Intestinal PPARδ protects against diet-induced obesity, insulin resistance and dyslipidemia

Marcela Doktorova; Irene Zwarts; Tim van Zutphen; Theo H. Van DIjk; Vincent W. Bloks; Liesbeth Harkema; Alain De Bruin; Michael Downes; Ronald M Evans; Henkjan J Verkade; Johan W Jonker

doi:10.1038/s41598-017-00889-z

Intestinal PPARδ protects against diet-induced obesity, insulin resistance and dyslipidemia

Marcela Doktorova, Irene Zwarts, Tim van Zutphen, Theo H. Van DIjk, Vincent W. Bloks, Liesbeth Harkema, Alain De Bruin, Michael Downes, Ronald M Evans, Henkjan J Verkade, Johan W Jonker

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Peroxisome proliferator-activated receptor δ (PPARδ) is a ligand-activated transcription factor that has an important role in lipid metabolism. Activation of PPARδ stimulates fatty acid oxidation in adipose tissue and skeletal muscle and improves dyslipidemia in mice and humans. PPARδ is highly expressed in the intestinal tract but its physiological function in this organ is not known. Using mice with an intestinal epithelial cell-specific deletion of PPARδ, we show that intestinal PPARδ protects against diet-induced obesity, insulin resistance and dyslipidemia. Furthermore, absence of intestinal PPARδ abolished the ability of PPARδ agonist GW501516 to increase plasma levels of HDL-cholesterol. Together, our findings show that intestinal PPARδ is important in maintaining metabolic homeostasis and suggest that intestinal-specific activation of PPARδ could be a therapeutic approach for treatment of the metabolic syndrome and dyslipidemia, while avoiding systemic toxicity.

Original language	English
Number of pages	10
Journal	Scientific Reports
Volume	7
DOIs	https://doi.org/10.1038/s41598-017-00889-z
Publication status	Published - 1 Dec 2017

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title = "Intestinal PPARδ protects against diet-induced obesity, insulin resistance and dyslipidemia",

abstract = "Peroxisome proliferator-activated receptor δ (PPARδ) is a ligand-activated transcription factor that has an important role in lipid metabolism. Activation of PPARδ stimulates fatty acid oxidation in adipose tissue and skeletal muscle and improves dyslipidemia in mice and humans. PPARδ is highly expressed in the intestinal tract but its physiological function in this organ is not known. Using mice with an intestinal epithelial cell-specific deletion of PPARδ, we show that intestinal PPARδ protects against diet-induced obesity, insulin resistance and dyslipidemia. Furthermore, absence of intestinal PPARδ abolished the ability of PPARδ agonist GW501516 to increase plasma levels of HDL-cholesterol. Together, our findings show that intestinal PPARδ is important in maintaining metabolic homeostasis and suggest that intestinal-specific activation of PPARδ could be a therapeutic approach for treatment of the metabolic syndrome and dyslipidemia, while avoiding systemic toxicity.",

author = "Marcela Doktorova and Irene Zwarts and {van Zutphen}, Tim and {Van DIjk}, {Theo H.} and Bloks, {Vincent W.} and Liesbeth Harkema and {De Bruin}, Alain and Michael Downes and Evans, {Ronald M} and Verkade, {Henkjan J} and Jonker, {Johan W}",

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doi = "10.1038/s41598-017-00889-z",

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T1 - Intestinal PPARδ protects against diet-induced obesity, insulin resistance and dyslipidemia

AU - Doktorova, Marcela

AU - Zwarts, Irene

AU - van Zutphen, Tim

AU - Van DIjk, Theo H.

AU - Bloks, Vincent W.

AU - Harkema, Liesbeth

AU - De Bruin, Alain

AU - Downes, Michael

AU - Evans, Ronald M

AU - Verkade, Henkjan J

AU - Jonker, Johan W

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Peroxisome proliferator-activated receptor δ (PPARδ) is a ligand-activated transcription factor that has an important role in lipid metabolism. Activation of PPARδ stimulates fatty acid oxidation in adipose tissue and skeletal muscle and improves dyslipidemia in mice and humans. PPARδ is highly expressed in the intestinal tract but its physiological function in this organ is not known. Using mice with an intestinal epithelial cell-specific deletion of PPARδ, we show that intestinal PPARδ protects against diet-induced obesity, insulin resistance and dyslipidemia. Furthermore, absence of intestinal PPARδ abolished the ability of PPARδ agonist GW501516 to increase plasma levels of HDL-cholesterol. Together, our findings show that intestinal PPARδ is important in maintaining metabolic homeostasis and suggest that intestinal-specific activation of PPARδ could be a therapeutic approach for treatment of the metabolic syndrome and dyslipidemia, while avoiding systemic toxicity.

AB - Peroxisome proliferator-activated receptor δ (PPARδ) is a ligand-activated transcription factor that has an important role in lipid metabolism. Activation of PPARδ stimulates fatty acid oxidation in adipose tissue and skeletal muscle and improves dyslipidemia in mice and humans. PPARδ is highly expressed in the intestinal tract but its physiological function in this organ is not known. Using mice with an intestinal epithelial cell-specific deletion of PPARδ, we show that intestinal PPARδ protects against diet-induced obesity, insulin resistance and dyslipidemia. Furthermore, absence of intestinal PPARδ abolished the ability of PPARδ agonist GW501516 to increase plasma levels of HDL-cholesterol. Together, our findings show that intestinal PPARδ is important in maintaining metabolic homeostasis and suggest that intestinal-specific activation of PPARδ could be a therapeutic approach for treatment of the metabolic syndrome and dyslipidemia, while avoiding systemic toxicity.

U2 - 10.1038/s41598-017-00889-z

DO - 10.1038/s41598-017-00889-z

M3 - Article

C2 - 28404991

SN - 2045-2322

VL - 7

JO - Scientific Reports

JF - Scientific Reports

ER -

Intestinal PPARδ protects against diet-induced obesity, insulin resistance and dyslipidemia

Abstract

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