Role Of Lipotoxicity Research Articles

Lipotoxicity-polarised macrophage-derived exosomes regulate mitochondrial fitness through Miro1-mediated mitophagy inhibition and contribute to type 2 diabetes development in mice.

Insulin resistance is a major pathophysiological defect in type 2 diabetes and obesity. Numerous experimental and clinical studies have provided evidence that sustained lipotoxicity-induced mitophagy deficiency can exacerbate insulin resistance, leading to a vicious cycle between mitophagy dysfunction and insulin resistance, and thereby the onset of type 2 diabetes. Emerging evidence suggests that exosomes (Exos) from M2 macrophages play an essential role in modulating metabolic homeostasis. However, how macrophages are affected by lipotoxicity and the role of lipotoxicity in promoting macrophage activation to the M1 state have not been determined. The objective of this study was to determine whether M1 macrophage-derived Exos polarised by lipopolysaccharide (LPS) + palmitic acid (PA)-induced lipotoxicity contribute to metabolic homeostasis and impact the development of insulin resistance in type 2 diabetes. Lipotoxicity-polarised macrophage-derived M1 Exos were isolated from bone marrow (C57BL/6J mouse)-derived macrophages treated with LPS+PA. Exos were characterised by transmission electron microscopy, nanoparticle tracking analysis and western blotting. Flow cytometry, H&E staining, quantitative real-time PCR, immunofluorescence, glucose uptake and output assays, confocal microscopy imaging, western blotting, GTTs and ITTs were conducted to investigate tissue inflammation, mitochondrial function and insulin resistance in vitro and in vivo. The roles of miR-27-3p and its target gene Miro1 (also known as Rhot1, encoding mitochondrial rho GTPase 1) and relevant pathways were predicted and assessed in vitro and in vivo using specific miRNA mimic, miRNA inhibitor, miRNA antagomir and siRNA. miR-27-3p was highly expressed in M1 Exos and functioned as a Miro1-inactivating miRNA through the miR-27-3p-Miro1 axis, leading to mitochondria fission rather than fusion as well as mitophagy impairment, resulting in NOD-like receptor 3 inflammatory activation and development of insulin resistance both in vivo and in vitro. Inactivation of miR-27-3p induced by M1 Exos prevented type 2 diabetes development in high-fat-diet-fed mice. These findings suggest that the miR-27-3p-Miro1 axis, as a novel regulatory mechanism for mitophagy, could be considered as a new therapeutic target for lipotoxicity-related type 2 diabetes disease development.

The role of lipotoxicity in cardiovascular disease

Abstract Fatty acids are the primary fuel for cardiac muscle. The physiological equilibrium of lipid uptake and oxidation may aid in the prevention of excessive lipid accumulation. Several pathological states, such as myocardial ischemia, obesity, and insulin resistance, are routinely associated with disorders of lipid metabolism. There is growing evidence that certain types of lipids trigger cardiac lipotoxicity and ultimately heart failure. This review focuses on recent advances in the pathogenesis of lipotoxic cardiomyopathy and the treatment prospects for the repair of cardiac damage caused by lipotoxicity.

PHYSIOLOGY AND ENDOCRINOLOGY SYMPOSIUM: Insulin action and lipotoxicity in the development of polycystic ovary syndrome: A review.

Polycystic ovary syndrome (PCOS) is a common condition affecting women of reproductive age. This disorder is characterized by hyperandrogenism and anovulation and is frequently associated with comorbidities such as infertility, metabolic syndrome, type 2 diabetes, and cardiovascular risk factors. Although the causes of PCOS are unknown, this review focuses on the most accepted theory involving insulin action but will also elaborate on a novel concept: the role of lipotoxicity in the development of androgen overproduction, in addition to its known role in insulin resistance. This review will also shed a spotlight on 2 drugs that target lipotoxicity and are, therefore, known or promising for the treatment of PCOS manifestations: peroxisome proliferator-activated receptor γ and angiotensin II type 2 receptor agonists. This paper, therefore, emphasizes the need to further explore the pathophysiology of PCOS and particularly the role of lipotoxicity. Indeed, this new mechanism deserves attention to develop therapeutic approaches that will directly target the root of this condition and not only bandage its associated consequences.

Follicular fluid concentrations of lipids and their metabolites are associated with intraovarian gonadotropin-stimulated androgen production in women undergoing in vitro fertilization.

Although growing evidence points toward a role of lipotoxicity in the development of hyperandrogenesis, the main feature of polycystic ovary syndrome, few studies directly assessed this association in vivo in humans, and none targeted the ovarian milieu. The main objective of this study was to correlate follicular fluid (FF) T levels with lipids, lipid metabolites, and inflammation markers. This was a cross-sectional study. Recruitment was performed in two fertility clinics at one private and one academic center. Eighty women requiring in vitro fertilization were recruited during one of their scheduled visit at the fertility clinic. All women aged between 18 and 40 years with a body mass index between 18 and 40 kg/m(2) were invited to participate. There were no interventions. At the time of oocyte aspiration, FF was collected and analyzed for total T, lipids [nonesterified fatty acids (NEFAs) plus triglycerides], NEFA metabolites (acylcarnitines; markers of ineffective NEFAs β-oxidation), and inflammatory marker composition. The hypothesis being tested was formulated before the data collection. FF T levels were significantly correlated with FF levels of lipids (r = 0.381, P = .001; independently of IL-6), acylcarnitines (r ≥ 0.255, all P = .008; not independently of lipids), and IL-6 (r = 0.300, P = .009, independently of lipids). Additionally, FF lipid levels were significantly and strongly correlated with acylcarnitines (r ≥ 0.594; all P < .001). These results suggest that ovarian androgen production is related to intraovarian exposure to lipids, independently of inflammation and mainly through ineffective NEFA β-oxidation (as shown by higher acylcarnitine levels). Inflammation is also associated with intraovarian androgenesis, independently of lipids.

The role of lipotoxicity in smoke cardiomyopathy.

Background/AimsExperimental and clinical studies have shown the direct toxic effects of cigarette smoke (CS) on the myocardium, independent of vascular effects. However, the underlying mechanisms are not well known.MethodsWistar rats were allocated to control (C) and cigarette smoke (CS) groups. CS rats were exposed to cigarette smoke for 2 months.ResultsAfter that morphometric, functional and biochemical parameters were measured. The echocardiographic study showed enlargement of the left atria, increase in the left ventricular systolic volume and reduced systolic function. Within the cardiac metabolism, exposure to CS decreased beta hydroxy acyl coenzyme A dehydrogenases and citrate synthases and increased lactate dehydrogenases. Peroxisome proliferator-activated receptor alpha (PPARα) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) were expressed similarly in both groups. CS increased serum lipids and myocardial triacylglycerols (TGs). These data suggest that impairment in fatty acid oxidation and the accumulation of cardiac lipids characterize lipotoxicity. CS group exhibited increased oxidative stress and decreased antioxidant defense. Finally, the myocyte cross-sectional area and active Caspase 3 were increased in the CS group.ConclusionThe cardiac remodeling that was observed in the CS exposure model may be explained by abnormalities in energy metabolism, including lipotoxicity and oxidative stress.

Role of lipotoxicity in insulin resistance in subtotally nephrectomized mouse model

Chronic kidney disease (CKD) is associated with a large range of metabolic alterations among which insulin resistance and dyslipidemia. We hypothesize that a phenomenon of lipotoxicity and ectopic fat redistribution could be responsible for the insulin-resistance associated to CKD. C57BL/6 mice underwent a 5/6 nephrectomy and were compared to pair fed sham-operated mice. Insulin sensitivity was estimated through intra-peritoneal insulin (ipITT) and glucose tolerance (ipGTT) tests. Anthropometric (body weight, lean and fad pad mass) and metabolic parameters (glycemia, insulin, cholesterol, triglycerides) were measured. The phosphorylation of a key protein of insulin signaling pathway (protein kinase B, PKB/Akt) was studied by Western blot. The intra-muscular and intra-hepatic lipids were extracted using Chloroform-Methanol (2:1, v/v). The CKD mice exhibited a marked decrease in insulin sensitivity (−76%, p p p p p In subtotally nephrectomized mouse model we showed an ectopic intramuscular and intrahepatic lipid redistribution concomitant with insulin resistance. Insulin resistance and lipotoxicity may represent the missing links (beyond the classical cardiovascular risk factors) that may help explain the increased risk of cardiovascular disease in CKD.

Metabolic characterization of volume overload heart failure due to aorto-caval fistula in rats

Metabolic interactions between adipose tissue and the heart may play an active role in progression of heart failure (HF). The aim of the study was to examine changes in myocardial and adipose tissue metabolism and gene expression in a rat HF model induced by chronic volume overload. HF was induced by volume overload from aorto-caval fistula (ACF) in 3-month-old male Wistar rats and animals were studied in the phase of decompensated HF (22nd week). HF rats showed marked eccentric cardiac hypertrophy, pulmonary congestion, increased LV end-diastolic pressure, and intraabdominal fat depletion. HF rats had preserved glucose tolerance, but increased circulating free fatty acids (FFA) and attenuated insulin response during oral glucose challenge. Isolated organ studies showed preserved responsiveness of adipose tissue lipolysis and lipogenesis to epinephrine and insulin in ACF. The heart of HF animals had markedly reduced triglyceride content (almost to half of controls), attenuated anti-oxidative reserve (GSH/GSSG), upregulated HF markers (ANP, periostin, thrombospondin-4), specific signaling pathways (Wnt, TGF-β), and downregulated enzymes of mitochondrial fatty acid oxidation, citric acid cycle, and respiratory chain. Adipose tissue transcription profiling showed upregulated receptor for gastric inhibitory polypeptide. In conclusion, ACF-induced HF model displays several deregulations of systemic metabolism. Despite elevation of systemic FFAs, myocardial triglycerides are low and insulin levels are attenuated, arguing against a role of lipotoxicity or insulin resistance in this model. Attenuated postprandial insulin response and relative lack of its antilipolytic effects may facilitate intraabdominal fat depletion observed in ACF-HF animals.

Increased cholesterol is vital to the development of coronary artery disease and type 2 diabetes in Ossabaw swine

Ossabaw swine fed excess kcal high fat/cholesterol diet develop metabolic syndrome. Many studies have linked a high‐fructose diet to development of metabolic syndrome without dyslipidemia. We tested the hypothesis that a high fructose diet will induce metabolic syndrome (MetS) and a high fructose/fat/cholesterol diet will induce more severe, dyslipidemic MetS (DMetS). We fed healthy, lean Ossabaw swine control chow (N=9), high fructose diet (MetS; N=8), or high fructose/fat/cholesterol diet (DMetS; N=6) for 28 weeks. Compared to lean pigs, both MetS and DMetS developed obesity, glucose intolerance, hypertriglyceridemia, and hypertension. However, increased cholesterol was seen only in DMetS compared to lean, while MetS was not different from lean. Importantly, DMetS developed type 2 diabetes, as evidenced by significantly increased fasting blood glucose and pancreatic beta‐cell failure (lack of both hyperinsulinemic response to intravenous glucose tolerance test and beta‐cell immunohistochemistry). Intravascular ultrasound revealed very minimal CAD in lean and MetS, but CAD in DMetS was occlusive and diffuse. In conclusion, although several risk factors for CAD are present in MetS Ossabaw swine, dyslipidemia is a crucial component in the development of type 2 diabetes and CAD. The data are consistent with a role of lipotoxicity. Support: NIH RR013223, HL062552.

Objetivos moleculares para diseñar nuevos fármacos para el tratamiento de la diabetes tipo 2 y la obesidad

Current strategies to treat type 2 diabetes (DMT2) include reducing insulin resistance using glitazones, supplementing with exogenous insulin, increasing endogenous insulin production with sulfonylureas and meglitinides, reducing hepatic glucose production through biguanides, and limiting postprandial glucose absorption with alpha-glucosidase inhibitors. In all of these areas, new generations of molecules with improved efficacy and safety profiles, are being investigated. Promising biological targets are rapidly emerging such as the role of lipotoxicity as a cause of glucometabolic insulin resistance, leading to a host of new molecular drug targets such as AMP-activated protein kinase (AMPK) activators, recombinant adiponectin derivatives, and fatty acid synthase (FAS) inhibitors. Insulin action can be enhanced in muscle, liver and fat, with small-molecule activators of the insulin receptor or inhibitors of protein tyrosine phosphatase (FTP)-IB. Defective glucose-stimulated insulin secretion by pancreatic B-cells could be alleviated with recombinant glucagon-like peptide (GLP-1) or agonists to the GLP-1 receptor. This review presents a new approach for obesity and DMT2 drug discovery through pharmacogenomics. Several compounds have already been validated through genetic engineering in animal models or the preliminary use of therapeutic compounds in humans.

Molecular targets for new drug discovery to treat type 2 diabetes and obesity

Current strategies to treat type 2 diabetes (DMT2) include reducing insulin resistance using glitazones, supplementing with exogenous insulin, increasing endogenous insulin production with sulfonylureas and meglitinides, reducing hepatic glucose production through biguanides, and limiting postprandial glucose absorption with alpha-glucosidase inhibitors. In all of these areas, new generations of molecules with improved efficacy and safety profiles, are being investigated. Promising biological targets are rapidly emerging such as the role of lipotoxicity as a cause of glucometabolic insulin resistance, leading to a host of new molecular drug targets such as AMP-activated protein kinase (AMPK) activators, recombinant adiponectin derivatives, and fatty acid synthase (FAS) inhibitors. Insulin action can be enhanced in muscle, liver and fat, with small-molecule activators of the insulin receptor or inhibitors of protein tyrosine phosphatase (FTP)-IB. Defective glucose-stimulated insulin secretion by pancreatic B-cells could be alleviated with recombinant glucagon-like peptide (GLP-1) or agonists to the GLP-1 receptor. This review presents a new approach for obesity and DMT2 drug discovery through pharmacogenomics. Several compounds have already been validated through genetic engineering in animal models or the preliminary use of therapeutic compounds in humans.