Constitutive Activation of IKKβ in Adipose Tissue Prevents Diet-Induced Obesity in Mice

Jiao, Peng; Feng, Bin; Ma, Jie; Nie, Yaohui; Paul, Erin; Li, Yujie; Xu, Haiyan

doi:10.1210/en.2011-1346

Cited by 44 publications

(49 citation statements)

References 31 publications

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“…It is generally believed that NF-B promotes inflammation through induction of transcriptional expression of proinflammatory cytokines. This activity is supported by the reduced adipose inflammation of F-p65-KO mice on chow diet in this study and increased adipose inflammation in mice with p65 or IKK overexpression in other studies (21,47). However, p65 inactivation did not inhibit the inflammation in F-p65-KO mice on HFD, suggesting that NF-B is not necessary for chronic inflammation in the obese condition.…”

Section: Discussionsupporting

confidence: 76%

“…It is generally believed that activation of the IKK␤/ NF-B signaling pathway in those cells occurs in obesity to promote the inflammatory response (42). In agreement, gainof-function of NF-B in adipose tissue promotes chronic inflammation in mice with overexpression of p65 subunit (47) or IKK␤ (21). Inhibition of the pathway is proposed as an approach in the control of obesity-associated inflammation for improvement of insulin resistance (8).…”

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confidence: 99%

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P65 inactivation in adipocytes and macrophages attenuates adipose inflammatory response in lean but not in obese mice

Gao

Zhang

Henagan

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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NF-κB induces transcriptional expression of proinflammatory genes and antiapoptotic genes. The two activities of NF-κB remain to be characterized in the mechanism of chronic inflammation in obesity. To address this issue, we inactivated NF-κB in adipose tissue by knocking out p65 (RelA) in mice (F-p65-KO) and examined the inflammation in lean and obese conditions. In the lean condition, KO mice exhibited a reduced inflammation in adipose tissue with a decrease in macrophage infiltration, M1 polarization, and proinflammatory cytokine expression. In the obese condition, KO mice had elevated inflammation with more macrophage infiltration, M1 polarization, and cytokine expression. In the mechanism of enhanced inflammation, adipocytes and macrophages exhibited an increase in cellular apoptosis, which was observed with more formation of crown-like structures (CLS) in fat tissue of KO mice. Body weight, glucose metabolism, and insulin sensitivity were not significantly altered in KO mice under the lean and obese conditions. A modest but significant reduction in body fat mass was observed in KO mice on HFD with an elevation in energy expenditure. The data suggest that in the control of adipose inflammation, NF-κB exhibits different activities in the lean vs. obese condition. NF-κB is required for expression of proinflammatory genes in the lean but not in the obese condition. NF-κB is required for inhibition of apoptosis in the obese condition, in which proinflammation is enhanced by NF-κB inactivation.

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Section: Discussionsupporting

confidence: 76%

mentioning

confidence: 99%

P65 inactivation in adipocytes and macrophages attenuates adipose inflammatory response in lean but not in obese mice

Gao

Zhang

Henagan

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…Increased NF-B-driven infl ammation has recently been shown to prevent obesity by increasing energy expenditure ( 26,27 ). Furthermore, low-grade infl ammation in WAT is expression, which is consistent with the induction of browning in these depots.…”

Section: Cla Treatments Increase Mrna Markers Of Low-grade Infl Ammatsupporting

confidence: 52%

Conjugated linoleic acid reduces adiposity and increases markers of browning and inflammation in white adipose tissue of mice

Shen

Chuang

Martinez

et al. 2013

Journal of Lipid Research

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mixtures of cis -9, trans -11 (9,11) conjugated linoleic acid (CLA) and trans -10, cis -12 (10,12) CLA. Indeed, consuming a mixture of these CLA isomers, or 10,12 CLA alone, reduced body fat in many animal (reviewed in Ref. 3 ) and human studies ( 4 ). Rodents that consumed higher amounts of the CLA than humans (e.g., 0.5-1.5% CLA in the diet or 600-1,800 mg/kg body weight) lost body fat more rapidly but concurrently developed side effects, including chronic infl ammation, insulin resistance, and lipoatrophy ( 5 ). Notably, intermediate levels of mixed CLA isomers (i.e., 0.1-0.3%, w/w) reduced adiposity in mice without adversely affecting liver weight or lipid content ( 6 ). However, individual isomers were not fed, the level of reduction in adiposity in the 0.1% group was marginal, and anti-obesity mechanisms were not identifi ed ( 6 ). In contrast, clinical trials routinely use lower doses of CLA (e.g., 3-6 g/day or 35-70 mg/kg body weight), although the relative decrease in adiposity is not as rapid or great as in the higher doses used in rodent studies.It has been reported that only the 10,12 CLA isomer reduces adiposity or delipidates adipocytes; however, at relatively high doses it also causes adverse side effects in Abstract The objective of this study was to examine the mechanism by which conjugated linoleic acid (CLA) reduces body fat. Young male mice were fed three combinations of fatty acids at three doses (0.06%, 0.2%, and 0.6%, w/w) incorporated into AIN76 diets for 7 weeks. The types of fatty acids were linoleic acid (control), an equal mixture of trans -10, cis -12 (10,12) CLA plus linoleic acid, and an equal isomer mixture of 10,12 plus cis -9, trans -11 (9,11) CLA. Mice receiving the 0.2% and 0.6% dose of 10,12 CLA plus linoleic acid or the CLA isomer mixture had decreased white adipose tissue (WAT) and brown adipose tissue (BAT) mass and increased incorporation of CLA isomers in epididymal WAT and liver. Notably, in mice receiving 0.2% of both CLA treatments, the mRNA levels of genes associated with browning, including uncoupling protein 1 (UCP1), UCP1 protein levels, and cytochrome c oxidase activity, were increased in epididymal WAT. CLA-induced browning in WAT was accompanied by increases in mRNA levels of markers of infl ammation. Muscle cytochrome c oxidase activity and BAT UCP1 protein levels were not affected by CLA treatment. These data suggest a linkage between decreased adiposity, browning in WAT, and low-grade infl ammation due to consumption of 10,12 CLA.

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“…Insulin sensitivity was not impaired in the mice on a chow diet and was improved in the mice on HFD. The observations were extended into fatspecific IKK␤-overexpressing mice that have been recently reported by another group (50). The fat-specific IKK␤ mice exhibited an increase in energy expenditure and resistance to diet-induced obesity.…”

Section: E470 Beneficial Activity Of Inflammationmentioning

confidence: 79%

Inflammation during obesity is not all bad: evidence from animal and human studies

McGuinness

2013

American Journal of Physiology-Endocrinology and Metabolism

140

119

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Chronic inflammation is a characteristic of obesity and is associated with accompanying insulin resistance, a hallmark of type 2 diabetes mellitus (T2DM). Although proinflammatory cytokines are known for their detrimental effects on adipose tissue function and insulin sensitivity, their beneficial effects in the regulation of metabolism have not drawn sufficient attention. In obesity, inflammation is initiated by a local hypoxia to augment angiogenesis and improve adipose tissue blood supply. A growing body of evidence suggests that macrophages and proinflammatory cytokines are essential for adipose remodeling and adipocyte differentiation. Phenotypes of multiple lines of transgenic mice consistently suggest that proinflammatory cytokines increase energy expenditure and act to prevent obesity. Removal of proinflammatory cytokines by gene knockout decreases energy expenditure and induces adult-onset obesity. In contrast, elevation of proinflammatory cytokines augments energy expenditure and decreases the risk for obesity. Anti-inflammatory therapies have been tested in more than a dozen clinical trials to improve insulin sensitivity and glucose homeostasis in patients with T2DM, and the results are not encouraging. One possible explanation is that anti-inflammatory therapies also attenuate the beneficial effects of inflammation in stimulating energy expenditure, which may have limited the efficacy of the treatment by promoting energy accumulation. Thus, the positive effects of proinflammatory events should be considered in evaluating the impact of inflammation in obesity and type 2 diabetes.

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Constitutive Activation of IKKβ in Adipose Tissue Prevents Diet-Induced Obesity in Mice

Cited by 44 publications

References 31 publications

P65 inactivation in adipocytes and macrophages attenuates adipose inflammatory response in lean but not in obese mice

P65 inactivation in adipocytes and macrophages attenuates adipose inflammatory response in lean but not in obese mice

Conjugated linoleic acid reduces adiposity and increases markers of browning and inflammation in white adipose tissue of mice

Inflammation during obesity is not all bad: evidence from animal and human studies

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