Effects of initial BMI and on-treatment weight change on the lipid-lowering efficacy of fibrates

Muls, Erik; Gaal, Luc Van; Autier, Philippe; Vansant, Greet

doi:10.1038/sj.ijo.0800370

Cited by 10 publications

(5 citation statements)

References 8 publications

(9 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, the efficacy of fibrate drugs in modulating circulating lipids in humans has been documented (19,64,65). Moreover, the recent report that the LDL-cholesterol-lowering efficacy of fibrate drugs is positively associated with on-treatment weight loss in humans (66), corroborated by an initial observation in rodents, is consistent with our report of weight gain when the murine PPAR␣ pathway is abolished. This model of monogenic, maturity onset, spontaneous obesity with deficient PPAR␣ transduction, could lead to new insights into the etiology of some form(s) of mammalian obesity and their heritability.…”

Section: Figsupporting

confidence: 91%

Peroxisome Proliferator-activated Receptor α-Isoform Deficiency Leads to Progressive Dyslipidemia with Sexually Dimorphic Obesity and Steatosis

Costet¹,

Legendre²,

Moré³

et al. 1998

Journal of Biological Chemistry

370

251

View full text Add to dashboard Cite

The ␣-isoform of the peroxisome proliferator-activated receptor (PPAR␣) is a nuclear transcription factor activated by structurally diverse chemicals referred to as peroxisome proliferators. Activators can be endogenous molecules (fatty acids/steroids) or xenobiotics (fibrate lipid-lowering drugs). Upon pharmacological activation, PPAR␣ modulates target genes encoding lipid metabolism enzymes, lipid transporters, or apolipoproteins, suggesting a role in lipid homeostasis. Transgenic mice deficient in PPAR␣ were shown to lack hepatic peroxisomal proliferation and have an impaired expression and induction of several hepatic target genes. Young adult males show hypercholesterolemia but normal triglycerides. Using a long term experimental set up, we identified these mice as a model of monogenic, spontaneous, late onset obesity with stable caloric intake and a marked sexual dimorphism. Serum triglycerides, elevated in aged animals, are higher in females that develop a more pronounced obesity than males. The latter show a marked and original centrilobular-restricted steatosis and a delayed occurrence of obesity. Fat cells from their liver express substantial levels of PPAR␥2 transcripts when compared with lean cells. These studies demonstrate, in rodents, the involvement of PPAR␣ nuclear receptor in lipid homeostasis, with a sexually dimorphic control of circulating lipids, fat storage, and obesity. Characterization of this pathological link may help to delineate new molecular targets for therapeutic intervention and could lead to new insights into the etiology and heritability of mammalian obesity.Obesity, an increasing health problem in wealthy societies, has been causatively linked to hyperlipidemia, diabetes, hypertension, and atherosclerosis. Adipose cell hypertrophy and hyperplasia occur as the ultimate consequence of a disequilibrium in energy balance and exert adverse effects on longevity (1, 2). Several causal genetic determinants responsible for spontaneous monogenic obesity in mice (ob, db, tub, A r , and fat genes) have been identified (reviewed in Ref. 3). In humans, a limited number of obese syndromes have been related to single gene disorders (e.g. Ahlstrom, Bardet Biedl, Cohen, Prader Willi). Recently, two mutations, affecting the leptin signal transduction pathway and leading to human early onset morbid obesity, have been characterized. They affect the ob gene (4), encoding leptin, and the leptin receptor gene (5), respectively. A mutation in the human prohormone convertase 1 gene, leading to childhood obesity, has been documented (6), and tissue-specific attenuation of the prohormone convertase 2 gene has been reported in two patients with Prader-Willi syndrome (7). Proconvertases act, proximally to carboxypeptidase E, in the pathway of post-translational processing of prohormones and neuropeptides, therefore associating this syndrome with the fat/fat murine phenotype. Prevalence of these mutations in the human obese population was reported as being rather limited (4, 5), and human counterparts ...

show abstract

Section: Figsupporting

confidence: 91%

Peroxisome Proliferator-activated Receptor α-Isoform Deficiency Leads to Progressive Dyslipidemia with Sexually Dimorphic Obesity and Steatosis

Costet¹,

Legendre²,

Moré³

et al. 1998

Journal of Biological Chemistry

370

251

View full text Add to dashboard Cite

show abstract

“…Also, an obesity-prone strain of mice, C57Bl/6J, fails to show an increase in UCP-2 expression in response to a high-fat diet, whereas an obesity-resistant strain increases expression twofold (13). Finally, the fibrates, which activate PPAR␣, decrease serum triglyceride levels and body weight in humans, indicating a potential role of PPAR␣ in body weight regulation (29). Our data indicate that UCP-2 could potentially be involved, in that PPAR␣ agonists result in a large increase in UCP-2 expression.…”

Section: Discussionmentioning

confidence: 99%

Polyunsaturated fatty acids stimulate hepatic UCP-2 expression via a PPARα-mediated pathway

Armstrong

Towle

2001

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

The discovery of homologs of the brown fat uncoupling protein(s) (UCP) UCP-2 and UCP-3 revived the hypothesis of uncoupling protein involvement in the regulation of energy metabolism. Thus we hypothesized that UCP-2 would be regulated in the hepatocyte by fatty acids, which are known to control other energy-related metabolic processes. Treatment with 250 microM palmitic acid was without effect on UCP-2 expression, whereas 250 microM oleic acid exhibited a modest eightfold increase. Eicosapentaenoic acid (EPA), a polyunsaturated fatty acid, exerted a 50-fold upregulation of UCP-2 that was concentration dependent. This effect was seen within 12 h and was maximal by 36 h. Aspirin blocked the induction of UCP-2 by EPA, indicating involvement of the prostaglandin pathway. Hepatocytes treated with arachidonic acid, the immediate precursor to the prostaglandins, also exhibited an aspirin-inhibitable increase in UCP-2 levels, further supporting the involvement of prostaglandins in regulating hepatic UCP-2. The peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist Wy-14643 stimulated UCP-2 mRNA levels as effectively as EPA. These data indicate that UCP-2 is upregulated by polyunsaturated fatty acids, potentially through a prostaglandin/PPARalpha-mediated pathway.

show abstract

“…Hepatic PPARα levels are likely 10‐fold lower in humans than mice, and fibrates cause hepatic toxicity in rodents but not humans, suggesting that rodents may not be a good model for predicting the effects of PPARα modulation in humans (104,112). Nevertheless, the ability of PPARα agonists to lower lipid levels in rodents is consistent with their lipid‐lowering effects in humans (103,110,111,113,114). In addition, there is more direct evidence that PPARα may play a role in human obesity.…”

Section: Introductionmentioning

confidence: 86%

“…When considering the ability of PPARα agonists to induce fat loss in humans, available data are too limited to draw firm conclusions. It is possible that PPARα agonists exert very modest effects on fat loss in a subset of humans, as they do in rodents (103–111,114), but detecting such subtle effects in humans will be very difficult without carefully designed trials.…”

Section: Potential Obesity Targets: Knockout Phenotypes Model Therapementioning

confidence: 99%

“…In an independent study, this same mutation was associated with lower BMI in patients with type 2 diabetes (116). Also, the ability of fibrates to lower low‐density lipoprotein (LDL)‐cholesterol in humans was positively associated with on‐treatment weight loss (114). These observations are consistent with the possibility that, similar to rodents, some humans may respond to PPARα activation with modest weight loss.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Obesity drugs and their targets: correlation of mouse knockout phenotypes with drug effects in vivo

Powell

2006

Obesity Reviews

View full text Add to dashboard Cite

Sequencing of the human genome has yielded thousands of potential drug targets. The difficulty now is in determining which targets have real therapeutic value and should be the focus of a drug discovery effort. The available evidence suggests that knockout technology can be used prospectively to identify targets that are amenable to drug development for the treatment of a variety of diseases. This review compares the knockout phenotypes of 21 potential obesity targets with the effects of therapeutics designed for those targets on rodents and, when data were available, on humans. The phenotypes of obesity target knockouts model the effects seen when therapeutics designed for those obesity targets are delivered to rodents; of the 21 obesity targets reviewed, 16 showed a correspondence between knockout phenotype and drug effect in mice and/or rats. This suggests that, at least in terms of evaluating obesity targets, it is rare for compensatory developmental changes caused by the gene knockout to prevent detection of the relevant phenotype. In the majority of cases, the knockout phenotypes also modelled the effects seen when the relevant therapeutics were delivered to humans. Thus, it seems rational to use mouse knockout technology prospectively to identify genes that regulate body fat in vivo, and then to develop anti-obesity therapeutics by targeting the human protein products of these genes. Ultimately, the value of using this approach to identify novel targets for human anti-obesity therapies will be judged by future studies examining the anti-obesity effect, in humans, of the therapeutics that result from this approach.

show abstract

Effects of initial BMI and on-treatment weight change on the lipid-lowering efficacy of fibrates

Cited by 10 publications

References 8 publications

Peroxisome Proliferator-activated Receptor α-Isoform Deficiency Leads to Progressive Dyslipidemia with Sexually Dimorphic Obesity and Steatosis

Peroxisome Proliferator-activated Receptor α-Isoform Deficiency Leads to Progressive Dyslipidemia with Sexually Dimorphic Obesity and Steatosis

Polyunsaturated fatty acids stimulate hepatic UCP-2 expression via a PPARα-mediated pathway

Obesity drugs and their targets: correlation of mouse knockout phenotypes with drug effects in vivo

Contact Info

Product

Resources

About