Metabolic Remodeling of Human Skeletal Myocytes by Cocultured Adipocytes Depends on the Lipolytic State of the System

Adipocyte infiltration of the musculoskeletal system is well recognized as a hallmark of aging, obesity, and type 2 diabetes. Intermuscular adipocytes might serve as a benign storage site for surplus lipid or play a role in disrupting energy homeostasis as a result of dysregulated lipolysis or secretion of proinflammatory cytokines. This investigation sought to understand the net impact of local adipocytes on skeletal myocyte metabolism. Interactions between these two tissues were modeled using a coculture system composed of primary human adipocytes and human skeletal myotubes derived from lean or obese donors. Metabolic analysis of myocytes was performed after coculture with lipolytically silent or activated adipocytes and included transcript and metabolite profiling along with assessment of substrate selection and insulin action. Cocultured adipocytes increased myotube mRNA expression of genes involved in oxidative metabolism, regardless of the donor and degree of lipolytic activity. Adipocytes in the basal state sequestered free fatty acids, thereby forcing neighboring myotubes to rely more heavily on glucose fuel. Under this condition, insulin action was enhanced in myotubes from lean but not obese donors. In contrast, when exposed to lipolytically active adipocytes, cocultured myotubes shifted substrate use in favor of fatty acids, which was accompanied by intracellular accumulation of triacylglycerol and even-chain acylcarnitines, decreased glucose oxidation, and modest attenuation of insulin signaling. The effects of cocultured adipocytes on myocyte substrate selection and insulin action depended on the metabolic state of the system. These findings are relevant to understanding the metabolic consequences of intermuscular adipogenesis

Glucose Induces Pancreatic Islet Cell Apoptosis That Requires the BH3-Only Proteins Bim and Puma and Multi-BH Domain Protein Bax

OBJECTIVE: High concentrations of circulating glucose are believed to contribute to defective insulin secretion and beta-cell function in diabetes and at least some of this effect appears to be caused by glucose-induced beta-cell apoptosis. In mammalian cells, apoptotic cell death is controlled by the interplay of proapoptotic and antiapoptotic members of the Bcl-2 family. We investigated the apoptotic pathway induced in mouse pancreatic islet cells after exposure to high concentrations of the reducing sugars ribose and glucose as a model of beta-cell death due to long-term metabolic stress. RESEARCH DESIGN AND METHODS: Islets isolated from mice lacking molecules implicated in cell death pathways were exposed to high concentrations of glucose or ribose. Apoptosis was measured by analysis of DNA fragmentation and release of mitochondrial cytochrome c. RESULTS: Deficiency of interleukin-1 receptors or Fas did not diminish apoptosis, making involvement of inflammatory cytokine receptor or death receptor signaling in glucose-induced apoptosis unlikely. In contrast, overexpression of the prosurvival protein Bcl-2 or deficiency of the apoptosis initiating BH3-only proteins Bim or Puma, or the downstream apoptosis effector Bax, markedly reduced glucose- or ribose-induced killing of islets. Loss of other BH3-only proteins Bid or Noxa, or the Bax-related effector Bak, had no impact on glucose-induced apoptosis. CONCLUSIONS: These results implicate the Bcl-2 regulated apoptotic pathway in glucose-induced islet cell killing and indicate points in the pathway at which interventional strategies can be designed

Alterations in Skeletal Muscle Fatty Acid Handling Predisposes Middle-Aged Mice to Diet-Induced Insulin Resistance

OBJECTIVE-Although advanced age is a risk factor for type 2 diabetes, a clear understanding of the changes that occur during middle age that contribute to the development of skeletal muscle insulin resistance is currently lacking. Therefore, we sought to investigate how middle age impacts skeletal muscle fatty acid handling and to determine how this contributes to the development of diet-induced insulin resistance. RESEARCH DESIGN AND METHODS-Whole-body and skeletal muscle insulin resistance were studied in young and middle-aged wild-type and CD36 knockout (KO) mice fed either a standard or a high-fat diet for 12 weeks. Molecular signaling pathways, intramuscular triglycerides accumulation, and targeted metabolomics of in vivo mitochondrial substrate flux were also analyzed in the skeletal muscle of mice of all ages. RESULTS-Middle-aged mice fed a standard diet demonstrated an increase in intramuscular triglycerides without a concomitant increase in insulin resistance. However, middle-aged mice fed a high-fat diet were more susceptible to the development of insulin resistance a condition that could be prevented by limiting skeletal muscle fatty acid transport and excessive lipid accumulation in middle-aged CD36 KO mice. CONCLUSION-Our data provide insight into the mechanisms by which aging becomes a risk factor for the development of insulin resistance. Our data also demonstrate that limiting skeletal muscle fatty acid transport is an effective approach for delaying the development of age-associated insulin resistance and metabolic disease during exposure to a high-fat diet. Diabetes 59:1366-1375, 201

The NUMEN project: NUclear Matrix Elements for Neutrinoless double beta decay

The article describes the main achievements of the NUMEN project togetherwith an updated and detailed overview of the related R&D activities andtheoretical developments. NUMEN proposes an innovative technique to access thenuclear matrix elements entering the expression of the lifetime of the doublebeta decay by cross section measurements of heavy-ion induced Double ChargeExchange (DCE) reactions. Despite the two processes, namely neutrinoless doublebeta decay and DCE reactions, are triggered by the weak and strong interactionrespectively, important analogies are suggested. The basic point is thecoincidence of the initial and final state many-body wave-functions in the twotypes of processes and the formal similarity of the transition operators. Firstexperimental results obtained at the INFN-LNS laboratory for the40Ca(18O,18Ne)40Ar reaction at 270 MeV, give encouraging indication on thecapability of the proposed technique to access relevant quantitativeinformation. The two major aspects for this project are the K800Superconducting Cyclotron and MAGNEX spectrometer. The former is used for theacceleration of the required high resolution and low emittance heavy ion beamsand the latter is the large acceptance magnetic spectrometer for the detectionof the ejectiles. The use of the high-order trajectory reconstructiontechnique, implemented in MAGNEX, allows to reach the experimental resolutionand sensitivity required for the accurate measurement of the DCE cross sectionsat forward angles. However, the tiny values of such cross sections and theresolution requirements demand beam intensities much larger than manageablewith the present facility. The on-going upgrade of the INFN-LNS facilities inthis perspective is part of the NUMEN project and will be discussed in thearticle

Experimental challenges for the measurement of the116Cd(20Ne,20O)116Sn double charge exchange reaction at 15 AMeV

The knowledge of the nuclear matrix elements (NME) entering in the expression of the half-life of the neutrinoless double beta decay is fundamental for neutrino physics . Information on the nuclear matrix elements can be obtained by measuring the absolute cross section of double charge exchange nuclear reactions. The two processes present some similarities, the initial and final-state wave functions are the same and the transition operators are similar. The experimental measurements of double charge exchange reactions induced by heavy ions present a number of challenging aspects, since such reactions are characterized by very low cross sections. Such difficulties are discussed for the measurement of the 116Cd(20Ne,20O)116Sn reaction at 15 AMeV