PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization - PubMed (original) (raw)

. 2009 Dec 29;106(52):22504-9.

doi: 10.1073/pnas.0912487106. Epub 2009 Dec 16.

Peter Olson, Dorothy D Sears, Maziyar Saberi, Annette R Atkins, Grant D Barish, Suk-Hyun Hong, Glenda L Castro, Yun-Qiang Yin, Michael C Nelson, Gene Hsiao, David R Greaves, Michael Downes, Ruth T Yu, Jerrold M Olefsky, Ronald M Evans

Affiliations

PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization

Shigeki Sugii et al. Proc Natl Acad Sci U S A. 2009.

Abstract

Although peroxisome proliferator-activated receptor gamma (PPARgamma) agonists such as thiazolidinediones (TZDs) are widely used to treat type 2 diabetes, how its activation in individual tissues contributes to TZD's therapeutic action remains controversial. As TZDs are known to have receptor-independent effects, we sought to establish gain-of-function animal models to delineate the receptor's insulin-sensitizing actions. Unexpectedly, we find that selective activation of PPARgamma in adipocytes, but not in macrophages, is sufficient for whole-body insulin sensitization equivalent to systemic TZD treatment. In addition to improved adipokine, inflammatory, and lipid profiles, PPARgamma activation in mature adipocytes normalizes serum insulin without increased adipogenesis. Co-culture studies indicated that PPARgamma-activated adipocytes broadly suppress induction of inflammatory cytokines and C-X-C family chemokines in macrophages. Collectively, these data describe an "adipocentric" model in which adipose activation of PPARgamma is sufficient for complete insulin sensitization and suggest a specific application for fat selective PPARgamma modulators in diabetic therapy.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Adipose-specific PPARγ transgene expression exhibits comparable insulin-sensitizing effects to thiazolidinediones. (A) Fasting plasma insulin is dramatically reduced in TG mice on HFD feeding. *, P < 0.05 vs. WT fed HFD. (B) ITT were performed on WT and TG mice fed HFD for 4.5 months treated with or without TZD for 1.5 months (n = 9–11). Note that both TZD treatment and transgene expression improve insulin sensitivities to a similar degree. #, P < 0.05 for WT vs. TG or TG+TZD, P < 0.09 for WT vs. WT+TZD; *, P < 0.05 for WT vs. WT+TZD or TG, P < 0.07 for WT vs. TG+TZD; **, P < 0.05 WT vs. all other groups. (C) GTT were conducted on WT and TG mice fed HFD for 4 months treated with or without TZD for one month (n = 11). Note that both TZD treated and transgenic mice exhibit comparable enhancement of glucose excursion curves. #, P < 0.05 for WT vs. WT+TZD or TG+TZD, P < 0.06 for WT vs. TG; *, P < 0.05 WT vs. all other groups. (D) Plasma insulin levels during GTT. *, P < 0.02 vs. WT. (E) The level of insulin resistance is calculated from the same group (n = 11). *, P < 10−8. (F) TZD-treated and transgenic mice exhibit higher glucose infusion rates (GIR) during euglycemic-hyperinsulinemic clamp. For the clamp experiments, mice were fed HFD for 8 months (n = 6). *, P < 0.05. (G) Glucose disposal rate (GDR) in skeletal muscle during clamp procedure is higher in TZD-treated and transgenic mice. #, P < 0.06; *, P < 0.05. (H) Basal hepatic glucose production (HGP) and insulin-stimulated HGP during clamp. *, P < 0.05. (I) The ability of insulin to suppress HGP is significantly enhanced by TZD treatment or PPARγ transgene expression. #, P < 0.06; *, P < 0.05.

Fig. 2.

Fig. 2.

Adipose PPARγ activation reduces adipocyte hypertrophy and leukocyte infiltration. (A) WAT cells are significantly smaller in TG mice fed HFD for 8 months as illustrated by H&E staining. Graphs show average cell size and cell number per mm2 calculated from four independent WAT sections per group. (Scale bar, 0.1 mm.) #, P < 0.005 vs. WT. (B) H&E staining of BAT sections. Cell size is significantly reduced and lipid accumulation is less in TG mice. (C) Macrophage staining of WAT sections. Immunohistochemistry was performed by using an antibody against the macrophage-specific marker CD68. The graph measures CD68-positive area versus entire fields from six independent sections. #, P < 0.005 vs. WT.

Fig. 3.

Fig. 3.

Gene chip analysis of HFD-fed white adipose tissue from PPARγ-activated mice highlights enrichment in categories of lipid and carbohydrate metabolism, immune response regulation, and insulin signaling. (A) Venn diagrams of gene expression changes from cDNA microarray in epididymal WAT after HFD feeding for 8 months. A large number of up-regulated (UP) and down-regulated (DOWN) genes compared to WT adipose tissue were found in TZD-treated WT, untreated TG, and TZD-treated TG groups. (B) Functional annotations of the microarray analysis in WAT. Gene clusters comprised of both UP and DOWN genes are listed from left to right in the order of significant enrichment. Gene ontology terms that are too broad or vague (e.g., “biological process,” “transport,” and “binding”) were omitted from the list. (C) Heat-map representation of a set of differentially regulated genes involved in selected biological categories.

Fig. 4.

Fig. 4.

Gene expression and protein analyses of white adipose tissue from PPARγ-activated mice reveal specific involvement of chemokine and insulin signaling pathways. (A) Real-time qPCR analysis of epididymal WAT (n = 4–6). *, P < 0.05 vs. WT. (B) qPCR analyses of CXC family chemokines in PPARγ activated epididymal WAT (upper graphs; in vivo) and in macrophages co-cultured with adipocytes (lower graphs; in vitro). RAW264.7 macrophage cells treated with or without 100 ng/mL LPS for 20 h were co-cultured with 3T3-L1 cells that stably express PPARγ and had been undifferentiated or differentiated (diff.). (C) Phosphorylation of Akt at Ser-473 from WAT, liver and muscle in basal and insulin-stimulated states (n = 4–6). #, P < 0.01 vs. insulin-stimulated WT.

References

    1. Imai T, et al. Peroxisome proliferator-activated receptor gamma is required in mature white and brown adipocytes for their survival in the mouse. Proc Natl Acad Sci USA. 2004;101:4543–4547. -PMC -PubMed
    1. Tontonoz P, Spiegelman BM. Fat and beyond: The diverse biology of PPARgamma. Annu Rev Biochem. 2008;77:289–312. -PubMed
    1. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: Tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994;8:1224–1234. -PubMed
    1. Lehmann JM, et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma) J Biol Chem. 1995;270:12953–12956. -PubMed
    1. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med. 2004;351:1106–1118. -PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources