The gene Ucp2 is a member of a family of genes found in animals and plants, encoding a protein homologous to the brown fat uncoupling protein Ucp1 (refs 1-3). As Ucp2 is widely expressed in mammalian tissues, uncouples respiration and resides within a region of genetic linkage to obesity, a role in energy dissipation has been proposed. We demonstrate here, however, that mice lacking Ucp2 following targeted gene disruption are not obese and have a normal response to cold exposure or high-fat diet. Expression of Ucp2 is robust in spleen, lung and isolated macrophages, suggesting a role for Ucp2 in immunity or inflammatory responsiveness. We investigated the response to infection with Toxoplasma gondii in Ucp2-/- mice, and found that they are completely resistant to infection, in contrast with the lethality observed in wild-type littermates. Parasitic cysts and inflammation sites in brain were significantly reduced in Ucp2-/- mice (63% decrease, P<0.04). Macrophages from Ucp2-/- mice generated more reactive oxygen species than wild-type mice (80% increase, P<0.001) in response to T. gondii, and had a fivefold greater toxoplasmacidal activity in vitro compared with wild-type mice (P<0.001 ), which was absent in the presence of a quencher of reactive oxygen species (ROS). Our results indicate a role for Ucp2 in the limitation of ROS and macrophage-mediated immunity.

One of the phenotypes of mice with targeted disruption of the uncoupling protein-2 gene (Ucp2؊/؊) is greater macrophage phagocytic activity and free radical production, resulting in a striking resistance to infectious microorganisms. In this study, the molecular mechanisms of this enhanced immune response were investigated. We found that levels of nitric oxide measured in either plasma or isolated macrophages from Ucp2؊/؊ mice are significantly elevated in response to bacterial lipopolysaccharide challenge compared with similarly treated Ucp2؉/؉ mice. Likewise, expression of inducible nitric-oxide synthase and inflammatory cytokines is higher in Ucp2؊/؊ mice in vivo and in vitro. Key steps in the activation cascade of nuclear factor (NF)-B, including IB kinase and nuclear translocation of NF-B subunits, are all remarkably enhanced in Ucp2؊/؊ mice, most notably even under basal conditions. The elevated basal activity of IB kinase in macrophages from Ucp2؊/؊ mice can be blocked by cell-permeable inhibitors of superoxide and hydrogen peroxide generation, but not by a specific inhibitor for inducible nitric-oxide synthase. Isolated mitochondria from Ucp2؊/؊ cells produced more superoxide/hydrogen peroxide. We conclude that mitochrondrially derived reactive oxygen from Ucp2؊/؊ cells constitutively activates NF-B, resulting in a "primed" state to both potentiate and amplify the inflammatory response upon subsequent stimulation. Uncoupling protein (UCP)1 -2 is a mitochondrial inner membrane carrier protein that was discovered through its homology to the brown fat UCP1 (1). Whereas UCP1 has been clearly established as the molecular mediator of non-shivering thermogenesis (reviewed in Ref. 2), the function of UCP2 remains somewhat of an enigma. Several features of UCP2 led us to initially propose that it was a bona fide uncoupling protein involved in the dissipation of excess metabolic fuel as heat. These aspects of UCP2 included its structural resemblance to UCP1, its ability to uncouple respiration in model assay systems, and a chromosomal location to a region with genetic linkage to obesity and hyperinsulinemia (1, 3). However, although Ucp2 mRNA is expressed in a broad array of tissues in humans and rodent models (3, 4), including metabolically important organs, it exists in minute amounts compared with the level of UCP1 in brown fat. Moreover, it is present in cell types such as pancreatic ␤-cells, lymphocytes, and neurons that are not typically associated with thermogenesis (5-7). These and other features of UCP2 (8), together with the critical finding that targeted disruption of the Ucp2 gene did not result in obesity, cold sensitivity, or demonstrable differences in coupling efficiency in isolated mitochondria (9 -11), strongly suggested a functionally distinct role for this protein.One of the phenotypes of Ucp2Ϫ/Ϫ mice was a striking resistance to infectious microorganisms associated with greater macrophage phagocytic activity and free radical production (9). We showed that macrophages from Ucp2Ϫ/Ϫ mice produced...

Patients with tumor-induced osteomalacia (TIO), an acquired paraneoplastic condition characterized by osteomalacia due to hypophosphatemia, exhibit a similar clinical picture to those with X-linked hypophosphatemic rickets/osteomalacia (XLH). The human monoclonal anti-fibroblast growth factor 23 (FGF23) antibody burosumab (KRN23) increases serum phosphate and improves bone turnover, fracture healing, pain, and physical function in XLH patients by inhibiting circulating FGF23; thus, burosumab is expected to be an effective treatment for TIO. We report here an interim analysis of a multicenter, open-label, intraindividual dose-adjustment study of burosumab (0.3 to 2.0 mg/kg every 4 weeks) in Japanese and Korean TIO patients. The primary endpoint was the fasting serum phosphate level at each visit. Key secondary endpoints were changes over time in bone biomarkers, pharmacodynamic markers, bone histomorphometric parameters, motor function, and patient-reported outcomes. Safety was assessed based on treatment-emergent adverse events (TEAEs). Thirteen patients received burosumab treatment, of whom 4 underwent bone biopsy. The mean dose after week 112 was approximately 1.0 mg/kg. After the first burosumab administration, mean serum phosphate levels increased and remained above the lower limit of normal and in the normal range from weeks 14 to 112. Bone biomarkers initially increased, reaching maximum values at week 16 or 24, and then gradually decreased. After burosumab treatment, patients were able to walk further (evaluated by the 6-minute walk test), reported decreased pain levels, and showed a tendency toward healing of baseline fractures and pseudofractures. Two patients discontinued, one each due to disease progression and consent withdrawal. Burosumab was generally well tolerated, with no treatment-related TEAEs of grade ≥3 and no treatment-related serious AEs. In conclusion, the interim results of this first study of burosumab to treat TIO patients indicate that this drug has the potential to provide clinical benefit for patients with unresectable tumors. The full study results are eagerly anticipated.

Old and New Ideas about the Role of Body Fat. In days of yore, to be well-endowed with a layer of fat was to be wealthy, respected, attractive, even godlike (Fig. I). In more recent times, it has been more popular to strive for the least amount of body fat, a concept glamorized by fashion, art, and even medicine, given that overweight or