Nuclear receptors and their coactivators have been shown to function as key regulators of adipose tissue biology. Here we show that a ligand-dependent transcriptional repressor for nuclear receptors plays a crucial role in regulating the balance between energy storage and energy expenditure. Mice devoid of the corepressor protein RIP140 are lean, show resistance to high-fat diet-induced obesity and hepatic steatosis, and have increased oxygen consumption. Although the process of adipogenesis is unaffected, expression of certain lipogenic enzymes is reduced. In contrast, genes involved in energy dissipation and mitochondrial uncoupling, including uncoupling protein 1, are markedly increased. Therefore, the maintenance of energy homeostasis requires the action of a transcriptional repressor in white adipose tissue, and ligand-dependent recruitment of RIP140 to nuclear receptors may provide a therapeutic target in the treatment of obesity and related disorders. E nergy homeostasis is a highly regulated process that requires precise control of food intake and energy expenditure (1). The major and most efficient storage of energy occurs in the form of triglycerides in white adipose tissue (WAT), and it is now clear that the adipocyte itself may act as an endocrine cell such that altered adipocyte function would cause changes in systemic energy balance (2, 3). From adipogenic stores, fatty acids are easily mobilized during periods of energy restriction or increased physical activity to provide enough fuel for energy synthesis in the form of ATP. In addition, energy is dissipated by generating heat in brown adipose tissue (BAT) and skeletal muscles by regulating the uncoupling of ATP production from respiration. Many of these metabolic processes are controlled in part by nuclear receptors (4, 5), including peroxisome proliferatoractivated receptors (PPARs) (6, 7), thyroid hormone receptor (8, 9), estrogen receptor ␣ (ER␣) (10, 11), and ER-related receptor ␣ (ERR␣) (12). The best characterized of these are the PPARs, with PPAR␥ and PPAR␣ playing an essential role in adipogenesis (13-16) and in thermogenesis and fatty acid oxidation (17-19), respectively, whereas recent studies have implicated a role for PPAR␦ in lipid homeostasis (20).Nuclear receptors stimulate target gene transcription by recruiting coactivators that are required to remodel chromatin and facilitate the assembly of the basal transcription machinery (21). The key coactivator in metabolic processes is the PPAR␥ coactivator 1␣ (PGC-1␣) (22-25), which was initially shown to promote adaptive thermogenesis in BAT and which has emerged as a target for integrating signals in the regulation of specific metabolic programs in other tissues, including muscle and liver. More recently, the related coactivator PGC-1␤ (26, 27) has been implicated in the regulation of energy expenditure as a potential coactivator for ERR␣ (28). In addition, the p160 family of coactivators has also been found to control energy balance in adipose tissue. For instance, SRC1, in associatio...

LEKTI is a 15-domain serine proteinase inhibitor whose defective expression underlies the severe autosomal recessive ichthyosiform skin disease, Netherton syndrome. Here, we show that LEKTI is produced as a precursor rapidly cleaved by furin, generating a variety of single or multidomain LEKTI fragments secreted in cultured keratinocytes and in the epidermis. The identity of these biological fragments (D1, D5, D6, D8 -D11, and D9 -D15) was inferred from biochemical analysis, using a panel of LEKTI antibodies. The functional inhibitory capacity of each fragment was tested on a panel of serine proteases. All LEKTI fragments, except D1, showed specific and differential inhibition of human kallikreins 5, 7, and 14. The strongest inhibition was observed with D8 -D11, toward KLK5. Kinetics analysis revealed that this interaction is rapid and irreversible, reflecting an extremely tight binding complex. We demonstrated that pH variations govern this interaction, leading to the release of active KLK5 from the complex at acidic pH. These results identify KLK5, a key actor of the desquamation process, as the major target of LEKTI. They disclose a new mechanism of skin homeostasis by which the epidermal pH gradient allows precisely regulated KLK5 activity and corneodesmosomal cleavage in the most superficial layers of the stratum corneum.