lipid-a and Obesity

Several studies have implicated obesity-induced macrophage-adipocyte cross-talk in adipose tissue dysfunction and insulin resistance. However, the molecular cues involved in the cross-talk of macrophage and adipocyte causing insulin resistance are currently unknown. Here, we found that a lipid-induced monokine cyclophilin-A (CyPA) significantly attenuates adipocyte functions and insulin sensitivity. Targeted inhibition of CyPA in diet-induced obese zebrafish notably reduced adipose tissue inflammation and restored adipocyte function resulting in improvement of insulin sensitivity. Silencing of macrophage CyPA or pharmacological inhibition of CyPA by TMN355 effectively restored adipocytes' functions and insulin sensitivity. Interestingly, CyPA incubation markedly increased adipocyte inflammation along with an impairment of adipogenesis, however, mutation of its cognate receptor CD147 at P309A and G310A significantly waived CyPA's effect on adipocyte inflammation and its differentiation. Mechanistically, CyPA-CD147 interaction activates NF-κB signaling which promotes adipocyte inflammation by upregulating various pro-inflammatory cytokines gene expression and attenuates adipocyte differentiation by inhibiting PPARγ and C/EBPβ expression via LZTS2-mediated downregulation of β-catenin. Moreover, inhibition of CyPA or its receptor CD147 notably restored palmitate or CyPA-induced adipose tissue dysfunctions and insulin sensitivity. All these results indicate that obesity-induced macrophage-adipocyte cross-talk involving CyPA-CD147 could be a novel target for the management of insulin resistance and type 2 diabetes.

Topics: Adipose Tissue; Animals; Cyclophilin A; Cyclophilins; Diabetes Mellitus, Type 2; Inflammation; Insulin Resistance; Lipid A; Mice; Monokines; Obesity; Zebrafish

The identification of a functional molecular moiety relating the lipopolysaccharides (LPSs) to their capacity to induce inflammation-mediated metabolic diseases needed to be performed. We previously described a proportional increase in the relative abundance of the 16 SrDNA bacterial gene from the genus Ralstonia, within the microbiota from the adipose tissue stroma vascular fraction of obese patients, suggesting a causal role of the bacteria. Therefore, we first characterized the structures of the lipids A, the inflammatory inducing moieties of LPSs, of three Ralstonia species: Ralstonia eutropha, R. mannitolilytica and R. pickettii, and then compared each, in terms of in vitro inflammatory capacities. R. pickettii lipid A displaying only 5 Fatty Acids (FA) was a weaker inducer of inflammation, compared to the two other species harboring hexa-acylated lipids A, despite the presence of 2 AraN substituents on the phosphate groups. With regard to in vitro pro-inflammatory activities, TNF-α and IL-6 inducing capacities were compared on THP-1 cells treated with LPSs isolated from the three Ralstonia. R. pickettii, with low inflammatory capacities, and recently involved in nosocomial outcomes, could explain the low inflammatory level reported in previous studies on diabetic patients and animals. In addition, transmission electron microscopy was performed on the three Ralstonia species. It showed that the R. pickettii under-acylated LPSs, with a higher level of phosphate substitution had the capacity of producing more outer membrane vesicles (OMVs). The latter could facilitate transfer of LPSs to the blood and explain the increased low-grade inflammation observed in obese/diabetic patients.

Topics: Cytokines; Humans; Inflammation; Lipid A; Obesity; Ralstonia; Structure-Activity Relationship; THP-1 Cells

Obesity-induced myocardial fibrosis may lead to diastolic dysfunction and ultimately heart failure. Activation of the transforming growth factor (TGF)-βl and its downstream Smad2/3 pathways may play a pivotal role in the pathogenesis of obesity-induced myocardial fibrosis, and the antidiabetic dipeptidyl peptidase 4 inhibitors (DPP4i) might affect these pathways. We investigated whether DPP4i reduces myocardial fibrosis by inhibiting the TGF-β1 and Smad2/3 pathways in the myocardium of a diet-induced obesity (DIO) rat model. Eight-week-old male spontaneously hypertensive rats (SHRs) were fed either a normal fat diet (chow) or a high-fat diet (HFD) and then the HFD-fed SHRs were randomized to either the DPP4i (MK-0626) or control (distilled water) groups for 12weeks. At 20weeks old, all the rats underwent hemodynamic and metabolic studies and Doppler echocardiography. Compared with the normal fat diet (chow)-fed SHRs, the HFD-fed SHRs developed a more intense degree of hyperglycemia and dyslipidemia and showed a constellation of left ventricular (LV) diastolic dysfunction, and exacerbated myocardial fibrosis, as well as activation of the TGF-β1 and Smad2/3 pathways. DPP4i significantly improved the metabolic and hemodynamic parameters. The echocardiogram showed that DPP4i improved the LV diastolic dysfunction (early to late ventricular filling velocity [E/A] ratio, 1.49±0.21 vs. 1.77±0.09, p<0.05). Furthermore, DPP4i significantly reduced myocardial fibrosis and collagen production by the myocardium and suppressed TGF-β1 and phosphorylation of Smad2/3 in the heart. In addition, DPP4i decreased TGF-β1-induced collagen production and TGF-β1-mediated phosphorylation and nuclear translocation of Smad2/3 in rat cardiac fibroblasts. In conclusion, DPP4 inhibition attenuated myocardial fibrosis and improved LV diastolic dysfunction in a DIO rat model by modulating the TGF-β1 and Smad2/3 pathways.

Topics: Animals; Blood Glucose; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Fibrosis; Insulin; Lipid A; Male; Myocardium; Obesity; Rats; Rats, Inbred SHR; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta1; Triazoles

To evaluate whether pharmacological TLR4 inhibition protects against acute and chronic fat-induced insulin resistance in rats.. For the acute experiment, rats received a TLR4 inhibitor [TAK-242 or E5564 (2x5 mg/kg i.v. bolus)] or vehicle, and an 8-h Intralipid (20%, 8.5 mg/kg/min) or saline infusion, followed by a two-step hyperinsulinemic-euglycemic clamp. For the chronic experiment, rats were subcutaneously implanted with a slow-release pellet of TAK-242 (1.5 mg/d) or placebo. Rats then received a high fat diet (HFD) or a low fat control diet (LFD) for 10 weeks, followed by a two-step insulin clamp.. Acute experiment; the lipid-induced reduction (18%) in insulin-stimulated glucose disposal (Rd) was attenuated by TAK-242 and E5564 (the effect of E5564 was more robust), suggesting improved peripheral insulin action. Insulin was able to suppress hepatic glucose production (HGP) in saline- but not lipid-treated rats. TAK-242, but not E5564, partially restored this effect, suggesting improved HGP. Chronic experiment; insulin-stimulated Rd was reduced ~30% by the HFD, but completely restored by TAK-242. Insulin could not suppress HGP in rats fed a HFD and TAK-242 had no effect on HGP.. Pharmacological TLR4 inhibition provides partial protection against acute and chronic fat-induced insulin resistance in vivo.

Topics: Animals; Body Weight; Diet, High-Fat; Glucose; Insulin Resistance; Lipid A; Lipids; Liver; Male; Obesity; Rats, Long-Evans; Rats, Wistar; Sulfonamides; Toll-Like Receptor 4

To assess lipid profile changes in post-menopausal women treated with testosterone gel.. Thirty-six oophorectomized women on estradiol treatment who received transdermal testosterone gel (5mg daily) were enrolled into our study. Cholesterol, triglycerides, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), very low density-lipoprotein cholesterol (VLDL-C), and lipoprotein (a) were tested before and after 6 months of treatment.. Selected participants had a mean age of 50.9±4.6 years and a body mass index of 30.1±3.8 kg/m(2). Significantly decreased cholesterol levels were found after 6 months of treatment (204.5±35.1 mg/dL before treatment as compared to 183.1±21.9 mg/dL after treatment; p<0.05). A significant reduction was also seen in LDL-C levels after 6 months of treatment with testosterone gel as compared to baseline (130.9±29.7 mg/dL versus 118.5±21.3 mg/dL; p<0.05). No differences were found in triglyceride, HDL-C, VLDL-C, and lipoprotein (a) levels (p=ns).. El gel de testosterona, asociado a tratamiento estrogénico en mujeres ooforectomizadas, produce disminución de las concentraciones de colesterol y LDL-C posterior a 6 meses de tratamiento, sin afectar las concentraciones de triglicéridos, HDL-C, VLDL-C y lipoproteína (a)Testosterone gel, associated to estrogen treatment in oophorectomized women, decreased cholesterol and LDL-C levels after 6 months of treatment, without affecting serum triglyceride, HDL-C, VLDL-C, and lipoprotein (a) levels.

Topics: Administration, Cutaneous; Body Mass Index; Cholesterol; Estradiol; Estrogen Replacement Therapy; Female; Gels; Humans; Hysterectomy; Lipid A; Lipids; Lipoproteins; Middle Aged; Obesity; Ovariectomy; Postmenopause; Testosterone; Triglycerides

We aimed to evaluate the association between serum lipocalin-2 level and clinical and metabolic parameters in obese children.. The study included obese children with a body mass index (BMI) >95th percentile who presented to Kecioren Teaching and Research Hospital with the complaint of weight gain and healthy children with a BMI <85th percentile. The height and weight of the patients were measured for compartment of anthropometric data. Fasting blood glucose, insulin, lipid profile, and serum lipocalin-2 level were measured to evaluate the laboratory parameters.. The study included 33 obese and 34 healthy nonobese children. Comparison of data on the obese subjects with those of the healthy subjects shows differences in BMI, BMI-SDS, triglyceride, insulin, and homeostasis model assessment index-insulin resistance levels between the two groups were statistically significant (p < 0.05), whereas serum lipocalin-2 was not statistically significant (p >0.05). There was no statistically significant difference in serum lipocalin-2 levels when obese and control groups were reclassified as prepubertal and pubertal ( p >0.05).. In this study, we did not find any relationships among serum lipocalin-2 level, anthropometric parameters, or metabolic parameters. According to the results of this study, we do not suggest routine investigation of serum lipocalin-2 level in obese subjects for risk stratification of the obesity-related complications.

Topics: Acute-Phase Proteins; Adolescent; Blood Glucose; Body Mass Index; Child; Female; Homeostasis; Humans; Insulin Resistance; Lipid A; Lipocalin-2; Lipocalins; Male; Obesity; Pilot Projects; Proto-Oncogene Proteins; Risk Factors

The aim of this study was to elucidate the effect of fish-oil-derived monounsaturated fatty acids (MUFAs) containing large amounts of C20:1 and C22:1 isomers on metabolic disorders in mice. Male C57BL/6J mice were fed a 32% lard diet (control) or a 27% lard plus 5% saury-oil-derived MUFA diet for 6 weeks. Dietary MUFA improved insulin resistance and alleviated metabolic syndrome risk factors by reducing blood glucose and lipids. These favorable changes may be attributed to an improved adipocytokine profile. MUFA ingestion resulted in favorable changes in mRNA expression of genes involved in glucose/lipid metabolism (SCD-1, CPT1a, UCPs, and CS) as well as inflammation (MAC1, MMP3, and SAA3) and alterations in fatty acid composition. Our data suggest that marine MUFA improved glucose/lipid homeostasis and hindered the development of metabolic syndrome in obese mice.

Topics: Animals; Blood Glucose; Dietary Fats; Dietary Fats, Unsaturated; Fatty Acids, Monounsaturated; Fish Oils; Insulin Resistance; Lipid A; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity

The study aimed to investigate the predictive value of the combination of high-sensitivity C-reactive protein (hs-CRP) and apolipoprotein B (apoB)/apoA-1 ratio for the outcomes of coronary angiography (CAG), echocardiography and oral glucose tolerance tests (OGTTs).. Hs-CRP, apoB, apoA-1, and the profiles of CAG, echocardiography and OGTTs as well as traditional risk factors were measured in 1757 cardiology patients.. Hs-CRP or apoB/apoA-1 ratio was significantly correlated with the presence and severity of angiographic profiles, the levels of left ventricular (LV) ejection fraction, LV mass and LV mass index, and the presence of abnormal glucose metabolism. The combination of hs-CRP and apoB/apoA-1 ratio had greater correlation with abnormal glucose metabolism than its individual components in patients with normal fasting glucose, and was an independent predictor for coronary artery disease.. The combination of hs-CRP and apoB/apoA-1 ratio may be a strong predictor for coronary artery disease and abnormal glucose metabolism.

Topics: Aged; Apolipoprotein A-I; Apolipoproteins B; C-Reactive Protein; Coronary Angiography; Coronary Artery Disease; Echocardiography; Female; Glucose; Glucose Tolerance Test; Humans; Hypertension; Lipid A; Male; Middle Aged; Obesity; Predictive Value of Tests; Risk Factors; Sensitivity and Specificity

Topics: Body Mass Index; Football; Humans; Hypertension; Lipid A; Male; Middle Aged; Obesity; Prevalence; Retirement; Sleep Apnea Syndromes; United States