Editors' ChoiceMetabolism

A SUMOylated Energy Switch

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Science Signaling  10 Jun 2008:
Vol. 1, Issue 23, pp. ec212
DOI: 10.1126/scisignal.123ec212

Energy homeostasis--and maintenance of body weight--depends on balancing energy intake and expenditure. Indeed, dysregulation of skeletal muscle energy metabolism may play a role in obesity and metabolic syndrome. Oishi et al. found that mice heterozygous for Krüppel-like transcription factor 5 (KLF5) fed a high-fat diet gained less weight--despite eating more food--than did wild-type littermates. Klf5+/– mice were also resistant to high fat-induced glucose intolerance and had lower serum cholesterol. Their O2 consumption and body temperature were higher and, in skeletal muscle, the expression of genes encoding proteins involved in lipid oxidation and energy uncoupling was increased. KLF5 inhibited C/EBP-β-dependent transactivation of the promoters of carnitine-palmitoyl transferase-1b (CPT1b, a rate-limiting enzyme in fatty enzyme oxidation) and uncoupling proteins 2 and 3 (UCP2 and UCP3) in C2C12 myotubes. KLF5 was subject to posttranslational modification by small ubiquitin-related modifier (SUMO) proteins, and a SUMOylation-deficient KLF5 mutant failed to inhibit C/EBP-β-dependent transactivation of the Cpt1b, Ucp2, and Ucp3 promoters; moreover, SUMOylation enhanced KLF5 interaction with the transcriptional corepressors NCoR and SMRT. The phenotype of the Klf5+/– mice resembled that of mice treated with agonists of the metabolic regulator peroxisome proliferator-activated receptor-δ (PPAR-δ), and KLF5 coimmunoprecipitated with PPAR-δ. Chromatin immunoprecipitation analysis indicated that KLF5, PPAR-δ, NCoR, and SMRT all associated with the Cpt1b, Ucp2, and Ucp3 promoters. The PPAR-δ agonist GW501516 stimulated recruitment of the SUMO protease SENP1 to these promoters, followed by local deSUMOylation, loss of NCoR and SMRT, and recruitment of the coactivator CBP. Experiments in which various combinations of KLF5, the SUMOylation-deficient KLF5 mutant, PPAR-δ, CBP, and SENP1 were coexpressed with a Ucp3 reporter indicated that GW501516 stimulated the Ucp3 promoter, a response that required SUMOylatable KLF5. Thus, ligand stimulation of PPAR-δ seems to trigger KLF5 deSUMOylation, thereby flipping a "switch" from a complex that inhibits the transcription of genes involved in energy expenditure to one that stimulates it. Jain provides thoughtful commentary.

Y. Oishi, I. Manabe, K. Tobe, M. Ohsugi, T. Kubota, K. Fujiu, K. Maemura, N. Kubota, T. Kadowaki, R. Nagai, SUMOylation of Krüppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-δ. Nat. Med. 14, 656-666 (2008). [PubMed]

M. K. Jain, Multiple layers of metabolism. Nat. Med. 14, 603-604 (2008). [PubMed]

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