Involvement of adipose tissues in the early hypolipidemic action of PPARγ agonism in the rat

Laplante, Mathieu; Festuccia, William T.; Soucy, Geneviève; Gélinas, Yves; Lalonde, Josée; Deshaies, Yves

doi:10.1152/ajpregu.00761.2006

Cited by 29 publications

(28 citation statements)

References 50 publications

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“…Thus the specific levels of UCP1 mRNA and protein (i.e., expressed per mRNA or protein units, respectively) were unchanged or only slightly increased (ϳ60% as a mean of the articles quoted below) in BAT of rodents treated with PPAR␥ agonists (2, 7, 9, 15-17, 28 -31, 36, 44, 46, 47) (however, total UCP1 content in BAT of treated animals was somewhat more increased, ϳ2-fold, due to tissue enlargement). In two recent investigations, robust 3-fold increases in specific UCP1 gene expression were reported (15,29), demonstrating that also in vivo PPAR␥ agonists have the ability to affect UCP1 gene expression. However, even threefold increases are marginal compared with the ϳ1,000-fold increase in UCP1 gene expression seen here in the cell culture system (estimated from quantitative PCR measurements of RNA from cultures grown as those examined in Fig.…”

Section: Resultsmentioning

confidence: 93%

Thermogenically competent nonadrenergic recruitment in brown preadipocytes by a PPARγ agonist

Petrovič

Shabalina²,

Timmons³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

125

111

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Most physiologically induced examples of recruitment of brown adipose tissue (BAT) occur as a consequence of chronic sympathetic stimulation (norepinephrine release within the tissue). However, in some physiological contexts (e.g., prenatal and prehibernation recruitment), this pathway is functionally contraindicated. Thus a nonsympathetically mediated mechanism of BAT recruitment must exist. Here we have tested whether a PPARγ activation pathway could competently recruit BAT, independently of sympathetic stimulation. We continuously treated primary cultures of mouse brown (pre)adipocytes with the potent peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone. In rosiglitazone-treated cultures, morphological signs of adipose differentiation and expression levels of the general adipogenic marker aP2 were manifested much earlier than in control cultures. Importantly, in the presence of the PPARγ agonist the brown adipocyte phenotype was significantly enhanced: UCP1 was expressed even in the absence of norepinephrine, and PPARα expression and norepinephrine-induced PGC-1α mRNA levels were significantly increased. However, the augmented levels of PPARα could not explain the brown-fat promoting effect of rosiglitazone, as this effect was still evident in PPARα-null cells. In continuously rosiglitazone-treated brown adipocytes, mitochondriogenesis, an essential part of BAT recruitment, was significantly enhanced. Most importantly, these mitochondria were capable of thermogenesis, as rosiglitazone-treated brown adipocytes responded to the addition of norepinephrine with a large increase in oxygen consumption. This thermogenic response was not observable in rosiglitazone-treated brown adipocytes originating from UCP1-ablated mice; hence, it was UCP1 dependent. Thus the PPARγ pathway represents an alternative, potent, and fully competent mechanism for BAT recruitment, which may be the cellular explanation for the enigmatic recruitment in prehibernation and prenatal states.

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Section: Resultsmentioning

confidence: 93%

Thermogenically competent nonadrenergic recruitment in brown preadipocytes by a PPARγ agonist

Petrovič

Shabalina²,

Timmons³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

125

111

View full text Add to dashboard Cite

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“…3 This study also confirms the robust hypotriglyceridemic action of PPAR-g agonism, which is, in contrast to 11b-HSD1 inhibition, mainly due to a marked potentiation of TG clearance by adipose tissues in the rat. 7 It can be noted that the combination of CA and RSG tended to exert additive effects on triglyceridemia; however, as in the case of insulinemia, RSG alone was quite potent and may have precluded any further large reduction. The distinct modes of action of these compounds on triglyceridemia render their combination of particular interest for further investigation.…”

Section: Discussionmentioning

confidence: 98%

“…6 At least in rodents, triglyceridemia is also dramatically reduced by PPAR-g agonists, mainly due to enhanced clearance by adipose tissues. 7 Both 11b-HSD1 inhibition and PPAR-g agonism therefore improve liver lipid metabolism and lipemia. The effect of their combination, however, has not been investigated to date.…”

Section: Introductionmentioning

confidence: 99%

Additive action of 11β-HSD1 inhibition and PPAR-γ agonism on hepatic steatosis and triglyceridemia in diet-induced obese rats

et al. 2009

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Both 11b-hydroxysteroid dehydrogenase (11b-HSD1) inhibition and peroxisome proliferator-activated receptor-g (PPAR-g) agonism reduce liver and plasma lipids in rodents through partly distinct mechanisms. This study aimed to assess their additivity of action on liver and plasma lipids in a model of diet-induced steatosis. Rats were fed an obesogenic diet and were treated either with an 11b-HSD1 inhibitor (Compound A, 3 mg kg À1 day À1 ) or rosiglitazone (RSG, 5 mg kg À1 day À1 ) or both for 6 weeks. Compound A and RSG reduced liver steatosis and triglyceridemia, and did so additively when given in combination. The 11b-HSD1 inhibitor had no effect on serum adiponectin, but increased liver adiponectin receptor type 2 (Adipo-R2) mRNA levels. Conversely, RSG increased serum adiponectin, a likely mediator of its antisteatotic action, but had no effect per se on the Adipo-R2 expression. mRNA levels of representative genes of fatty acid oxidation tended to be increased by both compounds. The study shows that combined 11b-HSD1 inhibition and PPAR-g agonism additively reduce liver steatosis and triglyceridemia, which may eventually prove therapeutically useful.

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“…Furthermore, surgical removal of visceral adipose tissue or exercise training that led to redistributing visceral to subcutaneous fat in nonpregnant rats improved insulin action (19,23). Thus it is possible that RG may partially exert its insulin-sensitizing effect by redistributing fat depots from visceral to a subcutaneous location (27,28). This WAT Fig.…”

Section: E493 Ppar␥ Agonist In the Iugr Offspringmentioning

confidence: 96%

“…In animals, TZDs improved insulin sensitivity in high-fat-diet-fed rats (44), obese Zucker rats, and Zucker diabetic fatty rats (45,47). However, in these situations, the rats demonstrated a prior accumulation of WAT providing a platform for TZD action (27,28). Whether a similar beneficial effect will be realized in the metabolically maladaptive pregestational female adult IUGR and/or PNGR rat offspring that lack a comparable accumulation of WAT is not known.…”

mentioning

confidence: 99%

Early exposure of the pregestational intrauterine and postnatal growth-restricted female offspring to a peroxisome proliferator-activated receptor-γ agonist

Garg

Thamotharan

Pan

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Garg M, Thamotharan M, Pan G, Lee PW, Devaskar SU. Early exposure of the pregestational intrauterine and postnatal growth-restricted female offspring to a peroxisome proliferator-activated receptor-␥ agonist. Am J Physiol Endocrinol Metab 298: E489 -E498, 2010. First published December 15, 2009; doi:10.1152/ajpendo.00361.2009.-Prenatal nutrient restriction with intrauterine growth restriction (IUGR) alters basal and glucose-stimulated insulin response and hepatic metabolic adaptation. The effect of early intervention with insulin-sensitizing peroxisome proliferator-activated receptor ␥ agonists was examined in the metabolically maladapted F 1 pregestational IUGR offspring with a propensity toward pregnancy-induced gestational diabetes. The effect of rosiglitazone maleate [RG; 11 mol/day from postnatal day (PN) 21 to PN60] vs. placebo (PL) on metabolic adaptations in 2-mo-old F 1 female rats subjected to prenatal (IUGR), postnatal (PNGR), or pre-and postnatal (IUGR ϩ PNGR) nutrient restriction was investigated compared with control (CON). RG vs. PL had no effect on body weight or plasma glucose concentrations but increased subcutaneous white and brown adipose tissue and plasma cholesterol concentrations in all three experimental groups. Glucose tolerance tests with a 1:1 mixture of [2-2 H2]-and [6,6-2 H2]glucose in RG IUGR vs. PL IUGR revealed glucose tolerance with a lower glucose-stimulated insulin release (GSIR) and suppressed endogenous hepatic glucose production (HGP) with no difference in glucose clearance (GC) and recycling (GR). RG PNGR, although similar to PL CON, was hyperglycemic vs. PL PNGR with reduced GR but no difference in the existent low GSIR, HGP, and GC. RG IUGR ϩ PNGR overall was no different from the PL counterpart. Insulin tolerance tests revealed perturbed recovery to baseline from the exaggerated hypoglycemia in RG vs. the PL groups with the only exception being RG PNGR where further worsening of hypoglycemia over PL PNGR was minimal with full recovery to baseline. These observations support that early intervention with RG suppressed HGP in IUGR vs. PL IUGR, without increasing GSIR similar to that seen in CON. Although RG reversed PNGR to the PL CON metabolic state, no such insulin-sensitizing effect was realized in IUGR ϩ PNGR.glucose tolerance test; hepatic glucose production; stable isotopes LOW BIRTH WEIGHT ALONE and in association with slow growth during early childhood has been epidemiologically associated with the acquisition of type 2 diabetes mellitus among various other adult-onset chronic diseases (2-4, 12, 24). Animal investigations employing differing nutrient restriction models of intrauterine growth restriction (IUGR) and postnatal growth restriction suggest that diabetes mellitus stems from an imbalance between insulin production because of decreased pancreatic ␤-cell mass (5, 22, 40) and reduced insulin sensitivity in select organs (15,21,43). Regardless of the exact pathophysiology, pregnancy in the adult IUGR rat offspring results in gestational diabetes (6). This gesta...

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Involvement of adipose tissues in the early hypolipidemic action of PPARγ agonism in the rat

Cited by 29 publications

References 50 publications

Thermogenically competent nonadrenergic recruitment in brown preadipocytes by a PPARγ agonist

Thermogenically competent nonadrenergic recruitment in brown preadipocytes by a PPARγ agonist

Additive action of 11β-HSD1 inhibition and PPAR-γ agonism on hepatic steatosis and triglyceridemia in diet-induced obese rats

Early exposure of the pregestational intrauterine and postnatal growth-restricted female offspring to a peroxisome proliferator-activated receptor-γ agonist

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