Abstract

Obesity and metabolic syndrome are increasingly recognized as major risk factors for cardiovascular disease. Herein we show that Krüppel-like transcription factor 5 (KLF5) is a crucial regulator of energy metabolism. Klf5^+/- mice were resistant to high fat–induced obesity, hypercholesterolemia and glucose intolerance, despite consuming more food than wild-type mice. This may in part reflect their enhanced energy expenditure. Expression of the genes involved in lipid oxidation and energy uncoupling, including those encoding carnitine-palmitoyl transferase-1b (Cpt1b) and uncoupling proteins 2 and 3 (Ucp2 and Ucp3), was upregulated in the soleus muscles of Klf5^+/- mice. Under basal conditions, KLF5 modified with small ubiquitin-related modifier (SUMO) proteins was associated with transcriptionally repressive regulatory complexes containing unliganded peroxisome proliferator–activated receptor- (PPAR-) and co-repressors and thus inhibited Cpt1b, Ucp2 and Ucp3 expression. Upon agonist stimulation of PPAR-, KLF5 was deSUMOylated, and became associated with transcriptional activation complexes containing both the liganded PPAR- and CREB binding protein (CBP). This activation complex increased the expression of Cpt1b, Ucp2 and Ucp3. Thus, SUMOylation seems to be a molecular switch affecting function of KLF5 and the transcriptional regulatory programs governing lipid metabolism.

1. Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo 113-8655, Japan.
2. Clinical Nutrition Program, National Institute of Health and Nutrition, 1-23-1, Toyama, Shinjuku, Tokyo 162-8636, Japan.
3. Nano-Bioengineering Education Program, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo 113-8655, Japan.
4. Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo 113-8655, Japan.
5. First Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.

Correspondence to: Ichiro Manabe^1,3Ryozo Nagai¹ e-mail: manabe-tky@umin.ac.jp

Correspondence to: e-mail: nagai-tky@umin.ac.jp

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