Elevated Free Fatty Acid Levels Research Articles

Free fatty acids: independent predictors of long-term adverse cardiovascular outcomes in heart failure patients

BackgroundThe association between plasma free fatty acid (FFA) and the outcomes in the heart failure (HF) patients remains unclear.MethodsA cohort study among HF patients was performed. Plasma FFA was analyzed as both a continuous and a categorical variable (grouped by tertiles) to assess its association with composite cardiovascular (CV) death and HF hospitalization (CV death & HHP), CV death alone, and all-cause mortality (ACM) using Cox regression models. Subgroup analyses of HF patients with preserved ejection fraction (HFpEF) and mildly reduced/reduced ejection fraction (HFmrEF/HFrEF) were performed. This work also assessed the effectiveness of combining FFA and NT-pro BNP biomarkers for risk stratification by calculating the concordance index (C-index).ResultsAmong the 4,109 HF patients, FFA levels exceeding 0.4–0.42 mmol/L were associated with increased risks of the three outcomes. Patients in the highest FFA tertile faced greater risks than those in the lowest tertile. Adjusted hazard ratios were 1.32 (95% CI: 1.11–1.58) for CV death & HHP, 1.45 (95% CI: 1.16–1.82) for CV death, and 1.39 (95% CI: 1.15–1.68) for ACM, with a maximum follow-up of 8 years (median: 25 months). Subgroup analyses revealed that elevated FFA levels consistently predicted worse outcomes in both HFmrEF/HFrEF and HFpEF patients. The C-index for predicting outcomes was significantly greater when NT-pro BNP and FFA were combined than when NT-pro BNP was used alone (P < 0.01).ConclusionIncreased plasma FFA concentrations were independently associated with greater risks of CV death & HHP, CV death, and ACM among HF patients, irrespective of the ejection fraction. The combination of FFA and NT-pro BNP biomarkers significantly improved risk stratification in HF patients.

Hydrogen-Rich Water (HRW) Reduces Fatty Acid-Induced Lipid Accumulation and Oxidative Stress Damage through Activating AMP-Activated Protein Kinase in HepG2 Cells.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excessive fat accumulation in the liver. Intracellular oxidative stress induced by lipid accumulation leads to various hepatocellular injuries including fibrosis. However, no effective method for mitigating MASLD without substantial side effects currently exists. Molecular hydrogen (H2) has garnered attention due to its efficiency in neutralizing harmful reactive oxygen species (ROS) and its ability to penetrate cell membranes. Some clinical evidence suggests that H2 may alleviate fatty liver disease, but the precise molecular mechanisms, particularly the regulation of lipid droplet (LD) metabolism, remain unclear. This study utilized an in vitro model of hepatocyte lipid accumulation induced by free fatty acids (FFAs) to replicate MASLD in HepG2 cells. The results demonstrated a significant increase in LD accumulation due to elevated FFA levels. However, the addition of hydrogen-rich water (HRW) effectively reduced LD accumulation. HRW decreased the diameter of LDs and reduced lipid peroxidation and FFA-induced oxidative stress by activating the AMPK/Nrf2/HO-1 pathway. Overall, our findings suggest that HRW has potential as an adjunctive supplement in managing fatty liver disease by reducing LD accumulation and enhancing antioxidant pathways, presenting a novel strategy for impeding MASLD progression.

Elevated Lipid Metabolites in Stored Clinical OCA Media Correlate With Chondrocyte Death

Background: A major limitation of osteochondral allografts (OCA) is the deterioration of cartilage health associated with cell death during prolonged storage. However, little is known about the mechanisms that contribute to chondrocyte death during storage. Purpose/Hypothesis: This study aimed to determine whether bioactive lipid metabolites accumulate in the storage media of OCA and whether they are associated with a loss of chondrocyte viability during prolonged storage. It was hypothesized that free fatty acids (FFAs) would accumulate over time in the storage media of OCA and adversely affect cartilage health during storage. Study Design: Controlled laboratory study. Methods: A group of 21 (n = 6-8 OCA/treatment group) fresh human hemicondylar OCA tissues and media were analyzed after 7, 28, and 68 days of prolonged cold (4°C) storage. Targeted mass spectrometry analysis was used to quantify bioactive FFAs, as well as primary (lipid hydroperoxide [ROOH]) and secondary (malondialdehyde) lipid oxidation products. Chondrocyte viability was measured using a fluorescence-based live/dead assay and confocal microscopy. Results: The concentration of all targeted fatty acid metabolites in storage media was significantly increased with increased cold storage time (P < .05). ROOH was significantly higher on day 28 of cold storage. No difference in secondary ROOH products in storage media was observed. Chondrocyte viability significantly declined in both the en face and the vertical cross-sectional analysis with increased cold storage time and inversely correlated with fatty acid metabolites (P < .05). Conclusion: It is well established that elevated levels of certain FFAs and lipid oxidation products can alter cell function and cause cell death via lipotoxicity and other mechanisms. This work is the first to identify elevated levels of FFA metabolites and primary oxidation lipid products in the storage media from clinical OCA. The concentrations of FFA metabolites were measured at levels (>100 µM) known to induce cell death and were directly correlated with chondrocyte viability. Clinical Relevance: These findings provide important targets for understanding why cartilage health declines during cold storage, which can be used to optimize media formulations and improve graft health.

Fat Accumulation and Elevated Free Fatty Acid Are Associated With Age-Related Glucose Intolerance: Bunkyo Health Study.

Older adults have a high prevalence of new-onset diabetes, often attributed to age-related decreases in insulin sensitivity and secretion. It remains unclear whether both insulin sensitivity and secretion continue to deteriorate after age 65. To investigate the effects of aging on glucose metabolism after age 65 and to identify its determinants. This cross-sectional study involved 1438 Japanese older adults without diabetes. All participants underwent a 75-g oral glucose tolerance test (OGTT). Body composition and fat distribution were measured with dual-energy X-ray absorptiometry and magnetic resonance imaging. Participants were divided into 4 groups by age (65-69, 70-74, 75-79, and 80-84 years) to compare differences in metabolic parameters. Mean age and body mass index were 73.0 ± 5.4 years and 22.7 ± 3.0 kg/m2. The prevalence of newly diagnosed diabetes increased with age. Fasting glucose, fasting insulin, the area under the curve (AUC)-insulin/AUC-glucose and insulinogenic index were comparable between groups. AUC-glucose and AUC-insulin during OGTT were significantly higher and Matsuda index and disposition index (Matsuda index · AUC-insulin/AUC-glucose) were significantly lower in the age 80-84 group than in the age 65-69 group. Age-related fat accumulation, particularly increased visceral fat area (VFA), and elevated free fatty acid (FFA) levels were observed. Multiple regression revealed strong correlations of both Matsuda index and disposition index with VFA and FFA. Glucose tolerance declined with age in Japanese older adults, possibly due to age-related insulin resistance and β-cell deterioration associated with fat accumulation and elevated FFA levels.

1554-P: Carnosic Acid Protects against Short-Term Lipid-Infusion–Induced Glucose Intolerance in Mice

Background: Obesity and type 2 diabetes (T2D) are associated with elevated plasma free fatty acids (FFA). In vivo exposure to FFAs, such as palmitate, by lipid infusion results in insulin resistance as observed in obesity and T2D. In recent years, compounds found in herbs and plants have attracted attention for prevention and treatment of insulin resistance and T2D. In recent studies by our group, carnosic acid (CA), found in rosemary, increased glucose uptake and attenuated the FFA (palmitate)-induced insulin resistance in muscle cells and adipocytes. In addition, CA caused a robust activation of AMP-activated protein kinase (AMPK). Our present study aimed to examine the effects of CA in short-term FFA-induced glucose intolerance in mice. Material and Methods: C57Bl/6J mice were cannulated in their jugular veins and infused for 48h with ethylpalmitate (EtP, nontoxic method of elevating circulating palmitate because of hydrolysis to palmitate and ethanol by plasma esterases), mimicking elevated FFA levels seen in obesity. In addition, a group of mice were infused with EtP plus 50 mg/kg CA for 48h. Ethanol vehicle with or without CA were two additional control groups. At the end of the infusions, the mice were subjected to a 2 hr hyperglycemic clamp (20 mM glucose) and the glucose infusion rate was measured to assess glucose tolerance. Results: Preliminary data revealed that mice infused with EtP and CA had a higher glucose infusion rate (GIR; mg/kg*min) (66.5±10, mean±SEM) than mice infused with EtP alone (22.7±10). The EtP and CA was comparable to the GIR of ethanol vehicle infused mice (73±9). Future Directions: Further analysis of collected plasma and tissue will be used to assess insulin resistance and beta cell function in vivo and to elucidate the mechanisms of CA alleviation of FFA-induced insulin resistance. Conclusions: Our data indicate that CA has the potential to counteract FFA-induced glucose intolerance in mice. Disclosure N.Tsakiridis: None. F.Vlavcheski: None. E.Tsiani: None. A.Giacca: None.

Muscle Cell Insulin Resistance Is Attenuated by Rosmarinic Acid: Elucidating the Mechanisms Involved

Obesity and elevated blood free fatty acid (FFA) levels lead to impaired insulin action causing insulin resistance in skeletal muscle, and contributing to the development of type 2 diabetes mellitus (T2DM). Mechanistically, insulin resistance is associated with increased serine phosphorylation of the insulin receptor substrate (IRS) mediated by serine/threonine kinases including mTOR and p70S6K. Evidence demonstrated that activation of the energy sensor AMP-activated protein kinase (AMPK) may be an attractive target to counteract insulin resistance. We reported previously that rosemary extract (RE) and the RE polyphenol carnosic acid (CA) activated AMPK and counteracted the FFA-induced insulin resistance in muscle cells. The effect of rosmarinic acid (RA), another polyphenolic constituent of RE, on FFA-induced muscle insulin resistance has never been examined and is the focus of the current study. Muscle cell (L6) exposure to FFA palmitate resulted in increased serine phosphorylation of IRS-1 and reduced insulin-mediated (i) Akt activation, (ii) GLUT4 glucose transporter translocation, and (iii) glucose uptake. Notably, RA treatment abolished these effects, and restored the insulin-stimulated glucose uptake. Palmitate treatment increased the phosphorylation/activation of mTOR and p70S6K, kinases known to be involved in insulin resistance and RA significantly reduced these effects. RA increased the phosphorylation of AMPK, even in the presence of palmitate. Our data indicate that RA has the potential to counteract the palmitate-induced insulin resistance in muscle cells, and further studies are required to explore its antidiabetic properties.

Correlates of Insulin Resistance in Nascent Metabolic Syndrome.

Metabolic Syndrome (MetS), a major global problem, is a cluster of cardio-metabolic risk factors that predisposes to both type 2 diabetes mellitus (T2DM) and premature atherosclerotic cardiovascular disease (ASCVD). Insulin resistance is a major underpinning of MetS. We investigated the relationship between insulin resistance and biomarkers of inflammation, oxidative stress, free fatty acids (FFA) levels and adipokine dysregulation in a cohort of nascent MetS. This was a cross-sectional study comparing patients with MetS with matched controls. Participants included 47 patients with MetS and 41 controls. Persons with diabetes, ASCVD, smoking and macro-inflammation were excluded. Fasting blood was obtained for both plasma and monocyte isolation. Homeostasis model assessment insulin resistance index (HOMA-IR) was calculated from fasting glucose and insulin levels. The patients were insulin resistant as determined by a valid measure, HOMA-IR. HOMA-IR increased with increasing severity of MetS and correlated with cardio-metabolic features, hsCRP, FFA levels, and adipose tissue insulin resistance. Insulin resistance also correlated with biomarkers of oxidative stress and both circulating and cellular biomarkers of inflammation. Receiver operating Characteristic (ROC) curve analysis revealed that HOMA-IR was an excellent predictor of MetS with an area under the curve of 0.80. In our patients with nascent MetS we show that they have significant insulin resistance. Based on our findings, elevated FFA levels, oxidative stress and inflammation could contribute to the insulin resistance.

Free fatty acids stabilize integrin β1via S-nitrosylation to promote monocyte–endothelial adhesion

Hyperlipidemia characterized by high blood levels of free fatty acids (FFAs) is important for the progression of inflammatory cardiovascular diseases. Integrin β1 is a transmembrane receptor that drives various cellular functions, including differentiation, migration, and phagocytosis. However, the underlying mechanisms modifying integrin β1 protein and activity in mediating monocyte/macrophage adhesion to endothelium remain poorly understood. In this study, we demonstrated that integrin β1 protein underwent S-nitrosylation in response to nitrosative stress in macrophages. To examine the effect of elevated levels of FFA on the modulation of integrin β1 expression, we treated the macrophages with a combination of oleic acid and palmitic acid (2:1) and found that FFA activated inducible nitric oxide synthase/nitric oxide and increased the integrin β1 protein level without altering the mRNA level. FFA promoted integrin β1 S-nitrosylation via inducible nitric oxide synthase/nitric oxide and prevented its degradation by decreasing binding to E3 ubiquitin ligase c-Cbl. Furthermore, we found that increased integrin α4β1 heterodimerization resulted in monocyte/macrophage adhesion to endothelium. In conclusion, these results provided novel evidence that FFA-stimulated N--O stabilizes integrin β1via S-nitrosylation, favoring integrin α4β1 ligation to promote vascular inflammation.

Polydatin prevents lipotoxicity-induced dysfunction in pancreatic β-cells by inhibiting endoplasmic reticulum stress and excessive autophagy

BackgroundChronically elevated free fatty acid levels can adversely affect pancreatic β-cells, leading to insulin resistance and eventually type 2 diabetes mellitus (T2DM). Polydatin (PD) from Polygonum cuspidatum has been shown to regulate blood lipid content and lower cholesterol levels. However, there have been no reports on the potential therapeutic effects and actions of PD on lipotoxicity in β-cells. PurposeThis study aimed to investigate the protective effects of PD on palmitate (PA)-treated INS-1 insulinoma cells and diabetic mice. MethodsCells were incubated with PA and varying concentrations of PD for 24 h. Viability assays, morphological observations, flow cytometric analysis, western blotting, and reverse transcription–quantitative polymerase chain reaction were used to assess the effects of PD on PA-induced lipotoxicity. Western blotting was used to measure the endoplasmic reticulum stress (ERS) and the levels of autophagy-related factors after incubation with inducers and inhibitors of ERS and autophagy. Diabetic mice were treated with intragastric PD for 6 weeks followed by the measurement of their physiological and blood lipid indices and assessment of the results of histological and immunofluorescence analyses. ResultsTreatment with PD after PA exposure enhanced insulin secretion and the expression of diabetes-associated genes. PD promoted β-cell function by reducing the levels of proteins associated with ERS and autophagy while also attenuating ERS triggered by tunicamycin. PD also reduced tunicamycin-induced autophagy, indicating that it regulated ERS-mediated autophagy and reduced PA-induced cellular dysfunction. In addition, treatment of db/db mice with PD substantially reduced body weight gain, alleviated dyslipidemia, improved β-cell function, and reduced insulin resistance. ConclusionThese results suggest that PD protects β-cells from lipotoxicity-induced dysfunction and apoptosis by inhibiting ERS and preventing excessive autophagy. Our study provides a new basis for exploring the potential of PD against β-cell lipotoxicity and T2DM.

Serum free fatty acid elevation is related to acute kidney injury in primary nephrotic syndrome

The aim of this research was to examine the clinical characteristics of acute kidney injury (AKI) in primary nephrotic syndrome (NS) and discuss the relationship between serum lipids and AKI. A total of 1028 patients diagnosed with primary NS with renal biopsy results were enrolled in this study. The patients were divided into AKI (n = 81) and non-AKI (n = 947) groups, and their characteristics were compared using a propensity score analysis for the best matching. Serum free fatty acid (FFA) was an independent predictor for AKI in the postmatch samples (p = 0.011). No significant difference in FFA levels was observed among AKI stages or different pathological types in the AKI and non-AKI groups. The AUC (area under the ROC curve) was 0.63 for FFA levels to distinguish AKI. In primary NS, elevated FFA levels tend to be related to a high risk of AKI. FFAs have diagnostic value and may serve as biomarkers for AKI in NS.

1329-P: A RIPK2 Inhibitor Protects against Saturated-Fat–Induced Glucose Intolerance in Mice

Background: Obesity and type 2 diabetes (T2D) are associated with chronic low-grade inflammation. Elevated free fatty acids (FFAs) , as seen in obesity and T2D, can act as damage associated molecular patterns (DAMPs) activating the innate immune system. Recent studies have identified nucleotide binding oligomerization domain 1 (NOD1) , an intracellular pattern recognition receptor, can be activated by saturated fatty acids (sFA) . NOD1 activates inflammatory kinase RIPK2, leading to increased cytokine production by the innate immune system. Our study aimed to determine whether wild type mice treated with GSK583, a RIPK2 inhibitor, are protected against FFA-induced glucose intolerance. Material and Methods: C57Bl/6J mice were surgically cannulated in their jugular veins and were infused with ethylpalmitate (EtP) for 48h, which results in increased plasma palmitate levels and mimics the elevated FFA levels seen in vivo. Furthermore, mice were also infused with EtP and GSK583 for 48h. After infusion, the mice were subjected to a hyperglycemic clamp and the glucose infusion rate was measured to assess glucose tolerance that under hyperglycemic clamp conditions, is mainly determined by the beta cell ability to compensate for FFA-induced insulin resistance. Results: Preliminary data revealed that mice infused with EtP and GSK583 had a higher glucose infusion rate (GIR; mg/kgmin) (83+20, mean+SEM) than mice infused with EtP alone (57+4) . The EtP and GSK583 was comparable to the GIR of control (EtP vehicle infused) mice (84+7) . Conclusions: Our data indicate that pharmacological inhibition of NOD1 signaling protects against FFA-induced glucose intolerance in mice. Targeting NOD1 may be an effective strategy for treating beta cell dysfunction in T2D. Disclosure N.Tsakiridis: None. A.Ivovic: None. S.Rahman: None. Y.Tan: None. A.Giacca: None.

Hepatic Lipidomic Analysis of Dietary Different Type of Fats and Fructose Interactions in the Pathogenesis of Nonalcoholic Fatty Liver Diseases

ObjectiveDietary nutrient interactions are key determinants to the development of nonalcoholic fatty liver disease (NAFLD). Fat and fructose are two major components of Western diet. This study aimed to determine the combined effects of different type of dietary fats and fructose on the development of NAFLD in a murine model.MethodsMale adult C57BL/6J mice were assigned to six groups and fed with diets (AIN‐93G based) enriched with different types of fat, such as saturated fat (SF‐beef tallow), n‐6 polyunsaturated fat (n6USF‐corn oil), or n‐3 polyunsaturated fat (n3USF‐menhaden fish oil), respectively, with or without fructose supplementation through 10% fructose (w/v) in the drinking water ad lib for 20 weeks. 42% of calories was derived from the fat. Metabolic phenotypes were characterized by liver histology, plasma ALT and AST, glucose tolerance test, hepatic mRNA expression of genes involved in lipid metabolism, and lipidomic analysis of hepatic fatty acid composition.ResultsWhile both SF and n6USF fed mice developed obesity and hepatic steatosis with or without fructose, SFA fed mice were characterized with hepatomegaly, liver injury and fibrosis, which were further exacerbated by fructose; conversely, plasma triglyceride levels were lower compared to controls. Interestingly, n6USF fed mice exhibited steatosis without hepatomegaly, and this was associated with markedly elevated plasma triglyceride and free fatty acid levels, which were blunted by fructose. Moreover, fructose and n6USF led to markedly elevated glucose intolerance tests compared to controls. Hepatic lipidomic analysis revealed that total monounsaturated fatty acids, but not total SFA, exhibited a stepwise decrease from SF to n6USF and n3USF fed mice across most of the lipid pools, which parallels the hepatic triglyceride content, irrespective the presence of fructose. In line with this, hepatic mRNA levels of lipogenesis genes, including Srebf1, Scd1, Fasn, Acacaand Acacb, displayed a similar pattern of alterations (SF&gt;n6USF&gt;n3USF), suggesting that increased lipogenesis contributes to hepatic steatosis in SF and n6USF fed mice. Of note, fructose play a mild, but significant role in the alterations of specific individual fatty acids in certain fatty acid pools, despite the predominant role played by the dietary fats.ConclusionOur data suggest that excess energy from SF intake results in fat storage in the liver, likely due to impaired triglyceride secretion; whereas excess energy from n6USF intake is stored in the periphery. Both effects were exacerbated by fructose supplementation. n3USF is beneficial even in the presence of fructose.

Adipocyte Gq signaling is a regulator of glucose and lipid homeostasis in mice

Obesity is the major driver of the global epidemic in type 2 diabetes (T2D). In individuals with obesity, impaired insulin action leads to increased lipolysis in adipocytes, resulting in elevated plasma free fatty acid (FFA) levels that promote peripheral insulin resistance, a hallmark of T2D. Here we show, by using a combined genetic/biochemical/pharmacologic approach, that increased adipocyte lipolysis can be prevented by selective activation of adipocyte Gq signaling in vitro and in vivo (in mice). Activation of this pathway by a Gq-coupled designer receptor or by an agonist acting on an endogenous adipocyte Gq-coupled receptor (CysLT2 receptor) greatly improved glucose and lipid homeostasis in obese mice or in mice with adipocyte insulin receptor deficiency. Our findings identify adipocyte Gq signaling as an essential regulator of whole-body glucose and lipid homeostasis and should inform the development of novel classes of GPCR-based antidiabetic drugs.

Molecular Mechanism of Lipotoxicity as an Interesting Aspect in the Development of Pathological States-Current View of Knowledge.

Free fatty acids (FFAs) play numerous vital roles in the organism, such as contribution to energy generation and reserve, serving as an essential component of the cell membrane, or as ligands for nuclear receptors. However, the disturbance in fatty acid homeostasis, such as inefficient metabolism or intensified release from the site of storage, may result in increased serum FFA levels and eventually result in ectopic fat deposition, which is unfavorable for the organism. The cells are adjusted for the accumulation of FFA to a limited extent and so prolonged exposure to elevated FFA levels results in deleterious effects referred to as lipotoxicity. Lipotoxicity contributes to the development of diseases such as insulin resistance, diabetes, cardiovascular diseases, metabolic syndrome, and inflammation. The nonobvious organs recognized as the main lipotoxic goal of action are the pancreas, liver, skeletal muscles, cardiac muscle, and kidneys. However, lipotoxic effects to a significant extent are not organ-specific but affect fundamental cellular processes occurring in most cells. Therefore, the wider perception of cellular lipotoxic mechanisms and their interrelation may be beneficial for a better understanding of various diseases’ pathogenesis and seeking new pharmacological treatment approaches.

Діабетична дисліпідемія: фокус на патогенез і лікування

Atherosclerotic cardiovascular diseases are the most common cause of death in the developed countries of the world. Patients with diabetes mellitus 2 type are 2-4 times more likely to die from these diseases compared to patients without diabetes. This review discusses the pathophysiology of lipid disorders, which are the main cause of cardiovascular disease in patients with diabetes mellitus 2 type, and the current approaches to the medical therapy of these disorders. Obesity, metabolic syndrome, and diabetes mellitus 2 type are characterized by insulin resistance, which leads to excessive lipolysis of visceral adipose tissue. The consequence of this disorder is the excessive production of free fatty acids, which become the source for excessive synthesis of proatherogenic lipoproteins saturated with triglycerides. These lipid profile abnormalities are the main pathogenetic link between diabetes and increased risk of atherosclerosis. Chronically elevated levels of free fatty acids reduce insulin synthesis, glucose-stimulated insulin secretion, and β-cell sensitivity to glucose, resulting in a very high risk of developing diabetes mellitus 2 type. Numerous factors contribute to elevated plasma free fatty acid levels and subsequent impairment of metabolic health, such as unhealthy diet, obesity, low physical activity, obstructive sleep apnea, sleep deprivation, and smoking. Currently, lifestyle changes are the best tool for long-term normalization of the concentration of free fatty acids in the blood plasma. The results of modern research have proven that a healthy lifestyle and glycemic control, treatment with statins, ezetimibe, and hypoglycemic drugs improve the lipid profile, reduce insulin resistance and inflammation, which reduces the risk of cardiovascular diseases.

Nicotinamide Mononucleotide Prevents Free Fatty Acid-Induced Reduction in Glucose Tolerance by Decreasing Insulin Clearance.

The NAD-dependent deacetylase SIRT1 improves β cell function. Accordingly, nicotinamide mononucleotide (NMN), the product of the rate-limiting step in NAD synthesis, prevents β cell dysfunction and glucose intolerance in mice fed a high-fat diet. The current study was performed to assess the effects of NMN on β cell dysfunction and glucose intolerance that are caused specifically by increased circulating free fatty acids (FFAs). NMN was intravenously infused, with or without oleate, in C57BL/6J mice over a 48-h-period to elevate intracellular NAD levels and consequently increase SIRT1 activity. Administration of NMN in the context of elevated plasma FFA levels considerably improved glucose tolerance. This was due not only to partial protection from FFA-induced β cell dysfunction but also, unexpectedly, to a significant decrease in insulin clearance. However, in conditions of normal FFA levels, NMN impaired glucose tolerance due to decreased β cell function. The presence of this dual action of NMN suggests caution in its proposed therapeutic use in humans.

PA and OA induce abnormal glucose metabolism by inhibiting KLF15 in adipocytes

BackgroundObesity-induced elevated serum free fatty acids (FFAs) levels result in the occurrence of type 2 diabetes mellitus (T2DM). However, the molecular mechanism remains largely enigmatic. This study was to explore the effect and mechanism of KLF15 on FFAs-induced abnormal glucose metabolism.MethodsLevels of TG, TC, HDL-C, LDL-C, and glucose were measured by different assay kits. qRT-PCR and Western Blot were used to detect the levels of GPR120, GPR40, phosphorylation of p38 MAPK, KLF15, and downstream factors.ResultsKLF15 was decreased in visceral adipose tissue of obesity subjects and high-fat diet (HFD) mice. In HFD mice, GPR120 antagonist significantly promoted KLF15 protein expression level and phosphorylation of p38 MAPK, meanwhile reduced the blood glucose levels. While, blocking GPR40 inhibited the KLF15 expression. In 3T3-L1 adipocytes, 1500 μM PA inhibited KLF15 through a GPR120/P-p38 MAPK signal pathway, and 750 μM OA inhibited KLF15 mainly through GPR120 while not dependent on P-p38 MAPK, ultimately resulting in abnormal glucose metabolism. Unfortunately, GPR40 didn’t contribute to PA or OA-induced KLF15 reduction.ConclusionsBoth PA and OA inhibit KLF15 expression through GPR120, leading to abnormal glucose metabolism in adipocytes. Notably, the inhibition of KLF15 expression by PA depends on phosphorylation of p38 MAPK.

Adipocyte P2Y14 receptors play a key role in regulating whole-body glucose and lipid homeostasis.

Obesity is the major driver of the worldwide epidemic in type 2 diabetes (T2D). In the obese state, chronically elevated plasma free fatty acid levels contribute to peripheral insulin resistance, which can ultimately lead to the development of T2D. For this reason, drugs that are able to regulate lipolytic processes in adipocytes are predicted to have considerable therapeutic potential. Gi-coupled P2Y14 receptor (P2Y14R; endogenous agonist, UDP-glucose) is abundantly expressed in both mouse and human adipocytes. Because activated Gi-type G proteins exert an antilipolytic effect, we explored the potential physiological relevance of adipocyte P2Y14Rs in regulating lipid and glucose homeostasis. Metabolic studies indicate that the lack of adipocyte P2Y14R enhanced lipolysis only in the fasting state, decreased body weight, and improved glucose tolerance and insulin sensitivity. Mechanistic studies suggested that adipocyte P2Y14R inhibits lipolysis by reducing lipolytic enzyme activity, including ATGL and HSL. In agreement with these findings, agonist treatment of control mice with a P2Y14R agonist decreased lipolysis, an effect that was sensitive to inhibition by a P2Y14R antagonist. In conclusion, we demonstrate that adipose P2Y14Rs were critical regulators of whole-body glucose and lipid homeostasis, suggesting that P2Y14R antagonists might be beneficial for the therapy of obesity and T2D.

Spinal Cord Injury Reduces Serum Levels of Fibroblast Growth Factor-21 and Impairs Its Signaling Pathways in Liver and Adipose Tissue in Mice.

Spinal cord injury (SCI) results in dysregulation of carbohydrate and lipid metabolism; the underlying cellular and physiological mechanisms remain unclear. Fibroblast growth factor 21 (FGF21) is a circulating protein primarily secreted by the liver that lowers blood glucose levels, corrects abnormal lipid profiles, and mitigates non-alcoholic fatty liver disease. FGF21 acts via activating FGF receptor 1 and ß-klotho in adipose tissue and stimulating release of adiponectin from adipose tissue which in turn signals in the liver and skeletal muscle. We examined FGF21/adiponectin signaling after spinal cord transection in mice fed a high fat diet (HFD) or a standard mouse chow. Tissues were collected at 84 days after spinal cord transection or a sham SCI surgery. SCI reduced serum FGF21 levels and hepatic FGF21 expression, as well as β-klotho and FGF receptor-1 (FGFR1) mRNA expression in adipose tissue. SCI also reduced serum levels and adipose tissue mRNA expression of adiponectin and leptin, two major adipokines. In addition, SCI suppressed hepatic type 2 adiponectin receptor (AdipoR2) mRNA expression and PPARα activation in the liver. Post-SCI mice fed a HFD had further suppression of serum FGF21 levels and hepatic FGF21 expression. Elevated serum free fatty acid (FFA) levels after HFD feeding were observed in post-SCI mice but not in sham-mice, suggesting defective FFA uptake after SCI. Moreover, after SCI several genes that are implicated in insulin’s action had reduced expression in tissues of interest. These findings suggest that downregulated FGF21/adiponectin signaling and impaired responsiveness of adipose tissues to FGF21 may, at least in part, contribute to the overall picture of metabolic dysfunction after SCI.

P2Y 14 receptor regulates adipocyte lipid mobilization and whole‐body glucose homeostasis

The incidence and prevalence of obesity and type 2 diabetes (T2D) is rapidly increasing worldwide. Obesity is associated with chronically elevated plasma free fatty acid (FFA) levels, causing peripheral insulin resistance and T2D. Drugs that are able to regulate adipocyte lipolytic processes, improving insulin sensitivity and whole-body glucose homeostasis, have considerable therapeutic potential. Gi-coupled P2Y14 receptor (P2Y14R), activated by UDP-glucose is abundantly expressed in mouse and human adipocytes. P2Y14R activation in primary mouse adipocytes decreased cAMP levels and CL-316,243 (β3-adrenoceptor agonist) induced lipolysis. To investigate the physiological relevance of adipocyte P2Y14Rs in regulating lipid and glucose homeostasis in-vivo, we generated a mouse model lacking P2Y14R specifically in adipocytes. Lack of adipocyte P2Y14R increased lipolysis only in the fasting state, resulting in decreased body weight, improved glucose tolerance and insulin sensitivity. Accordingly, high fat diet increased, whereas fasting decreased P2Y14R expression in visceral white adipocytes. Mechanistic studies suggested that activation of P2Y14R reduced the activity of lipolytic enzymes including ATGL and HSL, thereby inhibiting lipolysis. Supporting these findings, administration of P2Y14R agonist in control mice decreased lipolysis. Coadministration of P2Y14R antagonist with the P2Y14R agonist rescued the decrease in lipolysis. In conclusion, we demonstrate that lack of adipocyte P2Y14R decreased diet-induced obesity by enhancing lipolysis in the fasting state, suggesting that P2Y14R antagonists may prove beneficial for the therapy of obesity and T2D.