, our research results indicated that miR-383-5p can promote the proliferation and differentiation of rabbit preadipocytes, and there is a direct targeting relationship with RAD51AP1. Mechanistically, miR-383-5p directly interacts with the lipid metabolism and participates in adipogenesis and lipid accumulation by targeting RAD51AP1. In conclusion, our data highlight a physiological role for miRNA in lipid metabolism and suggest the miR-383-5p/RAD51AP1 axis may represent a potential mechanism for controlling lipid accumulation in obesity.

Interference of a mammalian circRNA regulates lipid metabolism reprogramming by targeting miR-24-3p/Igf2/PI3K-AKT-mTOR and Igf2bp2/Ucp1 axis.

White adipose tissue (WAT) is important for regulating the whole systemic energy homeostasis. Excessive WAT accumulation further contributes to the development of obesity and obesity-related illnesses. More detailed mechanisms for WAT lipid metabolism reprogramming, however, are still elusive. Here, we report the abnormally high expression of a circular RNA (circRNA) mmu_circ_0001874 in the WAT and liver of mice with obesity. mmu_circ_0001874 interference achieved using a specific adeno-associated virus infects target tissues, down-regulating lipid accumulation in the obesity mice WAT, and liver tissues. Mechanistically, miR-24-3p directly interacts with the lipid metabolism effect of mmu_circ_0001874 and participates in adipogenesis and lipid accumulation by targeting Igf2/PI3K-AKT-mTOR axis. Moreover, mmu_circ_0001874 binds to Igf2bp2 to interact with Ucp1, up-regulating Ucp1 translation and increasing thermogenesis to decrease lipid accumulation. In conclusion, our data highlight a physiological role for circRNA in lipid metabolism reprogramming and suggest mmu_circ_0001874/miR-24-3p/Igf2/PI3K-AKT-mTOR and mmu_circ_0001874/Igf2bp2/Ucp1 axis may represent a potential mechanism for controlling lipid accumulation in obesity.

Berberine Reduces Lipid Accumulation in Obesity via Mediating Transcriptional Function of PPARδ.

Obesity is defined as a dampness-heat syndrome in traditional Chinese medicine. Coptidis Rhizoma is an herb used to clear heat and eliminate dampness in obesity and its complications. Berberine (BBR), the main active compound in Coptidis Rhizoma, shows anti-obesity effects. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that regulate the expression of genes involved in energy metabolism, lipid metabolism, inflammation, and adipogenesis. However, whether PPARs are involved in the anti-obesity effect of BBR remains unclear. As such, the aim of this study was to elucidate the role of PPARs in BBR treatment on obesity and the underlying molecular mechanisms. Our data showed that BBR produced a dose-dependent regulation of the levels of PPARγ and PPARδ but not PPARα. The results of gene silencing and specific antagonist treatment demonstrated that PPARδ is key to the effect of BBR. In 3T3L1 preadipocytes, BBR reduced lipid accumulation; in high-fat-diet (HFD)-induced obese mice, BBR reduced weight gain and white adipose tissue mass and corrected the disturbed biochemical parameters, including lipid levels and inflammatory and oxidative markers. Both the in vitro and in vivo efficacies of BBR were reversed by the presence of a specific antagonist of PPARδ. The results of a mechanistic study revealed that BBR could activate PPARδ in both 3T3L1 cells and HFD mice, as evidenced by the significant upregulation of PPARδ endogenous downstream genes. After activating by BBR, the transcriptional functions of PPARδ were invoked, exhibiting negative regulation of CCAAT/enhancer-binding protein α (Cebpα) and Pparγ promoters and positive mediation of heme oxygenase-1 (Ho-1) promoter. In summary, this is the first report of a novel anti-obesity mechanism of BBR, which was achieved through the PPARδ-dependent reduction in lipid accumulation.

Cardiac specific PPAR alpha knock-down protects against cardiac lipid accumulation during metabolic stress

A dysregulated lipid metabolism contributes to the pathological development of a wide array of diseases including Type 2 Diabetes and associated cardiovascular diseases. One main regulator of cardiac lipid metabolism is the transcription factor Peroxisome Proliferator Activated Receptor α (PPARα). PPARα has been shown to have regulatory effects on many proteins that are integral for the proper regulation of lipid metabolism including those involved in fatty acid oxidation, mitochondria, and lipid droplets. After triglycerides (TG) accumulate and are stored in lipid droplets, the fat is then transferred from lipid droplets to mitochondria where the fatty acids undergo fatty acid oxidation and are used for ATP synthesis. In this research we aimed to determine how cardiac PPARα regulates lipid metabolism and the organelles responsible for its homeostasis in the heart during metabolic stress in the context of obesity. To study this, we used our tamoxifen-inducible cardiomyocyte specific PPARα knockout (cPPARα -/- ) mouse. To induce obesity, we fed Control and cPPARα -/- mice a high fat diet (HFD) for 5 weeks. Our results show that the TG content is lower in hearts from cPPARα -/- vs Control mice fed the HFD. cPPARα -/- vs Control hearts also had a lower expression of Plin2 (a key lipid droplet protein) when fed a HFD. also agrees with our previous findings in fasted/fed hearts. Interestingly, this agrees with our previous findings that the hearts in cPPARα -/- mice were protected against the elevation in TG that normally occurs in response to short term fasting (16 hr fast). Therefore, a reduction in cardiac PPARα protects against lipid accumulation in the heart. As mitochondrial dysfunction has been linked to the cardiac dysfunction present in diabetic hearts and may be involved in regulating lipid accumulation, we next wanted to test whether cPPARα -/- affected mitochondrial function. Measurements of mitochondrial stress proteins have not suggested any elevation in mitochondrial dysfunction in the cPPARα -/- hearts either at baseline or in response to the HFD or 16 hr fast. Interestingly, cPPARα -/- hearts had a higher expression of the uncut ATF6 protein than the control hearts when fasted which suggests that the cPPARα -/- hearts may have less mitochondrial stress due to less excess ROS in the heart. In agreement with this, echocardiography measurements have so far not indicated any reduction in the cardiac function of cPPARα -/- vs control mice. In the future it will be important to look into mitochondrial dysfunction in greater depth including the regulation of mitochondrial fission and fusion pathways. Overall, this suggests that cardiac PPARα may protect against cardiac lipid accumulation in obesity and that this may be through the regulation of Plin2 and mitochondrial stress pathways. ND EPSCoR This is the full abstract presented at the American Physiology Summit 2023 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.

Covalent inhibition of endoplasmic reticulum chaperone GRP78 disconnects the transduction of ER stress signals to inflammation and lipid accumulation in diet-induced obese mice.

Targeting endoplasmic reticulum (ER) stress, inflammation, and metabolic dysfunctions may halt the pathogenesis of obesity and thereby reduce the prevalence of diabetes, cardiovascular disesases, and cancers. The present study was designed to elucidate the mechnaisms by which plant-derived celastrol ameliorated inflammation and lipid accumulation in obesity. The mouse model of diet-induced obesity was induced by feeding high-fat diet for 3 months and subsequently intervented with celastrol for 21 days. Hepatic and adipose tissues were analyzed for lipid accumulation, macrophage activation, and biomarker expression. As result, celastrol effectively reduced body weight, suppressed ER stress, inflammation, and lipogenesis while promoted hepatic lipolysis. RNA-sequencing revealed that celastrol-loaded nanomicelles restored the expression of 49 genes that regulate ER stress, inflammation, and lipid metabolism. On the other hand, celastrol-PEG4-alkyne was synthesized for identifying celastrol-bound proteins in RAW264.7 macrophages. ER chaperone GRP78 (78 kDa glucose-regulated protein) was identified by proteomics approach for celastrol binding to the residue Cys41. Upon binding and conjugation, celastrol diminished the chaperone activity of GRP78 by 130-fold and reduced ER stress in palmitate-challenged cells, while celastrol analog lacking quinone methide failed to exhibit antiobesity effects. Thus, covalent GRP78 inhibition may induce the reprograming of ER signaling, inflammation, and metabolism against diet-induced obesity.

Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release.

SUMMARYHepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity.

Reduced lipolysis in lipoma phenocopies lipid accumulation in obesity

BackgroundElucidation of lipid metabolism and accumulation mechanisms is of paramount importance to understanding obesity and unveiling therapeutic targets. In vitro cell models have been extensively used for these purposes, yet, they do not entirely reflect the in vivo setup. Conventional lipomas, characterized by the presence of mature adipocytes and increased adipogenesis, could overcome the drawbacks of cell cultures. Also, they have the unique advantage of easily accessible matched controls in the form of subcutaneous adipose tissue (SAT) from the same individual. We aimed to determine whether lipomas are a good model to understand lipid accumulation.MethodsWe histologically compared lipomas and control SAT, followed by assessment of the lipidome using high-resolution 1H NMR spectroscopy and ESI-IT mass spectrometry. RNA-sequencing was used to obtain the transcriptome of lipomas and the matched SAT.ResultsWe found a significant increase of small-size (maximal axis < 70 µm) and very big (maximal axis > 150 µm) adipocytes within lipomas. This suggests both enhanced adipocyte proliferation and increased lipid accumulation. We further show that there is no significant change in the lipid composition compared to matched SAT. To better delineate the pathophysiology of lipid accumulation, we considered two groups with different genetic backgrounds: (1) lipomas with HMGA2 fusions and (2) without gene fusions. To reduce the search space for genes that are relevant for lipid pathophysiology, we focused on the overlapping differentially expressed (DE) genes between the two groups. Gene Ontology analysis revealed that DE genes are enriched in pathways related to lipid accumulation.ConclusionsWe show that the common shared lipid accumulation mechanism in lipoma is a reduction in lipolysis, with most gene dysregulations leading to a reduced cAMP in the adipocyte. Superficial lipomas could thus be used as a model for lipid accumulation through altered lipolysis as found in obese patients.

Combination of dapagliflozin and statins attenuate renal lipotoxicity in high‐fat high‐fructose diet‐induced insulin resistant rats

High‐fat high‐fructose diet (HFF) can induce dyslipidemia and lipid accumulation in the kidney which are related to insulin resistance and metabolic syndrome. Dyslipidemia and lipid accumulation in obesity can lead to lipotoxicity and cellular damage particularly kidney injury by activating oxidative stress, fibrotic and apoptotic pathways. This study investigated whether dapagliflozin alone or combined with atorvastatin could improve metabolic parameters, lipid metabolism and lipid accumulation induced kidney injury in HFF‐induced insulin resistant rats. Male Wistar rats were fed with high‐fat diet with 10% fructose in drinking water for 16 weeks. After that, these rats were received drug treatments for 4 weeks; vehicle (HFF), SGLT2 inhibitor dapagliflozin (HFFD), atorvastatin (HFFA) and SGLT2 inhibitor combined with atorvastatin (HFFDA) groups. HFF rats demonstrated insulin resistance, dyslipidemia, and renal dysfunction associated with impaired renal lipid metabolism and lipid accumulation. Lipid accumulation in the kidney could promote renal dysfunction in HFF rats via the activation of oxidative stress, fibrosis and apoptosis. Dapagliflozin treatment could improve insulin resistance, lipid synthesis and lipotoxicity‐related renal oxidative stress, fibrosis and apoptosis leading to reversal of kidney dysfunction in HFF model. The combined treatment (HFFDA group) could also improve metabolic parameters which was not different from single drug treatment (HFFD or HFFA group). Notably, the reduced lipid accumulation in kidney which were linked to the improvement in lipid oxidation was better in the combined treatment group when compared to a single drug treatment. In summary, dapagliflozin combined with atorvastatin treatment exert the beneficial effects on metabolic parameters, lipid metabolism, and lipid accumulation induced kidney injury via the attenuation of oxidative stress, fibrosis and apoptosis in high‐fat high‐fructose diet‐induced insulin resistant model.Support or Funding InformationThailand Research Fund (RSA6080015 AL); the Royal Golden Jubilee PhD program (PhD/0063/2560 LT and AL); the Faculty of Medicine Research Fund, Chiang Mai University (AL and AP); the Graduate Research Scholarship Chiang Mai University (LT); and the Functional Food Research Center for Well‐being, Chiang Mai University (AL).

African Walnuts (Tetracarpidium conophorum) Modulate Hepatic Lipid Accumulation in Obesity via Reciprocal Actions on HMG-CoA Reductase and Paraoxonase.

Obesity is characterized by increased body fat and involves an imbalance between the synthesis and degradation of lipids. The study aimed to investigate the effect of African walnuts (Tetracarpidium conophorum) on lipids storage and the regulatory enzymes of hepatic lipid metabolism in obese rats. Nuts were extracted in ethanol (WE) and further separated to obtain the ethyl-acetate fraction (ET) and the residue (RES). These were administered orally to 3 groups of monosodium glutamate- obese rats (n = 6), respectively, for 6 weeks. Other groups in the study were: normal (NC), obese control (OC) and standard control (SC) which received orlistat. Hepatic total lipids, total phospholipids, triacylglycerol (TG), total cholesterol (TCHOL), 3-hydroxyl-3-methylglutaryl-CoA (HMG-CoA) reductase and paraoxonase were studied. Total lipids, TG and TCHOL which increased in OC compared to NC group, decreased. HMG-CoA reductase activity decreased in the 3 study groups relative to OC. Paraoxonase activity which decreased in OC was up-regulated, while the magnitude of hepatic cholesterol decreased from 94.32 % in OC to 52.19, 65.43 and 47.04 % with WE, ET and RES, respectively. Flavonoids, alkaloids, glycosides, tannins and saponins were detected in the nut. GC-MS analysis revealed 16, 18 and 10 volatile components in WE, ET and RES, respectively. Unsaturated fatty acids (linolenic acids: 33.33, 47.95 and 50.93 %, and α-linolenic acids: 25, 19.66 and 26.63 %) in WE, ET and RES, respectively, are the most abundant, and likely to be responsible for the observed activity. African walnuts can prevent hepatic lipid accumulation through reciprocal actions on HMG-CoA reductase and paraoxonase in obesity.

289-LB: Hepatic Gamma-Amino Butyric Acid Release Drives Hyperinsulinemia and Insulin Resistance

The degree of hepatic lipid accumulation in obesity directly correlates with the severity of hyperinsulinemia and systemic insulin resistance. Here, we propose a mechanism that explains this associative link, whereby, hepatic steatosis dysregulates glucose and insulin homeostasis. Obesity-induced lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic vagal afferent nerve (HVAN) firing (22.9 ± 7.6%; P &amp;lt; 0.05). The HVAN plays a key role in regulating whole-body glucose homeostasis. Accordingly, we propose that dysregulated hepatocyte-vagal communication underlies the metabolic dysfunction in obesity. Using an ex vivo explant liver slice model, we showed that diet induced obesity nearly triples hepatic GABA release/mg DNA in mice (P &amp;lt; 0.05). We hypothesize that hepatic GABA release decreases HVAN activity to stimulate insulin release and decrease peripheral insulin sensitivity. To establish that hepatocyte depolarization encourages GABA export in obesity, we virally induced expression of Kir2.1, a hyperpolarizing channel, in hepatocytes. Kir2.1 expression decreased hepatic slice GABA release to half of that observed in control obese mice, while protecting against hyperinsulinemia and insulin resistance on a high fat diet. Hepatic GABA is synthesized by GABA-Transaminase (GABA-T). To determine the role of hepatic GABA production in diet induced metabolic dysfunction, we treated obese mice with the irreversible GABA-T inhibitors, ethanolamine-O-sulphate (EOS) or vigabatrin (8mg/day; IP). Within 5 days, GABA-T inhibition ameliorated the hyperinsulinemia and insulin resistance of obesity (P &amp;lt; 0.05). These improvements in glucose homeostasis are dependent on an intact HVAN, as EOS did not affect serum insulin or insulin sensitivity in obese hepatic vagotomized mice. This work establishes that limiting hepatocyte GABA production or release can mute the glucoregulatory dysfunction common to obesity. Disclosure C. Geisler: None. S. Ghimire: None. B.J. Renquist: None. Funding Arizona Biomedical Research Commission (ADHS14-082986, ADHS18-201472 to B.J.R.); American Heart Association (15BGIA25090300 to B.J.R.)

Spleen supports a pool of innate-like B cells in white adipose tissue that protects against obesity-associated insulin resistance.

Lipid accumulation in obesity triggers a low-grade inflammation that results from an imbalance between pro- and anti-inflammatory components of the immune system and acts as the major underlying mechanism for the development of obesity-associated diseases, notably insulin resistance and type 2 diabetes. Innate-like B cells are a subgroup of B cells that respond to innate signals and modulate inflammatory responses through production of immunomodulatory mediators such as the anti-inflammatory cytokine IL-10. In this study, we examined innate-like B cells in visceral white adipose tissue (VAT) and the relationship of these cells with their counterparts in the peritoneal cavity and spleen during diet-induced obesity (DIO) in mice. We show that a considerable number of innate-like B cells bearing a surface phenotype distinct from the recently identified "adipose natural regulatory B cells" populate VAT of lean animals, and that spleen represents a source for the recruitment of these cells in VAT during DIO. However, demand for these cells in the expanding VAT outpaces their recruitment during DIO, and the obese environment in VAT further impairs their function. We further show that removal of splenic precursors of innate-like B cells through splenectomy exacerbates, whereas supplementation of these cells via adoptive transfer ameliorates, DIO-associated insulin resistance. Additional adoptive transfer experiments pointed toward a dominant role of IL-10 in mediating the protective effects of innate-like B cells against DIO-induced insulin resistance. These findings identify spleen-supplied innate-like B cells in VAT as previously unrecognized players and therapeutic targets for obesity-associated diseases.

Rescue of cardiac leptin receptors in db/db mice prevents myocardial triglyceride accumulation.

Increased leptin levels have been suggested to contribute to cardiac hypertrophy and attenuate cardiac lipid accumulation in obesity, although it has been difficult to separate leptin's direct effects from those caused by changes in body weight and adiposity. To determine whether leptin attenuates cardiac lipid accumulation in obesity or directly causes left ventricular hypertrophy (LVH), we generated a novel mouse model in which the long form of the leptin receptor (LepR) was "rescued" only in cardiomyocytes of obese db/db mice. Reexpression of cardiomyocyte leptin receptors in db/db mice did not cause LVH but reduced cardiac triglycerides and improved cardiac function. Compared with lean wild-type (WT) or db/db-cardiac LepR rescue mice, db/db mice exhibited significantly lower E/A ratio, a measurement of early to late diastolic filling, which averaged 1.5 ± 0.07 in db/db vs. 1.9 ± 0.08 and 1.8 ± 0.11 in WT and db/db-cardiac LepR rescue mice, respectively. No differences in systolic function were observed. Although db/db and db/db-cardiac LepR rescue mice exhibited similar increases in plasma triglycerides, insulin, glucose, and body weight, cardiac triglycerides were significantly higher in db/db compared with WT and db/db cardiac LepR rescue mice, averaging 13.4 ± 4.2 vs. 3.8 ± 1.6 vs. 3.8 ± 0.7 mg/g, respectively. These results demonstrate that despite significant obesity and increases in plasma glucose and triglycerides, db/db cardiac LepR rescue mice are protected against myocardial lipid accumulation. However, we found no evidence that leptin directly causes LVH.

Inhibitory Effects of Ethyl Acetate-Soluble Fraction from Morus alba on Lipid Accumulation in 3T3-L1 Cells

Fruits of mulberry (Morus alba) have been widely used for therapeutic purposes in Asian countries for centuries. Treatment of 3T3-L1 cells with ethanolic extracts of M. alba decreased adipocyte differentiation at 100 microg/mL by 18.6%. Treatment suppressed mRNA levels of PPARgamma and C/EBPalpha expression in 3T3-L1 cells. However, the extract did not change free glycerol release from mature adipocytes. Thus, M. alba inhibited lipid accumulation by regulating transcription factors in 3T3-L1 adipocytes without a lipolytic effect. Among the soluble- fractions, the ethyl acetate-soluble fraction had the highest antiadipogenic effects on 3T3-L1 cells. This fraction decreasing intracellular lipid accumulation by 38.5% in response to treatment with 100 microg/mL. In addition, HPLC analysis of the ethyl acetate-soluble fraction of M. alba contained 167.7 microM of protocatechulic acid in 1 mg/mL of fraction, which inhibited lipid accumulation by 44.8% in response to treatment with 100 microM. From these results, M. alba is a possible candidate for regulating lipid accumulation in obesity.

Determination of protocatechuic acid from Rubus coreanus fruits and their inhibitory effects of triglyceride accumulation on 3T3‐L1 cells

Obesity is a serious health problem in industrialized countries because it is implicated in various diseases. With the recent increased interest in antiobesity, many investigators are interested in finding phytochemicals such as triterpenoid, essential oil, flavonoid that play a role in this adipocyte differentiation mechanism. Fruits of black raspberry (Rubus coreanus) belonging to the Rosaceae family has been used for centuries as a traditional alternative medicine. This study was investigated determination of protocatechuic acid and their effects of TG accumulation on adipocyte differentiation in 3T3‐L1cells. From this extract fractionated with petroleum ether (A1) and MtBE (A2). We used HPLC to determine the level of protocatechulic acid in A2 fraction from Rubus coreanus. The protocatechulic acid in A2 fraction from Rubus coreanus were confirmed by comparison of the retention times and UV spectra of the samples with those of standard compounds. Thousand ppm of A2 fraction from Rubus coreanus contained 76.64 μM of protocatechulic acid. Anti‐adipogenic effects of A2 fraction from Rubus coreanus were investigated by measuring cell viability and differentiation in 3T3‐L1cells. Treatment of 3T3‐L1 cells with A2 fraction of Rubus coreanus decreased cell viability in time‐dependently. And treatment of A2 fraction inhibited lipid accumulation on adipocytes by 28.8% in 100ug/ml. We also found that containing compounds exerted inhibitory activity in the adipocyte differentiation in this study. Protocatechuic acid which is contained in A2 fraction form Rubus coreanus inhibited lipid accumulation on adipocyte by 26.8 % in 10ug/ml. Thus, Rubus coreanus is a possible candidate for regulating lipid accumulation in obesity.

VEGF-B: a thing of beauty

VEGF-B: a thing of beauty

Dual modulation of both lipid oxidation and synthesis by peroxisome proliferator‐activated receptor‐γ coactivator‐1α and ‐1β in cultured myotubes

The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family is a key regulator of mitochondrial function, and reduced mRNA expression may contribute to muscle lipid accumulation in obesity and type 2 diabetes. To characterize the effects of PGC-1 on lipid metabolism, we overexpressed PGC-1alpha and PGC-1beta in C2C12 myotubes using adenoviral vectors. Both PGC-1alpha and -1beta increased palmitate oxidation [31% (P<0.01) and 26% (P<0.05), respectively] despite reductions in cellular uptake [by 6% (P<0.05) and 21% (P<0.001)]. Moreover, PGC-1alpha and -1beta increased mRNA expression of genes regulating both lipid oxidation (e.g., CPT1b and ACADL/M) and synthesis (FAS, CS, ACC1/2, and DGAT1). To determine the net effect, we assessed lipid composition in PGC-1-expressing cells. Total lipid content decreased by 42% in palmitate-loaded serum-starved cells overexpressing PGC-1alpha (P<0.05). In contrast, in serum-replete cells, total lipid content was not significantly altered, but fatty acids C14:0, C16:0, C18:0, and C18:1 were increased 2- to 4-fold for PGC-1alpha/beta (P<0.05). Stable isotope-based dynamic metabolic profiling in serum-replete cells labeled with (13)C substrates revealed both increased de novo fatty acid synthesis from glucose and increased fatty acid synthesis by chain elongation with either PGC-1alpha or -1beta expression. These results indicate that PGC-1 can promote both lipid oxidation and synthesis, with net balance determined by the nutrient/hormonal environment.-Espinoza, D. O., Boros, L. G., Crunkhorn, S., Gami, H., Patti, M.-E. Dual Modulation of both lipid oxidation and synthesis by peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -1beta in cultured myotubes.

Skeletal muscle lipid accumulation in obesity, insulin resistance, and type 2 diabetes

In addition to obesity, many factors, including the distribution of body fat, contribute to the development of insulin resistance and type 2 diabetes mellitus (T2DM). Lipid contained within skeletal muscle as triglyceride is a parameter of regional fat accumulation thought to be an important link among obesity, insulin resistance, and type 2 diabetes, even in the pediatric population. Intramuscular triglycerides can also be a fuel source for healthy muscle during periods of physical activity. Thus, the balance between storage and efficient utilization of muscle triglycerides is likely a key to a better understanding of the interaction between dysregulated fat and glucose metabolism by muscle in both adults and children. This review examines the evidence that muscle lipid accumulation is linked with insulin resistance and type 2 diabetes of both adults and children. In addition, we explore the potential mechanisms for muscle lipid accumulation as well as the effects of weight loss and physical activity on muscle lipid. Further defining the links between muscle lipid accumulation and insulin action should help develop more effective strategies to prevent or treat type 2 diabetes and other obesity-associated disorders.