Cholesterol is important for normal brain function. The brain synthesizes its own cholesterol, presumably in astrocytes. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in sterol regulatory elementbinding protein 2 (SREBP2)-regulated transcription. Here we show that coculture of control astrocytes with neurons enhances neurite outgrowth, and this is reduced with SREBP2 knockdown astrocytes. In vivo, mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor defects. These mice also have altered energy balance, altered body composition, and a shift in metabolism toward carbohydrate oxidation driven by increased glucose oxidation by the brain. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain and neuronal development and function, and altered brain cholesterol synthesis may contribute to the interaction between metabolic diseases, such as diabetes and altered brain function.T he brain is one of the most cholesterol-rich organs in the body, with cholesterol playing an important role in membrane fluidity, vesicle formation, and synaptogenesis (1). Cholesterol levels are tightly controlled by sterol regulatory element-binding protein 2 (SREBP2), the major transcription factor regulating cholesterol synthetic genes (2). In contrast to fatty acids, which are in equilibrium with the rest of the body, nearly all brain cholesterol is synthesized in the brain because cholesterol-carrying lipoproteins, with the exception of some very dense HDL, cannot readily cross the blood-brain barrier (3-5).When cholesterol is abundant, SREBP2 precursor remains sequestered in the endoplasmic reticulum by SREBP cleavage activating protein (SCAP). As cholesterol is needed, SCAP shuttles SREBP2 to the Golgi for cleavage into a transcriptionally active form that translocates to the nucleus, binds to sterol regulatory elements in DNA, and activates transcription of enzymes of cholesterol synthesis (2). Insulin can regulate SREBP2 expression and activity, in part via two insulin-induced regulatory proteins, Insig1 and Insig2 (6, 7). Furthermore, in insulindeficient diabetes, there is a decrease in SREBP2 and SCAP in the brain leading to decreased brain cholesterol synthesis (8). We have previously shown that both neurons and glial cells express SREBP2 and the enzymes of cholesterol synthesis, and in both cell types expression of the cholesterol synthesis pathway is stimulated by insulin (7).Among the subtypes of glia, astrocytes serve the most diverse roles, providing both structural support to neurons and playing a major role in maintaining the blood-brain barrier. In addition, astrocytes provide a variety of metabolic functions, including storage of glycogen and uptake of ions and neurotransmitters from the synaptic cleft (9, 10).Astrocytes/glial cells have also been suggested to play an important role in brain cholesterol metabolism. When neuronallike retinal ganglion cells are grown in culture and expose...

Sarcopenia, or skeletal muscle atrophy, is a debilitating comorbidity of many physiological and pathophysiological processes, including normal aging. There are no approved therapies for sarcopenia, but the antihypertrophic myokine myostatin is a potential therapeutic target. Here, we show that treatment of young and old mice with an antimyostatin antibody (ATA 842) for 4 wk increased muscle mass and muscle strength in both groups. Furthermore, ATA 842 treatment also increased insulin-stimulated whole body glucose metabolism in old mice, which could be attributed to increased insulin-stimulated skeletal muscle glucose uptake as measured by a hyperinsulinemic-euglycemic clamp. Taken together, these studies provide support for pharmacological inhibition of myostatin as a potential therapeutic approach for age-related sarcopenia and metabolic disease.aging | myostatin | muscle mass | insulin resistance | sarcopenia

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Insulin controls glucose uptake into adipose and muscle cells by regulating the amount of GLUT4 in the plasma membrane. The effect of insulin is to promote the translocation of intracellular GLUT4 to the plasma membrane. The small Rab GTPase, Rab10, is required for insulin-stimulated GLUT4 translocation in cultured 3T3-L1 adipocytes. Here we demonstrate that both insulin-stimulated glucose uptake and GLUT4 translocation to the plasma membrane are reduced by about half in adipocytes from adipose-specific Rab10 knockout (KO) mice. These data demonstrate that the full effect of insulin on adipose glucose uptake is the integrated effect of Rab10-dependent and Rab10-independent pathways, establishing a divergence in insulin signal transduction to the regulation of GLUT4 trafficking. In adipose-specific Rab10 KO female mice, the partial inhibition of stimulated glucose uptake in adipocytes induces insulin resistance independent of diet challenge. During euglycemic-hyperinsulinemic clamp, there is no suppression of hepatic glucose production despite normal insulin suppression of plasma free fatty acids. The impact of incomplete disruption of stimulated adipocyte GLUT4 translocation on whole-body glucose homeostasis is driven by a near complete failure of insulin to suppress hepatic glucose production rather than a significant inhibition in muscle glucose uptake. These data underscore the physiological significance of the precise control of insulin-regulated trafficking in adipocytes.

The healing process is complex in diabetic wounds, and the healing mechanism of burn wounds is different from that of incisional or excisional wounds. Data from our previous study indicated that topical insulin cream reduced wound closure time in diabetic rats. Our aim was to investigate the effect of topical insulin cream on wound healing following second-degree burns in control and diabetic rats. Rats were divided into four groups: control (nondiabetic) rats treated with placebo (CP), control (nondiabetic) rats treated with topical insulin cream (CI), diabetic rats treated with placebo (DP), and diabetic rats treated with topical insulin cream (DI). The wounds were assessed at 4 time points (1, 7, 14, and 26 days) post-wounding for morphometric analysis of wound sections stained with hematoxylin/eosin, α-smooth muscle actin, and Picrosirius red to evaluate general aspects of the wound, inflammatory infiltrate, blood vessels, and Types I and III collagen fibers. Histological analysis showed that topical insulin cream increased the inflammatory cell infiltrate in the DI group (at 7 and 14 days postburn, p< .05) and blood vessels (at 14 days postburn, p < .05) to levels similar to those of groups CP and CI. Wounds treated with topical insulin cream (CI and DI groups) showed significantly stronger staining for fibrillar collagen than wounds of the DP group. The use of topical insulin may reduce the duration of the inflammatory phase; improve wound reepithelialization, tissue granulation, and wound contraction; and increase collagen deposition in second-degree burns in healthy and diabetic animals.

In recent years,extensive sequencing and annotation of bacterial genomes has revealed an unexpectedly large number of secondary metabolite biosynthetic gene clusters whose products are yet to be discovered. Fore xample, cyanobacterial genomes contain avariety of gene clusters that likely incorporate fatty acid derived moieties,b ut for most cases we lack the knowledge and tools to effectively predict or detect the encoded natural products.H ere,w ee xploit the apparent absence of af unctional b-oxidation pathway in cyanobacteria to achieve efficient stable-isotope-labeling of their fatty acid derived lipidome.W es how that supplementation of cyanobacterial cultures with deuterated fatty acids can be used to easily detect natural product signatures in individual strains.T he utility of this strategy is demonstrated in two cultured cyanobacteria by uncovering analogues of the multidrug-resistance reverting hapalosin, and novel, cytotoxic, lactylate-nocuolin Ah ybrids-the nocuolactylates.

In the face of the lack of research that investigates the relations between Mathematics teachers and students with special educational needs, an investigation was launched with the aim of identifying the social representations that these professionals have regarding disability, in addition to learning about their knowledge, opinions and doubts on this theme. The research was carried out with the participation of 65 mathematics teachers and data collection resulted from replies given to three proposed situations in an interview. Collective subject discourse methodology was used, with social representation Theory employed as a theoretical-methodological reference. The results showed the presence of distinct representations concerning the theme, with attitudes that range from support and incentive for the inclusion of students with disabilities, with evidence of knowledge of the theme, to representations that revealed the manifestation of doubts, opinions and attitudes, with positions contrary to the philosophy of inclusion.

The healing time of burn wounds depends on surface area and depth of the burn and associated comorbidities. Diabetes mellitus (DM) causes delays in the healing process by extending the inflammatory phase. Treatment with topical insulin can improve the inflammatory phase, restore metabolic dysregulation, and modulate impaired cellular signaling in burn wounds. The objective of this study was to evaluate markers of the inflammatory and proliferative phases of second-degree burns after topical insulin treatment in diabetic rats. Type I DM was induced with streptozotocin in male Wistar rats. The animals’ backs were shaved and subjected to thermal burning. Rats were randomized into two groups: control diabetic (DC) and insulin diabetic (DI). At Days 7 and 14 postburn, rats were euthanized, and wound-tissue sections were evaluated by hematoxylin and eosin, Weigert, and Verhöeff staining, immunohistochemistry-paraffin, and enzyme-linked immunosorbent assay. A significant increase in reepithelialization was seen on Days 7 and 14 in DI versus DC rats. On Day 7, interleukin (IL)-1β, IL-6, monocyte chemotactic protein (MCP)-1, and F4/80 expression were increased in DI versus DC rats. On Day 14, MCP-1 expression was decreased and F4/80 increased in DI versus DC rats. On Days 7 and 14, Ki-67, transforming growth factor-β1, vascular endothelial growth factor expression, and formation of elastic fibers were increased in DI versus DC rats. Topical insulin modulates burn-wound healing in diabetic animals by balancing inflammation and promoting angiogenesis and formation of elastic fibers.