A Unique PPARγ Ligand with Potent Insulin-Sensitizing yet Weak Adipogenic Activity

Rocchi, Stéphane; Picard, Frédéric; Vamecq, Jòseph; Gelman, Laurent; Potier, Noëlle; Zeyer, Denis; Dubuquoy, Laurent; Bac, Pierre; Champy, Marie‐France; Plunket, Kelli D.; Leesnitzer, Lisa M.; Blanchard, Steven G.; Desreumaux, Pierre; Moras, Dino; Renaud, Jean‐Paul; Auwerx, Johan

doi:10.1016/s1097-2765(01)00353-7

Cited by 265 publications

(213 citation statements)

References 42 publications

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“…One of the first SPPARgMs that was tested, and which validated this idea, is FMOC-l-Leucine (F-lLeu), which separates insulin sensitivity from adipogenesis in vivo [232].…”

Section: Selective Pparg Modulators: a Better Alternative?mentioning

confidence: 99%

Fat poetry: a kingdom for PPARγ

2007

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Adipose tissue is not an inert cell mass contributing only to the storage of fat, but a sophisticated ensemble of cellular components with highly specialized and complex functions. In addition to managing the most important energy reserve of the body, it secretes a multitude of soluble proteins called adipokines, which have beneficial or, alternatively, deleterious effects on the homeostasis of the whole body. The expression of these adipokines is an integrated response to various signals received from many organs, which depends heavily on the integrity and physiological status of the adipose tissue. One of the main regulators of gene expression in fat is the transcription factor peroxisome proliferatoractivated receptor g (PPARg), which is a fatty acid-and eicosanoid-dependent nuclear receptor that plays key roles in the development and maintenance of the adipose tissue. Furthermore, synthetic PPARg agonists are therapeutic agents used in the treatment of type 2 diabetes.This review discusses recent knowledge on the link between fat physiology and metabolic diseases, and the roles of PPARg in this interplay via the regulation of lipid and glucose metabolism. Finally, we assess the putative benefits of targeting this nuclear receptor with still-to-be-identified highly selective PPARg modulators.

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“…One of the first SPPARgMs that was tested, and which validated this idea, is FMOC-l-Leucine (F-lLeu), which separates insulin sensitivity from adipogenesis in vivo [232].…”

Section: Selective Pparg Modulators: a Better Alternative?mentioning

confidence: 99%

Fat poetry: a kingdom for PPARγ

2007

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“…However, treatment did not cause significant body weight gain nor marked increases in mRNA levels of PPAR␥-regulated adipocyte-ADRP and LPL genes, which are involved in lipid uptake and storage in adipose tissue, in contrast to pioglitazone. It has been suggested that Fmoc-L-leucine, a potent insulin-sensitizing compound, acts as a selective PPAR␥ modulator and improves insulin resistance in diabetic mice despite only marginally inducing adipocyte-ADRP and LPL gene expression in adipose tissue (28). It should be noted that treatment with this compound also had no effect on body weight.…”

Section: Isohumulones Up-regulated the Expression Of Genes Involved Imentioning

confidence: 99%

Isohumulones, Bitter Acids Derived from Hops, Activate Both Peroxisome Proliferator-activated Receptor α and γ and Reduce Insulin Resistance

Yajima

Ikeshima

Shiraki

et al. 2004

Journal of Biological Chemistry

154

132

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The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects of fibrate drugs and the therapeutic benefits of the thiazolidinedione drugs are due to their activation of PPAR␣ and -␥, respectively. In this study, isohumulones, the bitter compounds derived from hops that are present in beer, were found to activate PPAR␣ and -␥ in transient co-transfection studies. Among the three major isohumulone homologs, isohumulone and isocohumulone were found to activate PPAR␣ and -␥. Diabetic KK-A y mice that were treated with isohumulones (isohumulone and isocohumulone) showed reduced plasma glucose, triglyceride, and free fatty acid levels (65.3, 62.6, and 73.1%, respectively, for isohumulone); similar reductions were found following treatment with the thiazolidinedione drug, pioglitazone. Isohumulone treatment did not result in significant body weight gain, although pioglitazone treatment did increase body weight (10.6% increase versus control group). C57BL/6N mice fed a high fat diet that were treated with isohumulones showed improved glucose tolerance and reduced insulin resistance. Furthermore, these animals showed increased liver fatty acid oxidation and a decrease in size and an increase in apoptosis of their hypertrophic adipocytes. A double-blind, placebo-controlled pilot study for studying the effect of isohumulones on diabetes suggested that isohumulones significantly decreased blood glucose and hemoglobin A1c levels after 8 weeks (by 10.1 and 6.4%, respectively, versus week 0). These results suggest that isohumulones can improve insulin sensitivity in high fat diet-fed mice with insulin resistance and in patients with type 2 diabetes.

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“…From day 3 on, cells were incubated with DMEM, 10% serum, 10 mg/ml insulin, and 10 À6 m rosiglitazone when stated. Oil-red-O staining is described elsewhere (Rocchi et al, 2001). Human colon adenocarcinoma CaCo2 and HT-29 cells (ATCC) were grown in Mc Coy's medium supplemented with 10% FCS.…”

Section: Cell Culture Protein Extracts and Transfectionsmentioning

confidence: 99%

PPARγ controls cell proliferation and apoptosis in an RB-dependent manner

et al. 2003

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The nuclear receptor PPARc is implicated in the control of cell proliferation and apoptosis. However, the molecular mechanisms by which it controls these processes remain largely elusive. We show here that PPARc activation in the presence of the retinoblastoma protein (RB) results in the arrest of cells at the G1 phase of the cell cycle, whereas in the absence of RB, cells accumulate in G2/M, endoreduplicate, and undergo apoptosis. Through the use of HDAC inhibitors and coimmunoprecipitations, we furthermore demonstrate that the effects of RB on PPARc-mediated control of the cell cycle and apoptosis depend on the recruitment of histone deacetylase 3 (HDAC3) to PPARc. In combination, these data hence demonstrate that the effects of PPARc on cell proliferation and apoptosis are dependent on the presence of an RB-HDAC3 complex.

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A Unique PPARγ Ligand with Potent Insulin-Sensitizing yet Weak Adipogenic Activity

Cited by 265 publications

References 42 publications

Fat poetry: a kingdom for PPARγ

Fat poetry: a kingdom for PPARγ

Isohumulones, Bitter Acids Derived from Hops, Activate Both Peroxisome Proliferator-activated Receptor α and γ and Reduce Insulin Resistance

PPARγ controls cell proliferation and apoptosis in an RB-dependent manner

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