Although peroxisome proliferator-activated receptor gamma (PPARγ) 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 PPARγ 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, PPARγ activation in mature adipocytes normalizes serum insulin without increased adipogenesis. Co-culture studies indicated that PPARγ-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 PPARγ is sufficient for complete insulin sensitization and suggest a specific application for fat selective PPARγ modulators in diabetic therapy.

https://www.pnas.org/content/pnas/106/52/22504.full.pdf

PPARγ activation in adipocytes is sufficient for systemic insulin sensitization

MOON, HYUN-SEUK, CHUNG-SOO CHUNG, HONGGU LEE, TAE-GYU KIM, YUN-JAIE CHOI, AND CHONG-SU CHO. Inhibitory effect of ()epigallocatechin-3-gallate on lipid accumulation of 3T3-L1 cells. Obesity. 2007;15:2571–2582. Objective: The objective of this study was to investigate the molecular mechanisms underlying the attenuating effect of ()-epigallocatechin-3-gallate (EGCG) on proliferation and lipid accumulation of 3T3-L1 cells, with a focus on the duration of EGCG treatment. Research Methods and Procedures: Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay and diamidino-2-phenylindole staining. The anti-adipogenic effect of EGCG on 3T3-L1 cells was analyzed by glycerol-3-phosphate dehydrogenase activity and Oil red O staining. Western blot analysis was used to detect adenosine monophosphate-activated protein kinase (AMPK) activation and phosphorylation of its substrate, acetyl-CoA carboxylase (ACC), and expression of insulin (INS) receptor, INS receptor substrate-1 (IRS-1), and adipocyte marker proteins. Results: Exposure to EGCG during the early period of adipogenesis (7 days) was sufficient to prevent lipid accumulation. During this period, EGCG greatly decreased expression of the adipocyte marker proteins peroxisome proliferator-activated receptor 2 (PPAR2) and liver X receptor (LXR)-. Furthermore, EGCG significantly induced generation of reactive oxygen species (ROS), which led to AMPK activation, and these effects were eliminated by N-acetylcysteine (NAC) treatment. Also, EGCG increased the tyrosine phosphorylation of INS receptor and INS-1 with increasing incubation time. In contrast, EGCG treatment did not alter glycerol release in the presence or absence of 2,5-dideoxyadenosine (DDA), indicating that EGCG had no effect on lipolysis. Discussion: Our data demonstrate that EGCG decreased cell viability and inhibited differentiation of 3T3-L1 cells in a manner dependent on the duration of treatment. Also, we showed that inhibition of adipocyte differentiation by EGCG was associated with decreased glycerol-3-phosphate dehydrogenase (GPDH) activity accompanied by a strong inhibition of PPAR2-induced transcriptional activity. Furthermore, the inhibition of adipocyte differentiation by EGCG involved generation of ROS and activation of AMPK.

Inhibitory Effect of (-)-Epigallocatechin-3-Gallate on Lipid Accumulation of 3T3-L1 Cells

Proposed mechanisms of (-)-epigallocatechin-3-gallate for anti-obesity

Antiobesity effects of quercetin-rich onion peel extract on the differentiation of 3T3-L1 preadipocytes and the adipogenesis in high fat-fed rats.

Kruppel-like transcription factor 2 (KLF2), a critical gene for mouse embryogenesis, was recently identified as an inhibitor of adipogenesis. However, it is still unknown whether KLF2 is a natural repressor of adipocyte differentiation and if KLF2 affects the formation of preadipocytes. It may also be important for preadipocyte formation, as KLF2 is crucial for lung development and blood vessel formation. In this study, we show that differentiation of preadipocytes not only results in a concomitant decrease in the levels of KLF2 protein but also significantly reduces KLF2 promoter activity. We have generated tet-responsive lines of 3T3L1 that express physiological levels of KLF2 and show that reexpression of KLF2 prevents preadipocyte differentiation, thereby confirming the inhibition of adipogenesis by KLF2, partially via the restoration of Pref-1. In addition, we studied the contribution of KLF2-negative cells to the formation and subsequent differentiation of preadipocytes. We demonstrate that embryoid...

The KLF2 transcription factor does not affect the formation of preadipocytes but inhibits their differentiation into adipocytes.

This review highlights the presentations and discussions held during the 2003 Stock Conference in Lisbon focussed on the identification of new therapeutic targets for the treatment of obesity and identified through molecular and genetic studies. Transcription factors and their cofactors, signalling pathways and new insights provided by cellular and genetic studies were discussed as potential new avenues to modulate adipocyte formation and function

J. Auwerx

Papers

Adipose tissue: new therapeutic targets from molecular and genetic studies – IASO Stock Conference 2003 report