Diets with high fat content induce steatosis, insulin resistance, and type 2 diabetes. The lipid droplet protein adipose differentiation-related protein (ADRP) mediates hepatic steatosis, but whether this affects insulin action in the liver or peripheral organs in diet-induced obesity is uncertain. We fed C57BL/6J mice a high-fat diet and simultaneously treated them with an antisense oligonucleotide (ASO) against ADRP for 4 wk. Glucose homeostasis was assessed with clamp and tracer techniques. ADRP ASO decreased the levels of triglycerides and diacylglycerol in the liver, but fatty acids, long-chain fatty acyl CoAs, ceramides, and cholesterol were unchanged. Insulin action in the liver was enhanced after ADRP ASO treatment, whereas muscle and adipose tissue were not affected. ADRP ASO increased the phosphorylation of insulin receptor substrate (IRS)1, IRS2, and Akt, and decreased gluconeogenic enzymes and PKCepsilon, consistent with its insulin-sensitizing action. These results demonstrate an important role for ADRP in the pathogenesis of diet-induced insulin resistance.

Resistin levels are increased in obesity, and hyperresistinemia impairs glucose homeostasis in rodents. Here, we have determined the role of resistin in ob/ob mice that are obese and insulin resistant because of genetic deficiency of leptin. Loss of resistin increased obesity in ob/ob mice by further lowering the metabolic rate without affecting food intake. Nevertheless, resistin deficiency improved glucose tolerance and insulin sensitivity in these severely obese mice, largely by enhancing insulin-mediated glucose disposal in muscle and adipose tissue. In contrast, in C57BL/6J mice with diet-induced obesity but wild-type leptin alleles, resistin deficiency reduced hepatic glucose production and increased peripheral glucose uptake. Resistin deficiency enhanced Akt phosphorylation in muscle and liver and decreased suppressor of cytokine signaling-3 level in muscle, and these changes were reversed by resistin replacement. Together, these results provide strong support for an important role of resistin in insulin resistance and diabetes associated with genetic or diet-induced obesity. Diabetes 55:3083-3090, 2006 R esistin is a circulating protein derived from adipocytes in rodents and mononuclear cells in humans that has been implicated in obesityassociated diabetes (1). The secreted form of resistin is a trimer of disulfide-linked dimers of 9-kDa subunits (2,3). Hyperresistinemia created by acute resistin infusion or stable resistin gene transfer leads to insulin resistance and glucose intolerance because of increased hepatic glucose production (HGP) and, in some reports, inhibition of muscle glucose uptake, depending on the model being studied (4 -6). Conversely, resistin deficiency produced by deletion of the resistin gene or by antisense therapy improves insulin resistance and glucose metabolism (7,8). A dominant-negative form of resistin had a similar effect on glucose (9).Previous studies of the metabolic consequences of altered resistin levels have been performed in wild-type rodents (3-10). The role of resistin in the development of insulin resistance in ob/ob mice genetically lacking leptin is uncertain. As is the case in diet-induced obese (DIO) mice, adipose resistin gene expression is markedly decreased in ob/ob mice, yet serum resistin protein levels are increased (11,12). To clarify the role of resistin in insulin resistance and diabetes associated with leptin deficiency, we generated and analyzed ob/ob mice lacking resistin. Despite massive obesity caused by reduced energy expenditure, resistin deficiency in ob/ob mice resulted in improvements in glucose tolerance and insulin sensitivity, attributable largely to improved insulin sensitivity in muscle. In contrast, DIO resistin-null mice on similar C57BL/6J genetic background showed both a marked reduction in hepatic insulin resistance and increased peripheral glucose uptake. Thus, resistin contributes to insulin resistance and glucose intolerance in genetic and acquired obese states, although the tissue targets differ, potentially as a function of t...

It has traditionally been assumed that processing within the visual system proceeds in a bottom-up, feedforward manner from retina to higher cortical areas. In addition to feedforward processing, it is now clear that there are also important contributions to sensory encoding that rely upon top-down, feedback (reentrant) projections from higher visual areas to lower ones. By utilizing transcranial magnetic stimulation (TMS) in a metacontrast masking paradigm, we addressed whether feedback processes in early visual cortex play a role in visual awareness. We show that TMS of visual cortex, when timed to produce visual suppression of an annulus serving as a metacontrast mask, induces recovery of an otherwise imperceptible disk. In addition to producing disk recovery, TMS suppression of an annulus was greater when a disk preceded it than when an annulus was presented alone. This latter result suggests that there are effects of the disk on the perceptibility of the subsequent mask that are additive and are revealed with TMS of the visual cortex. These results demonstrate spatial and temporal interactions of conscious vision in visual cortex and suggest that a prior visual stimulus can influence subsequent perception at early stages of visual encoding via feedback projections.

Adipose tissue secretes factors that control various physiological systems. The fall in leptin during fasting mediates hyperphagia and suppresses thermogenesis, thyroid and reproductive hormones, and immune system. On the other hand, rising leptin levels in the fed state stimulate fatty acid oxidation, decrease appetite, and limit weight gain. These divergent effects of leptin occur through neuronal circuits in the hypothalamus and other brain areas. Leptin also regulates the activities of enzymes involved in lipid metabolism, e.g., AMP-activated protein kinase and stearoyl-CoA desaturase-1, and also interacts with insulin signaling in the brain. Adiponectin enhances fatty acid oxidation and insulin sensitivity, in part by stimulating AMP-activated protein kinase phosphorylation and activity in liver and muscle. Moreover, adiponectin decreases body fat by increasing energy expenditure and lipid catabolism. These effects involve peripheral and possibly central mechanisms. Adipose tissue mediates interconversion of steroid hormones and secretes proinflammatory cytokines, vasoactive peptides, and coagulation and complement proteins. Understanding the actions of these "adipocytokines" will provide insight into the pathogenesis and treatment of obesity and related diseases. Diabetes 55 (Suppl. 2): S145-S154, 2006 ADIPOSE TISSUE

oltage-gated potassium channel (VGKC)-complex/ leucine-rich, glioma-inactivated 1 (LGI1) antibodyassociated encephalopathy has a subacute onset with features that include cognitive impairment, seizures of medial temporal lobe origin, faciobrachial dystonic seizures (FBDS), and serum hyponatremia. [1][2][3] Leucine-rich, gliomainactivated 1 antibody-associated encephalopathy is a treatable differential diagnosis within the rapidly progressive dementias. 4 Most patients improve with glucocorticoid therapy, which is often accompanied by treatment with intravenous immunoglobulins (IVIG), plasma exchange (PLEX), or both. [1][2][3] Despite this, residual cognitive impairment is common (B.