Health and mortality consequences of abdominal obesity: evidence from the AusDiab study

Cameron, Adrian J.; Dunstan, David W.; Owen, Neville; Zimmet, Paul; Barr, Elizabeth L. M.; Tonkin, Andrew; Magliano, Dianna J.; Murray, Shirley G; Welborn, T.; Shaw, Jonathan E.

doi:10.5694/j.1326-5377.2009.tb02753.x

Cited by 71 publications

(59 citation statements)

References 23 publications

(44 reference statements)

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“…We next asked whether the reduction in body mass by NF treatment was associated with a change in the distribution of visceral and subcutaneous fat depots. Increased abdominal or visceral fat is associated with a higher risk of metabolic syndrome, heart disease, diabetes, and many other diseases (Cameron et al , 2009). Although the total fat mass to body mass ratio was not significantly different (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1

Moyer

Rojas

Kerley-Hamilton

et al. 2016

Toxicology and Applied Pharmacology

100

110

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Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHR antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor β1 (TGFβ1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFβ1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR, with its broad ligand binding specificity, is a promising candidate for a potentially simple therapeutic approach for the prevention and treatment of obesity and associated complications.

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Section: Resultsmentioning

confidence: 99%

Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1

Moyer

Rojas

Kerley-Hamilton

et al. 2016

Toxicology and Applied Pharmacology

100

110

View full text Add to dashboard Cite

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“…Increased abdominal or visceral fat is associated with a higher risk of metabolic syndrome [32], heart disease, diabetes, and many other diseases [33]. Visceral and subcutaneous fat compartment volumes were determined using MRI of ~20 whole body cross-sections through the thoracic and abdominal regions (Fig.…”

Section: Resultsmentioning

confidence: 99%

Obesity and fatty liver are prevented by inhibition of the aryl hydrocarbon receptor in both female and male mice

et al. 2017

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Inhibition of the aryl hydrocarbon receptor (AHR) prevents Western diet-induced obesity and fatty liver in C57Bl/6J (B6) male mice. The AHR is a ligand-activated nuclear receptor that regulates genes involved in xenobiotic metabolism and T cell differentiation. Here, we tested the hypothesis that AHR antagonism would also prevent obesity and fatty liver in female mice and that B6 mice (higher-affinity AHR) and congenic B6.D2 mice (lower-affinity AHR) would differentially respond to AHR inhibition. Female and male adult B6 and B6.D2 mice were fed control and Western diets with and without α-naphthoflavone, an AHR inhibitor. A nonlinear mixed model analysis was developed to project asymptote body mass. We found that obesity, adiposity, and liver steatosis were reduced to near control levels in all female and male B6 and B6.D2 experimental groups fed Western diet with α-naphthoflavone. However, differences were noted in that female B6.D2 versus B6 mice on Western diet became more obese; and in general, female mice to that of male mice had a greater fat mass to body mass ratio, were less responsive to α-naphthoflavone, and had reduced liver steatosis and hepatomegaly. We report that male mice fed Western diet containing α-naphthoflavone or CH-223191, another AHR inhibitor, caused reduced mRNA levels of several liver genes involved in metabolism, including Cyp1b1 and Scd1, offering evidence for a possible mechanism by which the AHR regulates obesity. In conclusion, although there are some sex- and Ahr allelic-dependent differences, AHR inhibition prevents obesity and liver steatosis in both males and females regardless of the ligand-binding capacity of the AHR. We also present evidence consistent with the notion that an AHR-CYP1B1-SCD1 axis is involved in obesity providing potentially convenient and effective targets for treatment.

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“…This study was therefore designed to investigate the effects of individual CLA isomers on epididymal adipocyte size and to examine the relationship with the local adipose RAS in obesity. The study focused on epididymal adipose tissue as a visceral adipose depot because visceral adiposity is associated with metabolic complications of obesity and cardiovascular disease and is strong predictor of obesity-related risk factors and mortality [19, 20]. …”

Section: Introductionmentioning

confidence: 99%

Dietary t10,c12‐CLA but not c9,t11 CLA Reduces Adipocyte Size in the Absence of Changes in the Adipose Renin–Angiotensin System in fa/fa Zucker Rats

DeClercq

Zahradka

Taylor

2010

Lipids

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In obesity, increased activity of the local renin–angiotensin system (RAS) and enlarged adipocytes with altered adipokine production are linked to the development of obesity-related health problems and cardiovascular disease. Mixtures of conjugated linoleic acid (CLA) isomers have been shown to reduce adipocyte size and alter the production of adipokines. The objective of this study was to investigate the effects of feeding individual CLA isomers on adipocyte size and adipokines associated with the local adipose RAS. Male fa/fa Zucker rats received either (a) control, (b) cis(c)9,trans(t)11-CLA, or (c) t10,c12-CLA diet for 8 weeks. The t10,c12-CLA isomer reduced adipocyte size and increased cell number in epididymal adipose tissue. RT-PCR and Western blot analysis revealed that neither CLA isomer altered mRNA or protein levels of angiotensinogen or AngII receptors in adipose tissue. Likewise, levels of the pro-inflammatory cytokines TNF-α and IL-6 or the anti-inflammatory cytokine IL-10 were unchanged in adipose tissue. Similarly, neither CLA isomer had any effect on phosphorylation nor DNA binding of NF-κB. Our results suggest that although the t10,c12-CLA isomer had beneficial effects on reducing adipocyte size in obese rats, this did not translate into changes in the local adipose RAS or associated adipokines.

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Health and mortality consequences of abdominal obesity: evidence from the AusDiab study

Cited by 71 publications

References 23 publications

Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1

Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1

Obesity and fatty liver are prevented by inhibition of the aryl hydrocarbon receptor in both female and male mice

Dietary t10,c12‐CLA but not c9,t11 CLA Reduces Adipocyte Size in the Absence of Changes in the Adipose Renin–Angiotensin System in fa/fa Zucker Rats

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