Excess caloric intake can lead to insulin resistance. The underlying reasons are complex but likely related to ectopic lipid deposition in nonadipose tissue. We hypothesized that the inability to appropriately expand subcutaneous adipose tissue may be an underlying reason for insulin resistance and beta cell failure. Mice lacking leptin while overexpressing adiponectin showed normalized glucose and insulin levels and dramatically improved glucose as well as positively affected serum triglyceride levels. Therefore, modestly increasing the levels of circulating full-length adiponectin completely rescued the diabetic phenotype in ob/ob mice. They displayed increased expression of PPARgamma target genes and a reduction in macrophage infiltration in adipose tissue and systemic inflammation. As a result, the transgenic mice were morbidly obese, with significantly higher levels of adipose tissue than their ob/ob littermates, leading to an interesting dichotomy of increased fat mass associated with improvement in insulin sensitivity. Based on these data, we propose that adiponectin acts as a peripheral "starvation" signal promoting the storage of triglycerides preferentially in adipose tissue. As a consequence, reduced triglyceride levels in the liver and muscle convey improved systemic insulin sensitivity. These mice therefore represent what we believe is a novel model of morbid obesity associated with an improved metabolic profile.

Adiponectin is a secretory protein abundantly secreted from adipocytes. It assembles into a number of different higher-order complexes. Adipocytes maintain tight control over circulating plasma levels, suggesting the existence of a complex, highly regulated biosynthetic pathway. However, the critical mediators of adiponectin maturation within the secretory pathway have not been elucidated. Previously, we found that a significant portion of de novo-synthesized adiponectin is not secreted and retained in adipocytes. Here, we show that there is an abundant pool of properly folded adiponectin in the secretory pathway that is retained through thiol-mediated retention, as judged by the release of adiponectin in response to treatment of adipocytes with reducing agents. Adiponectin is covalently bound to the ER chaperone ERp44. An adiponectin mutant lacking cysteine 39 fails to stably interact with ERp44, demonstrating that this residue is the primary site mediating the covalent interaction. Another ER chaperone, Ero1-L␣, plays a critical role in the release of adiponectin from ERp44. Levels of both of these proteins are highly regulated in adipocytes and are influenced by the metabolic state of the cell. While less critical for the secretion of trimers, these chaperones play a major role in the assembly of higher-order adiponectin complexes. Our data highlight the importance of posttranslational events controlling adiponectin levels and the release of adiponectin from adipocytes. One mechanism for increasing circulating levels of specific adiponectin complexes by peroxisome proliferator-activated receptor gamma agonists may be selective upregulation of rate-limiting chaperones.Adiponectin, a secretory protein expressed at high levels in plasma, plays a beneficial role in diabetes and cardiovascular disease (5,21,25). Recently, adiponectin has been implicated as a critical mediator of peroxisome proliferator-activated receptor gamma (PPAR␥) agonist-induced insulin sensitization (13,22,27). The receptors for adiponectin that may mediate some aspects of adiponectin signaling in liver and muscle were recently described (20,46). The 247-amino-acid mouse adiponectin contains three domains, which include a short signal sequence followed by a hypervariable region, an N-terminal collagenous domain, and a C-terminal globular domain (30). Circulating adiponectin forms at least three complexes, which are referred to as the high-molecular-weight (HMW), lowmolecular-weight (LMW), and trimeric complexes (30, 43). Trimeric adiponectin is formed by interactions within the globular domain, further stabilized by a collagenous coiled coil that also supports formation of disulfide bonds between two of the three subunits mediated through cysteine 39 (Cys39). Different forms of adiponectin exert distinct functions. Absolute HMW levels and ratios of HMW to total levels of adiponectin in circulation change under different metabolic conditions (23,31,43,45). HMW levels are regulated in diabetic and cardiovascular disease states with reduced HMW...

The chemistry of metal-O 2 complexes has attracted much interest in the biological and bioinorganic chemistry communities, as such species are generated as key intermediates in the activation of dioxygen by metalloenzymes and corresponding model compounds. [1] In biomimetic studies, a number of metal-O 2 adducts have been synthesized and characterized with various spectroscopic methods, and their reactivities in the oxidation of organic substrates have been extensively investigated.[2] For example, peroxidoiron(III) complexes with heme and non-heme ligands have been synthesized as chemical models of cytochrome P450 aromatase and Rieske dioxygenases, and their reactivities have been demonstrated in various nucleophilic reactions, such as aldehyde deformylation. [3, 4] Peroxidocopper(III) and -nickel-(III) complexes have been synthesized and characterized recently, but their reactivities have not been well established in oxidative nucleophilic reactions of organic substrates. [2d,e, 5] Peroxidomanganese(III) complexes are also invoked as reactive intermediates in the reactions of Mn-containing enzymes, such as manganese superoxide dismutase, catalase, and the oxygen-evolving complex of photosystem II. [6] In biomimetic studies, a number of Mn-peroxido complexes have been synthesized and characterized with a variety of spectroscopic methods including X-ray crystallography. A notable example is the first X-ray crystal structure of a side-on peroxido manganese(III) porphyrin complex ([Mn III -(tpp)(O 2 )] À ; tpp = meso-tetraphenylporphyrin), reported by Valentine and co-workers.[7] The second crystal structure of a monomeric side-on peroxido manganese(III) complex bearing a non-porphyrinic ligand was reported by Kitajima et al. [8] However, reactivities of the peroxidomanganese(III) complexes have been rarely investigated in oxidation reactions. In the present work, we synthesized a peroxidomanganese (

Objective To estimate the effects of a relatively protruded head and neck posture on postural balance, in computer based worker. Method Thirty participants, who work with computers for over 6 hrs per day (Group I), and thirty participants, who rarely work with computers (Group II), were enrolled. The head and neck posture was measured by estimating angles A and B. A being the angle between the tragus of the ear, the lateral canthus of the eye, and horizontal line and B the angle between the C7 spinous process, the tragus of the ear, and the horizontal line. The severity of head protrusion with neck extension was assessed by the subtraction of angle A from angle B. We also measured the center of gravity (COG) and postural balance by using computerized dynamic posturography to determine the effect of computer-based work on postural balance. Results Results indicated that group I had a relatively more protruded head with extensive neck posture (angle B-A of group I and group II, 28.2±8.3, 32.9±6.0; p<.05). The COG of group I tended more toward the anterior than that of group II. Postural imbalance and impaired ability to regulate movement in forward and backward direction were also found. Conclusion The results of this study suggest that forward head postures during computer-based work may contribute to some disturbance in the balance of healthy adults. These results could be applied to education programs regarding correct postures when working at a computer for extended periods of time.

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