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.

Figure 1

Characterization of mice with an intestinal epithelial specific deletion of the PPARδ gene (PPARδ^IEC-KO). mRNA levels of (A) Cre recombinase and (B) PPARδ in mucosal scrapings from the small intestine (normalized to 36b4); ND = not detectable; (C) Fat balance (% of dietary fat absorption) in mice on a LFD and HFD (45% energy content in fat); (D) Fecal excretion of neutral sterols (NS) and bile acids (BA); (E) Total bacterial counts in the distal part of the intestine (in intestinal content and mucosa combined) in wild-type and PPARδ^IEC-KO mice (n = 7–9).

Figure 2

Effect of a HFD on diet-induced obesity, hepatic steatosis and insulin sensitivity in PPARδ^IEC-KO and wild-type mice. Effect of a HFD challenge on (A) Body weight; (B) Body weight gain; (C) Liver and white adipose tissue (WAT) (epididymal, omental and subcutaneous) weights; (D) Liver weight as % of body weight; (E) NAFLD activity score (NAS score); (F) Fasting blood glucose; (G) Fasting blood insulin; (H) Glucose stimulated insulin secretion (GSIS, 2 g/kg p.o. glucose); (I) Oral glucose tolerance test (OGTT, 2 g/kg p.o. glucose), graph insert showing area under the curve (AUC); (J) Insulin tolerance test (ITT, graph insert showing AUC, in PPARδ^IEC-KO mice and wild-type littermates (n = 7–10).

Figure 3

Effect of a HFD on plasma lipoprotein, plasma GLP1 and intestinal gene expression in PPARδ^IEC-KO and wild-type mice. (A,B) FPLC Lipoprotein cholesterol profiles of pooled plasma samples from PPARδ^IEC-KO mice and wild-type littermates fed a (A) LFD (n = 4–5) or (B) HFD (n = 10); Effect of a HFD challenge on (C) mRNA levels of proglucagon in distal small intestine (normalized to 36b4); (D) Plasma levels of Active GLP-1 (7–36) amide and GLP-1 (7–37) in wild-type and PPARδ^IEC-KO mice fed a LFD (n = 4–8) or HFD (n = 10); (E,F) mRNA levels of genes involved in lipoprotein metabolism and inflammation in the mucosa of the distal small intestine of (E) wild-type and (F) PPARδ^IEC-KO mice (normalized to 36b4).

Figure 4

Effect of PPARδ activation on cholesterol metabolism and intestinal gene expression in PPARδ^IEC-KO and wild-type mice. (A,B) FPLC Lipoprotein cholesterol profiles of pooled plasma samples from (A) wild-type and (B) PPARδ^IEC-KO mice treated with for 14 days with GW501516 or vehicle (n = 7). Plasma levels of (C) HDLc; and (D) Fecal neutral sterol (NS) excretion in wild-type and PPARδ^IEC-KO mice (n = 7) treated for 14 days with GW501516 (GW) or vehicle; (E,F) Levels of mRNA (normalized to 36b4) of genes involved in lipoprotein metabolism and inflammation in the mucosa of the small intestine of (F) wild-type and (G) PPARδ^IEC-KO mice treated for 14 days with GW501516 or vehicle (n = 7).