Free Fatty Acid Flux Research Articles

AN AYURVEDIC METHODOLOGY FOR MANAGING DIABETIC DYSLIPIDEMIA - A CASE REPORT

Diabetic dyslipidemia is characterized by elevated plasma triglyceride levels, decreased HDL cholesterol levels, and an increase in small dense LDL-cholesterol particles. These lipid alterations in diabetes are linked to heightened free fatty acid flux due to insulin resistance. With the availability of various lipid-lowering medications and supplements, patients now have more options to reach target lipid levels. Lipid-lowering therapies in modern medicine, such as statins and fibrates, are generally well-tolerated with minimal side effects. However, these treatments often necessitate lifelong usage, which can impose significant financial strain, particularly in developing countries like India.In Ayurveda, dyslipidemia is understood as the manifestation of an imbalance in the Medovahasrotas.Dyslipidemia manifests as the consequent output of Medovahasrotodushti. A 31-year-old male patient presented with complaints of pain in calf muscles and weight gain. Upon investigation, his total cholesterol level was found to be elevated at 211 mg/dl, and triglycerides were elevated to 683.80 mg/dl. Giloykwath along with arjunkwath, Madhunashinivati extra power, Tablet lipidom, and Tablet Madhugrit were administered for the shaman therapy. Upon completion of the treatment, significant improvements were observed in the patients complaints. Additionally, a significant improvement was noted in the Lipid Profile.

Albumin is an important factor in the control of serum free fatty acid flux in both male and female mice.

Albumin knockout (Alb-/-) mice exhibit a low plasma free fatty acid (FFA) concentration, but it was not known if the suppressed concentration reflects a lower rate of appearance (Ra) of FFA in the circulation (i.e., lower FFA flux) or if the absence of albumin alters the relationship between FFA flux and concentration. For understanding the role of albumin in FFA transport through the bloodstream, it is not sufficient to rely on FFA concentration data alone. Therefore, we developed a method to study FFA kinetics in Alb-/- mice. Using an albumin-free formulation of [U-13C]palmitate tracer, serum FFA kinetics were tested in Alb-/- and wild-type (WT) mice. Results indicate that the flux of FFA in serum of Alb-/- mice was significantly lower than in WT mice (P < 0.05), while albumin deficiency did not alter the relationship between FFA flux and concentration. Next, to test if suppressed lipolysis might have also been involved in the suppressed FFA kinetics, gene expression of a lipolytic enzyme (adipose triglyceride lipase, Atgl) and a marker of lipolysis (phosphorylation of hormone-sensitive lipase, p-HSL) were measured in adipose tissue. In contrast to the low FFA flux in Alb-/-, both Atgl gene expression and p-HSL protein were significantly higher in adipose tissue of Alb-/- than in WT mice (P < 0.05). Thus, the low FFA flux in Alb-/- appeared to be driven by the absence of albumin's FFA binding functions rather than through regulation of lipolysis, indicating that albumin is an important factor in determining the flux of FFA in circulation.NEW & NOTEWORTHY To improve understanding of the albumin protein's function in vivo, we tested plasma free fatty acid kinetics in albumin knockout mice compared with wild-type mice. Using a new tracer formulation strategy, it was discovered that the appearance rate of free fatty acids in serum is lower in albumin knockout mice than in wild-type mice. The results indicate that albumin is a major controller of free fatty acid kinetics.

Lipidomic analysis identifies long-chain acylcarnitine as a target for ischemic stroke

IntroductionLipid metabolism dysfunction is widely involved in the pathological process of acute ischemic stroke (AIS). The coordination of lipid metabolism between neurons and astrocytes is of great significance. However, the full scope of lipid dynamic changes and the function of key lipids during AIS remain unknown. Hence, identifying lipid alterations and characterizing their key roles in AIS is of great importance. MethodsUntargeted and targeted lipidomic analyses were applied to profile lipid changes in the ischemic penumbra and peripheral blood of transient middle cerebral artery occlusion (tMCAO) mice as well as the peripheral blood of AIS patients. Infarct volume and neurological deficits were assessed after tMCAO. The cell viability and dendritic complexity of primary neurons were evaluated by CCK8 assay and Sholl analysis. Seahorse, MitoTracker Green, tetramethyl rhodamine methyl ester (TMRM), 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSOX were used as markers of mitochondrial health. Fluorescent and isotopic free fatty acid (FFA) pulse-chase assays were used to track FFA flux in astrocytes. ResultsLong-chain acylcarnitines (LCACs) were the lipids with the most dramatic changes in the ischemic penumbra and peripheral blood of tMCAO mice. LCACs were significantly elevated on admission in AIS patients and associated with poor outcomes in AIS patients. Increasing LCACs through a bolus administration of palmitoylcarnitine amplified stroke injury, while decreasing LCACs by overexpressing carnitine palmitoyltransferase 2 (CPT2) ameliorated stroke injury. Palmitoylcarnitine aggravated astrocytic mitochondrial damage after OGD/R, while CPT2 overexpression in astrocytes ameliorated cocultured neuron viability. Further study revealed that astrocytes stimulated by OGD/R liberated FFAs from lipid droplets into mitochondria to form LCACs, resulting in mitochondrial damage and lowered astrocytic metabolic support and thereby aggravated neuronal damage. ConclusionLCACs could accumulate and damage neurons by inducing astrocytic mitochondrial dysfunction in AIS. LCACs play a crucial role in the pathology of AIS and are novel promising diagnostic and prognostic biomarkers for AIS.

To evaluate the efficacy and safety profile of rosuvastatin, simvastatin and atorvastatin in newly diagnosed type 2 diabetic patients with dyslipidaemia

Dyslipidemia is one of the major risk factors for cardiovascular disease in diabetes mellitus. The lipid changes associated with diabetes mellitus are attributed to increased free fatty acid flux secondary to insulin resistance. Newly diagnosed 90 cases of patients of Type II Diabetes Mellitus well controlled on oral hypoglycemic drugs were randomly divided into 3 groups of 30 each. The mean difference of Triglycerides between baseline versus after 6 months was 65.04 mg/dl in Group A, 39.99 mg/dl in Group B and 37.04 mg/dl in Group C. The mean difference of HDL between baseline versus after 6 months was 10.04 mg/dl in Group A, 10.26 mg/dl in Group B and 9.13 mg/dl in Group C. The mean difference of LDL between baseline versus after 6 months was 79.4 mg/dl in Group A, 67.6 mg/dl in Group B and 33.82 mg/dl in Group C. The mean difference of VLDL between baseline versus after 6 months was 13.01 mg/dl in Group A, 7.58 mg/dl in Group B and 7.41 mg/dl in Group C.

Evaluate the efficacy and safety profile of Rosuvastatin, Simvastatin and Atorvastatin in newly diagnosed type 2 diabetic patients with dyslipidaemia

Dyslipidemia is one of the major risk factors for cardiovascular disease in diabetes mellitus. The lipid changes associated with diabetes mellitus are attributed to increased free fatty acid flux secondary to insulin resistance. This is prospective, comparative, open label, randomized and parallel group. The subjects enrolled for this study were selected from the Out-Patient Department of Medicine collaboration with Department of Pharmacology, Tertiary care teaching hospital over a period of month. Newly diagnosed 90 cases of patients of Type II Diabetes Mellitus well controlled on oral hypoglycemic drugs were randomly divided into 3 groups of 30 each. Group A was received Rosuvastain 10 mg O.D for 3 months, Group B: Simvastatin 10 mg O.D and Group C was received Atrovastatin 10 mg O.D. In Group ‘A’ the mean difference of Total Cholesterol between baseline versus after 6 months was 82.37 mg/dl, 64.92 mg/dl and 52.23 mg/dl in Group B and Group C respectively. The mean difference of Triglycerides between baseline versus after 6 months was 65.04 mg/dl in Group A, 39.99 mg/dl in Group B and 37.04 mg/dl in Group C.

Metabolic dysfunction associated fatty liver disease (MAFLD) and serum vitamin D concentration in South Korea.

Non-alcoholic fatty liver disease (NAFLD) has recently been renamed as metabolic dysfunction-associated fatty liver disease (MAFLD) by the Asian Pacific Association for the Study of the Liver (APASL) to reflect metabolic dysfunction. Vitamin D regulates free fatty acid flux from the periphery to the liver. The association MAFLD and vitamin D has been controversial. We investigated the association of MAFLD, nutrient intake, and vitamin D status in South Korean adults. We analyzed patient responses from the Korea National Health and Nutrition Examination survey (KNHANES) 2010-2011. The disease group was selected as per the latest guidelines. Steatosis was evaluated by the fatty liver index (FLI). Frequency analysis was performed on general characteristics. We compared differences in nutritional status using complex sample adjusted chi-square tests and generalized linear models. After adjusting for age, complex sample logistic regression analysis was used to examine the relationship between MAFLD and vitamin D. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), LDL, triglyceride, creatinine, glucose, nutrient intake, and serum 25(OH)D concentrations were significantly elevated while HDL was reduced in the disease group than in the control group. The OR for 25(OH)D was 1.015 (95% CI: 1.004-1.026, p<0.0001). However, MAFLD presented no significant association with vitamin D concentration (OR 1.010, 95% CI: 0.985-1.037, p=0.431) after adjusting for age. We found no significant relationship between MAFLD and serum vitamin D concentration in South Korean adults.

Study to find out the significance of postprandial dyslipidemia in diabetic patients

: Diabetes Mellitus (DM) is a group of metabolic diseases, which is characterized by chronic hyperglycaemia, which results from the defects in the insulin action, insulin secretion or both. The most prevalent form of the disease, type 2 Diabetes Mellitus is often asymptomatic in the early stages and it may remain undiagnosed for many years.The insulin resistance in the liver leads to failure of the hyperinsulinaemia to suppress the gluconeogenesis, which increases fasting glucose levels and decreases. glycogen storage by the liver in the postprandial phase. Increased glucose production in the liver occurs early in the course of diabetes, and it is likely in skeletal muscles after the onset of the insulin secretory abnormalities and the insulin resistance. Due to the insulin resistance in the adipose tissue and obesity, the free fatty acid (FFA) flux from the adipocytes is increased, which in turn leads to an increase in lipid [very low-density lipoprotein (VLDL) and triglycerides] synthesis in the hepatocytes. This is responsible for the dyslipidaemia which is found in type2 diabetes mellitus [elevated triglycerides, reduced HDL, and increased low-density lipoprotein (LDL) particlesIndividuals with type 2 diabetes mellitus are at increased risk of developing microvascular and macrovascular complications.: To find out the significance of postprandial dyslipidemia in diabetic patients.: This is a cross-sectional study, wherein written informed consent was taken after giving detailed information to the participants regarding the study. Patients who were in the age group of 35-65 years, admitted in the Department of Medicine, RRMCH from November 2017 for next 18 months with Diabetes Mellitus who met a predefined inclusion and exclusion criteria were studied. The study was initiated after obtaining clearance from the institution's ethical committee.: There was a significant elevation of mean values of total serum cholesterol, LDL and TG of cases and controls in the postprandial state compared to their fasting state, statistical significance was found (P&amp;#60;0.05).Mean values of total serum cholesterol, LDL and TG of cases in fasting state were significantly more compared to controls in fasting state, statistical significance was found (P&amp;#60;0.05).Mean values of total serum cholesterol, LDL and TG of cases in the postprandial state were significantly more compared to controls in the postprandial state, statistical significance was found (P&amp;#60;0.05).Mean values of both FBS and PPBS in cases were higher compared to controls (P&amp;#60;0.05). Mean values of PPBS in cases and controls were significantly more compared to their respective FBS values (P&amp;#60;0.05).The mean HbA1c values in cases were higher(7.142) compared to controls (5.554).: Prevalence of diabetes was highest in the age group 56-65 years in our hospital.As the duration of diabetes increases, there is an increased prevalence of dyslipidemia in the cases.Past history of HTN, IHD, PVD and CVA were found significantly more in subjects with fasting and postprandial dyslipidemia (cases) compared to those without(controls).Patients on irregular treatment (63%) were more in the study group(cases) compared to controls. So it could be said that patient not on regular treatment are more prone to have dyslipidemia. (fasting as well as postprandial). There was a significant increase in total serum cholesterol, LDL and TG in postprandial states of cases compared to that in controls, so it could be said that diabetic patients with fasting dyslipidemia are more prone to have dyslipidemia in the postprandial state.

Correlation of fasting and postprandial dyslipidemia with macrovascular complications of diabetes mellitus

: The most prevalent form of the disease, type 2 Diabetes Mellitus is often asymptomatic in the early stages and it may remain undiagnosed for many years.The insulin resistance in the liver leads to failure of the hyperinsulinaemia to suppress the gluconeogenesis, which increases fasting glucose levels and decreases Postprandial hypertriglyceridemia results in a proatherogenic environment which leads to atherosclerosis and macrovascular complications in type 2 diabetes mellitus. It is believed that atherosclerosis is a postprandial phenomenon with respect to lipids, as we are in the postprandial state for most of the day. Increased glucose production in the liver occurs early in the course of diabetes, and it is likely in skeletal muscles after the onset of the insulin secretory abnormalities and the insulin resistance Due to the insulin resistance in the adipose tissue and obesity, the free fatty acid (FFA) flux from the adipocytes is increased, which in turn leads to an increase in lipid [very low-density lipoprotein (VLDL) and triglycerides] synthesis in the hepatocytes. This is responsible for the dyslipidaemia which is found in type2 diabetes mellitus [elevated triglycerides, reduced HDL, and increased low-density lipoprotein (LDL) particle.Individuals with type 2 diabetes mellitus are at increased risk of developing microvascular and macrovascular complications. Increased postprandial glucose (PPG) concentrations contribute to suboptimal glycemic control. : To correlate fasting and postprandial dyslipidemia with macrovascular complications of diabetes.: This is a cross-sectional study, wherein written informed consent was taken after giving detailed information to the participants regarding the study. Patients who were in the age group of 35-65 years, admitted in the Department of Medicine, RRMCH from November 2017 for next 18 months with Diabetes Mellitus who met a predefined inclusion and exclusion criteria were studied. The study was initiated after obtaining clearance from the institution's ethical committee.: IHD changes were found in 8 cases and 3 controls, LVH by voltage criteria was found in 15 cases and 8 controls. IHD changes found in cases and controls are 16% and 6% respectively. LVH changes found in cases and controls are 30% and 16% respectively.Abnormal 2D Echo findings in our study were mainly IHD and LVH. The occurrence of IHD was more in cases compared to controls with statistical significance(p&amp;#60;0.05).Peripheral vascular disease in our study was found in 25 patients i.e.25% of the study group. In cases, it was found in 20 patients and in controls, it was found in 5 patients i.e. 40% and 10% respectively. The occurrence of PVD was more in cases compared to controls with statistical significance(p&amp;#60;0.05).Stroke in our study is found in 7 patients i.e. 7% of the study group. In cases, it was found in 6 patients and in controls, it was found in 1 patient i.e. 12% and 2% respectively. : It could be said that there is an increase in the occurrence of postprandial dyslipidemia with increasing age, irregular treatment, increase in HbA1c, FBS ,PPBS and with the past history of HTN, CVA, PVD and IHD.All macrovascular complications (IHD, CVA, PVD) were found more in the case compared to controls with statistical significance. So it could be said that there is an increase in the occurrence of macrovascular complications with an increase in postprandial dyslipidemia.

Fatty Acid Production and Direct Acyl Transfer through Polar Lipids Control TAG Biosynthesis during Nitrogen Deprivation in the Halotolerant Alga Dunaliella tertiolecta.

The aims of this work were to evaluate the contribution of the free fatty acid (FA) pool to triacylglyceride (TAG) biosynthesis and to try to characterize the mechanism by which FA are assimilated into TAG in the green alga Dunaliella tertiolecta. A time-resolved lipidomic analysis showed that nitrogen (N) deprivation induces a redistribution of total lipidome, particularly of free FA and major polar lipid (PL), in parallel to enhanced accumulation of polyunsaturated TAG. The steady-state concentration of the FA pool, measured by prolonged 14C-bicarbonate pre-labeling, showed that N deprivation induced a 50% decrease in total FA level within the first 24 h and up to 85% after 96 h. The abundance of oleic acid increased from 50 to 70% of total free FA while polyunsaturated FA (PUFA) disappeared under N deprivation. The FA flux, measured by the rate of incorporation of 14C-palmitic acid (PlA), suggests partial suppression of phosphatidylcholine (PC) acyl editing and an enhanced turnover of the FA pool and of total digalactosyl-diacylglycerol (DGDG) during N deprivation. Taken together, these results imply that FA biosynthesis is a major rate-controlling stage in TAG biosynthesis in D. tertiolecta and that acyl transfer through PL such as PC and DGDG is the major FA assimilation pathway into TAG in that alga and possibly in other green microalgae. Increasing the availability of FA could lead to enhanced TAG biosynthesis and to improved production of high-value products from microalgae.

Comparison of Non-Fasting and Fasting Lipid Profile in Dyslipidemia Patients

Dyslipidemia, a metabolic syndrome characteristic, includes increased flux of free fatty acids, high densitylipoprotein cholesterol, low-density lipoprotein, and triglycerides. One of the main topics of screening andmanagement in adult and child populations has been dyslipidemiaThe aim of this study was to evaluate non-fasting and fasting when measuring the lipid profile of patientswith dyslipidemia.This study was performed 80 male of dyslipidemia patients, they were monitored and their lipid profilelevels measured during non- fasting were collected after 2 hours of meal, and varying hours of fastingperiods includes (4 hours, 6 hours, and 8 hours).In this study we did not found any significant clinical difference between non-fasting and fasting levels oftotal cholesterol, and low-density lipoprotein and high-density lipoprotein. Thus, we can use the non-fastingblood samples to estimate lipid profile in follow-up the dyslipidemia patients. When comparing the fastinghours, we observed mean triglyceride for all period of fasting were differences, as compared to the nonefforts fasting state significant differences P&lt; 0.001Finally, there is no need to make fasting lipid profile mandatory. This study suggests that should be made tosimplify the sampling of blood by replacing the profile of fasting lipids with the profile of non-fasting lipids.

Liver-specific dysregulation of clock-controlled output signal impairs energy metabolism in liver and muscle

The liver is the major organ maintaining metabolic homeostasis in animals during shifts between fed and fasted states. Circadian oscillations in peripheral tissues including the liver are connected with feeding-fasting cycles. We generated transgenic mice with hepatocyte specific E4BP4, D-box negative regulator, overexpression. Liver-specific E4BP4 overexpression was also achieved by adenoviral gene transfer. Interestingly, hepatic E4BP4 overexpression induced marked insulin resistance, that was rescued by DBP, a competing D-box positive regulator, overexpression. At basal conditions hepatocyte E4BP4 transgenic mice exhibited increased gluconeogenesis with reduced AKT phosphorylation in liver. In muscle, AKT phosphorylation was impaired after insulin stimulation. Such muscle insulin resistance was associated with elevated free fatty acid flux from the liver and reduced fatty acid utilization as an energy source during the inactive phase. E4BP4, one of the clock-controlled output genes, are key metabolic regulators in liver adjusting liver and muscle metabolism and insulin sensitivity in the feeding-fasting cycles. Its tuning is critical for preventing metabolic disorders.

Dyslipidemia and Its Associated Risk Factors Among Adult Type-2 Diabetic Patients at Jimma University Medical Center, Jimma, Southwest Ethiopia.

BackgroundDyslipidemia is one of the major modifiable risk factors for cardiovascular diseases (CVD) in a type-2 diabetic (T2DM) patient. Dyslipidemia in T2DM patients is attributed due to increased free fatty acid flux secondary to insulin resistance. Despite its high prevalence and related complication of dyslipidemia in T2DM patients, there is a paucity of data on the prevalence of dyslipidemia in T2DM patients in Ethiopia.ObjectiveTo determine the prevalence of dyslipidemia and its associated risk factors among T2DM patients at Jimma medical center (JUMC) Jimma, Ethiopia.Methods and MaterialsAn institution-based- cross-sectional study was conducted from June 1 to August 4, 2019. A convenience sampling technique was used to recruit 248 T2DM patients in the study. Data on socio-demographic characteristics, behavioral, and clinical factors were collected using a structured questionnaire through face to face interviews. Five milliliters of the fasting venous blood sample was collected for serum glucose and lipid profile analysis. Blood pressure, weight, and height were measured. Data were analyzed by SPSS version 21. Bivariate and multivariate logistic regression analyses were performed and p-value <0.05 was considered as statistically significant.ResultsThe overall prevalence of dyslipidemia among study participants was 68.1%. Isolated lipid profile abnormality of hypertriglyceridemia was found in 48%, hypercholesterolemia in 13.7%, high level of low-density lipoprotein (LDL-C) in 28.6%, and low level of high-density lipoprotein (HDL-C) in 50.8% study participants. Being in an age group ≥30 years, physical inactivity, being obese, hypertension, and high blood glucose value were significantly associated factors with dyslipidemia.ConclusionHigh prevalence of dyslipidemia was found among T2DM in the study area. The findings of this study should be taken into account to conduct appropriate intervention measures on the identified risk factor, and implement routine screening, treatments, and prevention of dyslipidemia.

Slc43a3 is a regulator of free fatty acid flux

Adipocytes take up long chain FAs through diffusion and protein-mediated transport, whereas FA efflux is considered to occur by diffusion. To identify potential membrane proteins that are involved in regulating FA flux in adipocytes, the expression levels of 55 membrane transporters without known function were screened in subcutaneous adipose samples from obese patients before and after bariatric surgery using branched DNA methodology. Among the 33 solute carrier (SLC) transporter family members screened, the expression of 14 members showed significant changes before and after bariatric surgery. One of them, Slc43a3, increased about 2.5-fold after bariatric surgery. Further investigation demonstrated that Slc43a3 is highly expressed in murine adipose tissue and induced during adipocyte differentiation in primary preadipocytes and in OP9 cells. Knockdown of Slc43a3 with siRNA in differentiated OP9 adipocytes reduced both basal and forskolin-stimulated FA efflux, while also increasing FA uptake and lipid droplet accumulation. In contrast, overexpression of Slc43a3 decreased FA uptake in differentiated OP9 cells and resulted in decreased lipid droplet accumulation. Therefore, Slc43a3 seems to regulate FA flux in adipocytes, functioning as a positive regulator of FA efflux and as a negative regulator of FA uptake.

Nanoformulated SOD1 ameliorates the combined NASH and alcohol-associated liver disease partly via regulating CYP2E1 expression in adipose tissue and liver

Enhanced free fatty acid (FFA) flux from adipose tissue (AT) to liver plays an important role in the development of nonalcoholic steatohepatitis (NASH) and alcohol-associated liver disease (AALD). We determined the effectiveness of nanoformulated superoxide dismutase 1 (Nano) in attenuating liver injury in a mouse model exhibiting a combination of NASH and AALD. Male C57BL6/J mice were fed a chow diet (CD) or a high-fat diet (HF) for 10 wk followed by pair feeding of the Lieber-DeCarli control (control) or ethanol (ET) diet for 4 wk. Nano was administered once every other day for the last 2 wk of ET feeding. Mice were divided into 1) CD + control diet (CD + Cont), 2) high-fat diet (HF) + control diet (HF + Cont), 3) HF + Cont + Nano, 4) HF + ET diet (HF + ET), and 5) HF + ET + Nano. The total fat mass, visceral AT mass (VAT), and VAT perilipin 1 content were significantly lower only in HF + ET-fed mice but not in HF + ET + Nano-treated mice compared with controls. The HF + ET-fed mice showed an upregulation of VAT CYP2E1 protein, and Nano abrogated this effect. We noted a significant rise in plasma FFAs, ALT, and monocyte chemoattractant protein-1 in HF + ET-fed mice, which was blunted in HF + ET + Nano-treated mice. HF + ET-induced increases in hepatic steatosis and inflammatory markers were attenuated upon Nano treatment. Nano reduced hepatic CYP2E1 and enhanced catalase levels in HF + ET-fed mice with a concomitant increase in SOD1 protein and activity in liver. Nano was effective in attenuating AT and liver injury in mice exhibiting a combination of NASH and AALD, partly via reduced CYP2E1-mediated ET metabolism in these organs.NEW & NOTEWORTHY Increased free fatty acid flux from adipose tissue (AT) to liver accompanied by oxidative stress promotes nonalcoholic steatohepatitis (NASH) and alcohol-associated liver injury (AALD). Obesity increases the severity of AALD. Using a two-hit model involving a high-fat diet and chronic ethanol feeding to mice, and treating them with nanoformulated superoxide dismutase (nanoSOD), we have shown that nanoSOD improves AT lipid storage, reduces CYP2E1 in AT and liver, and attenuates the combined NASH/AALD in mice.

Emerging Mechanisms of GH-Induced Lipolysis and Insulin Resistance.

Growth hormone (GH) is a pleiotropic hormone that coordinates an array of physiological processes including growth and metabolism. GH promotes anabolic action in all tissues except adipose, where it catabolizes stored fat to release energy for the promotion of growth in other tissues. However, chronic stimulation of lipolysis by GH results in an increased flux of free fatty acids (FFAs) into systemic circulation. Hence, a sustained release of high levels of GH contributes significantly to the development of insulin resistance by antagonizing the anti-lipolytic action of insulin. The molecular pathways associated with the lipolytic effect of GH in adipose tissue however, remain elusive. Recent studies have provided molecular insights into GH-induced lipolysis and impairment of insulin signaling. This review discusses the physiological and metabolic actions of GH on adipose tissue as well as GH-mediated deregulation of the FSP27-PPARγ axis which alters adipose tissue homeostasis and contributes to the development of insulin resistance and Type 2 diabetes.

Crosstalk between nonalcoholic fatty liver disease and cardiometabolic syndrome.

Nonalcoholic fatty liver disease (NAFLD) is a chronic condition characterized by fat accumulation combined with low-grade inflammation in the liver. A large body of clinical and experimental data shows that increased flux of free fatty acids from increased visceral adipose tissue and de novo lipogenesis can lead to NAFLD and insulin resistance. Thus, individuals with obesity, insulin resistance, and dyslipidaemia are at the greatest risk of developing NAFLD. Conversely, NAFLD is a phenotype of cardiometabolic syndrome. Notably, researchers have discovered a close association between NAFLD and impaired glucose metabolism and focused on the role of NAFLD in the development of type 2 diabetes. Moreover, recent studies provide substantial evidence for an association between NAFLD and atherosclerosis and cardiometabolic disorders. Even if NAFLD can progress into severe liver disorders including nonalcoholic steatohepatitis (NASH) and cirrhosis, the majority of subjects with NAFLD die from cardiovascular disease eventually. In this review, we propose a potential pathological link between NAFLD/NASH and cardiometabolic syndrome. The potential factors that can play a pivotal role in this link, such as inflammation, insulin resistance, alteration in lipid metabolism, oxidative stress, genetic predisposition, and gut microbiota are discussed.

Alterations in branched-chain amino acid kinetics in nonobese but insulin-resistant Asian men

Branched-chain amino acids (BCAAs) are elevated in the insulin-resistant (IR) state. The reasons for this increase remain unclear, but it may be related to abnormalities in BCAA metabolism and free fatty acid (FFA) metabolism. In this study, we quantified BCAA and FFA kinetics of IR and insulin-sensitive (IS) nonobese Asian men with the use of stable-isotope tracers. We hypothesized that in addition to greater substrate flux, the BCAA oxidative pathway is also impaired to account for the higher plasma BCAA concentration in the IR state. We recruited 12 IR and 14 IS nonobese and healthy Asian men. Oral-glucose-tolerance tests (OGTTs) were performed to quantify insulin sensitivity, and subjects underwent 2 stable-isotope infusion studies. [U-13C6]Leucine was infused to measure leucine flux and oxidation as indexes of BCAA metabolism, whereas [U-13C16]palmitate was infused to measure palmitate flux and oxidation to represent FFA metabolism, The 2H2O dilution method was used to estimate body composition. IR subjects had greater adiposity and significantly higher fasting and post-OGTT glucose and insulin concentrations compared with the IS group. However, none of the subjects were diabetic. Despite similar dietary protein intake, IR subjects had a significantly higher plasma BCAA concentration and greater leucine flux. Leucine oxidation was also greater in the IR group, but the relation between leucine oxidation and flux was significantly weaker in the IR group than in the IS group (r=0.530 compared with0.695, P<0.0388 for differences between slope). FFA oxidation was, however, unaffected despite higher FFA flux in the IR group. The higher plasma BCAA concentration in healthy nonobese individuals with IR is associated with a weaker relation between BCAA oxidation and BCAA flux and this occurs in the presence of accelerated FFA flux and oxidation.

Luteolin Targets the Toll-Like Receptor Signaling Pathway in Prevention of Hepatic and Adipocyte Fibrosis and Insulin Resistance in Diet-Induced Obese Mice.

This study was to investigate the protective role of luteolin on inflammation-mediated metabolic diseases, focusing on the role of luteolin in the modulation of the Toll-like receptor (TLR) signaling pathway. C57BL/6J mice were fed a normal, high-fat, or high-fat + 0.005% (w/w) luteolin diet for 16 weeks. Luteolin improved chronic low-grade inflammation by modulating the TLR signaling pathway, resulting in reduced pro-inflammatory cytokines and macrophage accumulation. A positive relationship was detected between gene expressions of Tlr5, Map2k7, Mapk12, Mapk13, and Mapk9 and lipogenesis in epididymal white adipose tissue (eWAT) of luteolin-treated mice, which was linked to attenuation of hepatic lipotoxicity by increasing free fatty acid (FFA) flux to the WAT. Luteolin prevented fibrosis by decreasing extracellular matrix accumulation and cathepsin gene expressions, while enhancing the hepatic antioxidant system. Emr1 and Ccl7, important markers inducing low-grade inflammation, were affected by advanced age and greater body weight, which were normalized by luteolin treatment. Luteolin improved insulin resistance by normalizing pancreatic islet dysfunction and differentially modulating the plasma glucagon-like peptide-1 and gastric inhibitory polypeptide levels. Our results suggest that luteolin ameliorates diet-induced obesity and its comorbidities. Overall, this study provides novel insights into the effect of luteolin on the links among adiposopathy, insulin resistance, hepatic steatosis, and fibrosis.

Uncoupling proteins as a therapeutic target to protect the diabetic heart.

Myocardial remodeling and dysfunction caused by accelerated oxidative damage is a widely reported phenomenon within a diabetic state. Altered myocardial substrate preference appears to be the major cause of enhanced oxidative stress-mediated cell injury within a diabetic heart. During this process, exacerbated free fatty acid flux causes an abnormal increase in mitochondrial membrane potential leading to the overproduction of free radical species and subsequent cell damage. Uncoupling proteins (UCPs) are expressed within the myocardium and can protect against free radical damage by modulating mitochondrial respiration, leading to reduced production of reactive oxygen species. Moreover, transgenic animals lacking UCPs have been shown to be more susceptible to oxidative damage and display reduced cardiac function when compared to wild type animals. This suggests that tight regulation of UCPs is necessary for normal cardiac function and in the prevention of diabetes-induced oxidative damage. This review aims to enhance our understanding of the pathophysiological mechanisms relating to the role of UCPs in a diabetic heart, and further discuss known pharmacological compounds and hormones that can protect a diabetic heart through the modulation of UCPs.

FSP27-Rab18-Vimentin Regulates Lipid Droplet Trafficking and Insulin Signaling in Adipocytes

Increased free fatty acid flux from white adipocytes exacerbates insulin resistance and increases the risk of its progression to type 2 diabetes. Distinct intracellular organelles called lipid droplets (LDs) in adipocytes play a key role in storing fatty acids (FAs) as triglycerides (TGs), hence protecting against FA-induced lipotoxicity. A highly coordinated cascade of LD-associated proteins and lipases is known to regulate the catabolism of stored TGs in LDs, but the molecular components of LDs that determine their dynamics and TG storing capacity in adipocytes remains understudied. Previously, we showed that Fat specific protein 27 (FSP27) is a lipid droplet associated protein that is positively associated with insulin sensitivity in humans, and plays a crucial role in lipid droplet dynamics by clustering and then fusion of LDs. The present investigation was designed to identify the molecular mechanism through which FSP27 mediates LD trafficking to regulate the initial step of LD clustering—a prerequisite of LD fusion. We found that a direct interaction between FSP27, Vimentin and Rab18, and FSP27-mediated activation of Rab18 GTPase activity is important for lipid droplet trafficking. Our results reveal a complex bi-directional cross-talk that takes place between LD-associated proteins and cytoskeletal elements that maintain lipid droplet dynamics in a highly organized manner. Our study provides a new insight in the regulation of LD dynamics and insulin signaling in adipocytes. Disclosure V. Puri: None. S. Banerjee: None. S. Jash: None.