Central Inhibition of IKKβ/NF-κB Signaling Attenuates High-Fat Diet–Induced Obesity and Glucose Intolerance

Benzler, Jonas; Ganjam, Goutham K.; Pretz, Dominik; Oelkrug, Rebecca; Koch, Christiane E; Legler, Karen; Stöhr, Sigrid; Culmsee, Carsten; Williams, Lynda M.; Tups, Alexander

doi:10.2337/db14-0093

Cited by 118 publications

(98 citation statements)

References 51 publications

(90 reference statements)

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“…In our study NFκB p50 was significantly increased in heart lysates of obese female rats. This finding is in agreement with others showing that a HF diet has a proinflammatory effect, increasing NFκB activity in several tissues [55][56][57][58].…”

Section: Discussionsupporting

confidence: 82%

Influence of a High-Fat Diet on Cardiac iNOS in Female Rats

Jovanović

Sudar-Milovanović

Obradović

et al. 2017

CVP

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Overexpression of inducible nitric oxide synthase (iNOS) is a key link between high-fat (HF) diet induced obesity and cardiovascular (CV) disease. Several studies have reported that oestradiol has cardioprotective effects that may be mediated through reduction of iNOS activity/expression. In the present study, female Wistar rats were fed a standard diet or a HF diet (balanced diet for laboratory rats enriched with 42% fat) for 10 weeks. Gene and protein expression of iNOS were measured in heart tissue. HF diet-fed rats exhibited a significant increase in cardiac iNOS mRNA by 695% (p<0.05), iNOS protein level by 248% (p<0.01), without changes in nitrate/nitrite levels. Expression of CD36 protein in plasma membranes was increased by 37% (p<0.05), while the concentration of free fatty acids (FFA) was reduced by 25% (p<0.01) in HF diet-fed rats. Expression of the p50 subunit of nuclear factor-κB (NFκB-p50) in heart lysate was increased by 77% (p<0.01) in HF diet-fed rats.Expression and phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinases 1/2 (ERK1/2) in control and HF diet-fed rats were also examined. Expression of Akt and ERK1/2 were unchanged between the groups. There was a significant increase in the ratio of phospho-Akt/total Akt but not for phospho-ERK1/2/total ERK1/2/ in HF-fed rats.Estrogen receptor-α levels (by 50%; p<0.05) and serum oestradiol concentrations (by 35%; p<0.05) were examined and shown to be significantly reduced in HF diet-fed rats. Our results revealed that a HF diet led to increased iNOS expression, most likely via a mechanism involving Akt and NFκB-p50 proteins. Decreased levels of oestradiol and ERα protein in the HF-fed group, in combination with increased iNOS levels are consistent with the hypothesis that oestradiol has a cardioprotective effect through its ability to regulate iNOS expression.Key words: cardioprotection, cardiovascular disease, oestradiol, inducible nitric oxide synthase, obesity Abbreviations: Akt, protein kinase B; CD36, cluster of differentiation 36; CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; DMT2, diabetes mellitus type 2; ERα, oestrogen receptor-α; ERs, oestrogen receptors; ERK1/2, extracellular signalregulated kinases 1/2; FFA, free fatty acids; HF, high fat; HOMA-IR, HOMA-index of insulin resistance; HOMA-β, HOMA-index of β-cell function; IκB, inhibitor of NFκB; iNOS, inducible nitric oxide synthase; IR, insulin resistance; NFκB-p50, the p50 subunit of nuclear factor-κB; TES, N-[Tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid; TG, triglycerides VSMCs, vascular smooth muscle cells.

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Section: Discussionsupporting

confidence: 82%

Influence of a High-Fat Diet on Cardiac iNOS in Female Rats

Jovanović

Sudar-Milovanović

Obradović

et al. 2017

CVP

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“…Glucose-lowering effect of berberine metabolites on high-fat-diet -induced hyperglycemia in mice The animal model of high-fat-diet (HFD)-induced hyperglycemia or insulin resistance has been widely used in the assessment of glucose-lowering effects [28,29] . After 9 weeks of continuous feeding with HFD, the glucose level in the plasma of the HFD mice was significantly elevated (12.17±1.70 vs 6.52±1.83 mmol/L, P<0.01).…”

Section: Resultsmentioning

confidence: 99%

In vitro assessment of the glucose-lowering effects of berberrubine-9-O-β-D-glucuronide, an active metabolite of berberrubine

et al. 2017

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Berberrubine (BRB) is the primary metabolite of berberine (BBR) that has shown a stronger glucose-lowering effect than BBR in vivo. On the other hand, BRB is quickly and extensively metabolized into berberrubine-9-O-β-D-glucuronide (BRBG) in rats after oral administration. In this study we compared the pharmacokinetic properties of BRB and BRBG in rats, and explored the mechanisms underlying their glucose-lowering activities. C57BL/6 mice with HFD-induced hyperglycemia were administered BRB (50 mg· kg -1 ·d -1 , ig) for 6 weeks, which caused greater reduction in the plasma glucose levels than those caused by BBR (120 mg· kg -1 ·d -1 ) or BRB (25 mg· kg -1 ·d -1 ). In addition, BRB dose-dependently decreased the activity of α-glucosidase in gut of the mice. After oral administration of BRB in rats, the exposures of BRBG in plasma at 3 different dosages (10, 40, 80 mg/kg) and in urine at different time intervals (0-4, 4-10, 10-24 h) were dramatically greater than those of BRB. In order to determine the effectiveness of BRBG in reducing glucose levels, we prepared BRBG from the urine pool of rats, and identified and confirmed it through LC-MS-IT-TOF and NMR spectra. In human normal liver cell line L-O2 in vitro, treatment with BRB or BRBG (5, 20, 50 μmol/L) increased glucose consumption, enhanced glycogenesis, stimulated the uptake of the glucose analog 2-NBDG, and modulated the mRNA levels of glucose-6-phosphatase and hexokinase. However, both BBR and BRB improved 2-NBDG uptake in insulin-resistant L-O2 cells, while BRBG has no effect. In conclusion, BRB exerts a stronger glucose-lowering effect than BBR in HFD-induced hyperglycemia mice. Although BRB significantly stimulated the insulin sensitivity and glycolysis in vitro, BRBG may have a greater contribution to the glucose-lowering effect because it has much greater system exposure than BRB after oral administration of BRB. The results suggest that BRBG is a potential agent for reducing glucose levels.

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“…Besides, HFD is reported to upregulate kidney TLR4/ NF-kB signaling pathway and inflammation-related chemokines. 40,41 In this regard, Emr-1, MCP-1, MIP-1α, Cxcr4, and TLR4/NF-kB signaling-related indicators were tested. As shown in Figure 4A-D, significant increases in mRNA of inflammation-related factors, including Emr-1, MCP-1, MIP-1α, and Cxcr4, were observed in the HFD group, suggesting that fat-rich diet activates the inflammatory responses and cellular infiltration.…”

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confidence: 99%