Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats

Hsiao, Gene; Chapman, Justin; Ofrecio, Jachelle M.; Wilkes, Jason J.; Resnik, Jamie L.; Thapar, Divya; Subramaniam, Shankar; Sears, Dorothy D.

doi:10.1152/ajpendo.00219.2010

Cited by 80 publications

(81 citation statements)

References 57 publications

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“…Our results in monogenic and polygenic rodent models of obesity confirm previous studies showing decreased BCKD protein abundance in adipose of obese and insulin-resistant rats and mice (23,40,42). Both fa/fa obese Zucker rats and obese db/db mice showed decreased RP WAT BCKD protein abundance relative to their lean counterparts, and a moderate obesity-inducing diet (45% kcal from fat) and a more extreme diet (60% kcal from fat) decreased RP WAT BCKD protein abundance in DIO mice.…”

Section: Discussionsupporting

confidence: 91%

“…Agonism of PPAR␥ in 3T3-L1 adipocytes increased transcript abundances of Bckdhb, Dld, Dbt, and Bcat2 during the course of 3T3-L1 adipocyte differentiation. These results are similar to those of Hsiao et al who showed that adipose tissue from rats treated with PPAR␥ ligand had increased Bckdhb, Dbt, and Dld mRNA expression (23). The results are also reminiscent of the increase in WAT BCAA catabolic pathway transcripts after TZD treatment in humans (40).…”

Section: Discussionsupporting

confidence: 90%

“…The TZD treatment led to a significant 38% reduction in fasting plasma glucose in the db/db mice (205 Ϯ 18 to 128 Ϯ 4 mg/dl, P Ͻ 0.01), with a smaller 20% effect in lean mice (144 Ϯ 9 vs. 116 Ϯ 14 mg/dl, not significant). Previously, it was reported that in vivo treatment of rats and humans with PPAR␥ agonists increases mRNA expression of BCKD complex and BCAA enzymes in WAT (23,40). Consistent with this, treatment with 10 mg/kg 12-day oral gavage of the PPAR␥ agonist RSG significantly increased RP WAT BCKD protein abundance in lean mice, but this effect was not as robust in db/db mice (Fig.…”

Section: Evidence That Ppar␥ Activation and Adipocyte Glucose Homeostsupporting

confidence: 68%

“…Little is known regarding the metabolic or endocrine factors that regulate gene and protein expression of BCAA-relevant enzymes in WAT. Expression of 18 genes related to BCAA catabolism were upregulated in WAT by administration of peroxisome proliferator-activated receptor (PPAR)-␥ agonists in obese Zucker rats (23), and there was a positive correlation between glucose disposal rate and BCAA catabolism-related transcript levels in WAT from human subjects before and after treatment with thiazolidinediones (TZDs) (40). Whether BCAA-associated enzymes are direct targets of PPAR␥ or if TZD-related differences result from improved insulin or glucose homeostasis is not known.…”

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confidence: 99%

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Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity

Lackey

Lynch

Olson

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

277

271

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Elevated blood branched-chain amino acids (BCAA) are often associated with insulin resistance and type 2 diabetes, which might result from a reduced cellular utilization and/or incomplete BCAA oxidation. White adipose tissue (WAT) has become appreciated as a potential player in whole body BCAA metabolism. We tested if expression of the mitochondrial BCAA oxidation checkpoint, branched-chain ␣-ketoacid dehydrogenase (BCKD) complex, is reduced in obese WAT and regulated by metabolic signals. WAT BCKD protein (E1␣ subunit) was significantly reduced by 35-50% in various obesity models (fa/fa rats, db/db mice, diet-induced obese mice), and BCKD component transcripts significantly lower in subcutaneous (SC) adipocytes from obese vs. lean Pima Indians. Treatment of 3T3-L1 adipocytes or mice with peroxisome proliferatoractivated receptor-␥ agonists increased WAT BCAA catabolism enzyme mRNAs, whereas the nonmetabolizable glucose analog 2-deoxy-D-glucose had the opposite effect. The results support the hypothesis that suboptimal insulin action and/or perturbed metabolic signals in WAT, as would be seen with insulin resistance/type 2 diabetes, could impair WAT BCAA utilization. However, cross-tissue flux studies comparing lean vs. insulin-sensitive or insulin-resistant obese subjects revealed an unexpected negligible uptake of BCAA from human abdominal SC WAT. This suggests that SC WAT may not be an important contributor to blood BCAA phenotypes associated with insulin resistance in the overnight-fasted state. mRNA abundances for BCAA catabolic enzymes were markedly reduced in omental (but not SC) WAT of obese persons with metabolic syndrome compared with weight-matched healthy obese subjects, raising the possibility that visceral WAT contributes to the BCAA metabolic phenotype of metabolically compromised individuals. bariatric; diabetes; hyperinsulinemia; mammalian target of rapamycin; protein IN THE SEARCH FOR BIOMARKERS that associate with or predict type 2 diabetes mellitus (T2DM), it has become appreciated that circulating concentrations of the branched-chain amino acids (BCAA; valine, leucine, isoleucine) are often increased in obese, insulin-resistant states and in T2DM. Higher fasting plasma BCAA concentrations were initially reported in obese subjects by Adibi and by Felig et al. (2,12). Recent metabolomic studies found that plasma concentrations of BCAAs and large neutral amino acids are negatively correlated with insulin sensitivity in overweight and obese subjects (24), whereas the principal component that differentiated lean and obese individuals contained BCAA, methionine, phenylalanine, and tyrosine, with a linear relationship between plasma BCAA and homeostasis model assessment of insulin resistance (HOMA-IR) (36). Plasma concentrations of leucine and valine, as well as the leucine metabolite ␣-ketoisocaproate, were increased in obese female African-American T2DM subjects compared with age-and body mass index (BMI)-matched nondiabetic subjects, and plasma leucine significantly correlated with hemoglobin A ...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Section: Evidence That Ppar␥ Activation and Adipocyte Glucose Homeostsupporting

confidence: 68%

mentioning

confidence: 99%

See 2 more Smart Citations

Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity

Lackey

Lynch

Olson

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

277

271

View full text Add to dashboard Cite

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“…In mice, adipose tissue expression of PPARG is down-regulated by fasting and increased when exposed to high fat feeding (Vidal-Puig et al, 1996) supporting data in obese humans demonstrating that a low energy diet can down-regulate adipocyte PPAR γ mRNA expression (Vidal-Puig et al, 1997). Additionally, its association with alterations in insulin sensitivity (Hsiao et al, 2011) and down-regulation of leptin expression in response to agonists (Zhang et al, 1996), both critical neuroendocrine signals/ hormones for orchestrating the central control of ingestive behaviour, are consistent with the notion that PPAR γ may be signifi cant in mediating the response to food and appetite.…”

Section: Peroxisome Proliferator-activated Receptor Gene -A Candidatesupporting

confidence: 73%

Obesity and eating behaviour in children and adolescents: Contribution of common gene polymorphisms

Cecil

Dalton

Finlayson

et al. 2012

International Review of Psychiatry

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The prevalence of childhood obesity is increasing in many countries and confers risks for early type 2 diabetes, cardiovascular disease and metabolic syndrome. In the presence of potent ' obesogenic ' environments not all children become obese, indicating the presence of susceptibility and resistance. Taking an energy balance approach, susceptibility could be mediated through a failure of appetite regulation leading to increased energy intake or via diminished energy expenditure. Evidence shows that heritability estimates for BMI and body fat are paralleled by similar coeffi cients for energy intake and preferences for dietary fat. Twin studies implicate weak satiety and enhanced food responsiveness as factors determining an increase in BMI. Single gene mutations, for example in the leptin receptor gene, that lead to extreme obesity appear to operate through appetite regulating mechanisms and the phenotypic response involves overconsumption and a failure to inhibit eating. Investigations of robustly characterized common gene variants of fat mass and obesity associated ( FTO ), peroxisome proliferator-activated receptor ( PPARG ) and melanocortin 4 receptor ( MC4R ) which contribute to variance in BMI also infl uence the variance in appetite factors such as measured energy intake, satiety responsiveness and the intake of palatable energy-dense food. A review of the evidence suggests that susceptibility to childhood obesity involving specifi c allelic variants of certain genes is mediated primarily through food consumption (appetite regulation) rather than through a decrease in activity-related energy expenditure. This conclusion has implications for early detection of susceptibility, and for prevention and management of childhood obesity.

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Impact of lifestyle Intervention on branched‐chain amino acid catabolism and insulin sensitivity in adolescents with obesity

Trub

Balikcioglu

Freemark

et al. 2021

Endocrino Diabet & Metabol

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Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats

Abstract: Subramaniam S, Sears DD. Multi-tissue, selective PPAR␥ modulation of insulin sensitivity and metabolic pathways in obese rats. Am

Cited by 80 publications

References 57 publications

Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity

Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity

Obesity and eating behaviour in children and adolescents: Contribution of common gene polymorphisms

Impact of lifestyle Intervention on branched‐chain amino acid catabolism and insulin sensitivity in adolescents with obesity

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