Featured ArticlesVolume 5 | No. 2 | February 2016
|Ataxin-10 is part of a cachexokine cocktail triggering cardiac metabolic dysfunctionCancer cachexia represents a severe clinical condition for which no effective diagnostic, preventive or therapeutic measures are available. The studies of Schäfer and colleagues provide a first unbiased and functional screening setup for the discovery of bona fide cachexokines with both sufficient and necessary cachexogenic properties. The researchers find a signature of seven secreted proteins that act in a combined manner to provoke cardiac atrophy and aberrant fatty acid oxidation.|
Abstract | PDF
Objectives: Cancer cachexia affects the majority of tumor patients and significantly contributes to high mortality rates in these subjects. Despite its clinical importance, the identity of tumor-borne signals and their impact on specific peripheral organ systems, particularly the heart, remain mostly unknown.
Methods and results: By combining differential colon cancer cell secretome profiling with large-scale cardiomyocyte phenotyping, we identified a signature panel of seven “cachexokines”, including Bridging integrator 1, Syntaxin 7, Multiple inositol-polyphosphate phosphatase 1, Glucosidase alpha acid, Chemokine ligand 2, Adamts like 4, and Ataxin-10, which were both sufficient and necessary to trigger cardiac atrophy and aberrant fatty acid metabolism in cardiomyocytes. As a prototypical example, engineered secretion of Ataxin-10 from non-cachexia-inducing cells was sufficient to induce cachexia phenotypes in cardiomyocytes, correlating with elevated Ataxin-10 serum levels in murine and human cancer cachexia models.
Conclusions: As Ataxin-10 serum levels were also found to be elevated in human cachectic cancer patients, the identification of Ataxin-10 as part of a cachexokine cocktail now provides a rational approach towards personalized predictive, diagnostic and therapeutic measures in cancer cachexia.[Hide abstract]
|Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 actionThe endocrine acting pleiotropic protein fibroblast growth factor 21 (FGF21) is proposed as key metabolic mediator of the mitochondrial stress adaptation.
Ost, Coleman and colleagues confirm that white adipose tissue (WAT) is a major target of circulating myokine FGF21. In contrast to prior expectations, the present study shows that the adaptive metabolic stress response operates independently of both WAT browning and FGF21 action.|
Abstract | PDF
Objective: Fibroblast growth factor 21 (FGF21) was recently discovered as stress-induced myokine during mitochondrial disease and proposed as key metabolic mediator of the integrated stress response (ISR) presumably causing systemic metabolic improvements. Curiously, the precise cell-non-autonomous and cell-autonomous relevance of endogenous FGF21 action remained poorly understood.
Methods: We made use of the established UCP1 transgenic (TG) mouse, a model of metabolic perturbations made by a specific decrease in muscle mitochondrial efficiency through increased respiratory uncoupling and robust metabolic adaptation and muscle ISR-driven FGF21 induction. In a cross of TG with Fgf21-knockout (FGF21−/−) mice, we determined the functional role of FGF21 as a muscle stress-induced myokine under low and high fat feeding conditions.
Results: Here we uncovered that FGF21 signaling is dispensable for metabolic improvements evoked by compromised mitochondrial function in skeletal muscle. Strikingly, genetic ablation of FGF21 fully counteracted the cell-non-autonomous metabolic remodeling and browning of subcutaneous white adipose tissue (WAT), together with the reduction of circulating triglycerides and cholesterol. Brown adipose tissue activity was similar in all groups. Remarkably, we found that FGF21 played a negligible role in muscle mitochondrial stress-related improved obesity resistance, glycemic control and hepatic lipid homeostasis. Furthermore, the protective cell-autonomous muscle mitohormesis and metabolic stress adaptation, including an increased muscle proteostasis via mitochondrial unfolded protein response (UPRmt) and amino acid biosynthetic pathways did not require the presence of FGF21.
Conclusions: Here we demonstrate that although FGF21 drives WAT remodeling, the adaptive pseudo-starvation response under elevated muscle mitochondrial stress conditions operates independently of both WAT browning and FGF21 action. Thus, our findings challenge FGF21 as key metabolic mediator of the mitochondrial stress adaptation and powerful therapeutic target during muscle mitochondrial disease.[Hide abstract]
|Bdnf is required to establish normal patterns of afferent GABAergic connectivity and responses to hypoglycemiaThe ventromedial nucleus of the hypothalamus (VMH) is a focal point for examination of neural circuits underlying regulation of food intake and body weight. Kamitakahara and colleagues demonstrate that expression of brain-derived neurotrophic factor (BDNF) by steroidogenic factor 1 (SF1) neurons is required for normal patterns of GABA innervation in the VMH. The loss of BDNF from SF1 neurons results in increased GABAergic innervation in the ventrolateral part of the VMH, as well as reduced glucagon secretion in response to insulin-induced hypoglycemia.|
Abstract | PDF
Objective: The ventromedial nucleus of the hypothalamus (VMH) controls energy and glucose homeostasis through direct connections to a distributed network of nuclei in the hypothalamus, midbrain, and hindbrain. Structural changes in VMH circuit morphology have the potential to alter VMH function throughout life, however, molecular signals responsible for specifying its neural connections are not fully defined. The VMH contains a high density of neurons that express brain-derived neurotrophic factor (BDNF), a potent neurodevelopmental effector known to regulate neuronal survival, growth, differentiation, and connectivity in a number of neural systems. In the current study, we examined whether BDNF impacts the afferent and efferent connections of the VMH, as well as energy homeostatic function.
Methods: To determine if BDNF is required for VMH circuit formation, a transgenic mouse model was used to conditionally delete Bdnf from steroidogenic factor 1 (SF1) expressing neurons of the VMH prior to the onset of establishing neural connections with other regions. Projections of SF1 expressing neurons were visualized with a genetically targeted fluorescent label and immunofluorescence was used to measure the density of afferents to SF1 neurons in the absence of BDNF. Physiological changes in body weight and circulating blood glucose were also evaluated in the mutant mice.
Results: Our findings suggest that BDNF is required to establish normal densities of GABAergic afferents onto SF1 neurons located in the ventrolateral part of the VMH. Furthermore, loss of BDNF from VMH SF1 neurons results in impaired physiological responses to insulin-induced hypoglycemia.
Conclusion: The results of this study indicate that BDNF is required for formation and/or maintenance of inhibitory inputs to SF1 neurons, with enduring effects on glycemic control.[Hide abstract]
|Mediobasal hypothalamic overexpression of DEPTOR protects against obesityThe mechanistic target of rapamycin (mTOR) plays an important role in the hypothalamic regulation of energy balance. DEP-domain containing mTOR-interacting
protein (DEPTOR) is a recently discovered component. Caron et al. report that systemic overexpression of DEPTOR prevents high-fat diet-induced obesity,
improves glucose metabolism and protects against the development of metabolic disturbances. These phenotypes are associated with a reduction in feed
Abstract | PDF
Background/Objective: The mechanistic target of rapamycin (mTOR) is a serine–threonine kinase that functions into distinct protein complexes (mTORC1 and mTORC2) that regulate energy homeostasis. DEP-domain containing mTOR-interacting protein (DEPTOR) is part of these complexes and is known to dampen mTORC1 function, consequently reducing mTORC1 negative feedbacks and promoting insulin signaling and Akt/PKB activation in several models. Recently, we observed that DEPTOR is expressed in several structures of the brain including the mediobasal hypothalamus (MBH), a region that regulates energy balance. Whether DEPTOR in the MBH plays a functional role in regulating energy balance and hypothalamic insulin signaling has never been tested.
Methods: We have generated a novel conditional transgenic mouse model based on the Cre-LoxP system allowing targeted overexpression of DEPTOR. Mice overexpressing DEPTOR in the MBH were subjected to a metabolic phenotyping and MBH insulin signaling was evaluated.
Results: We first report that systemic (brain and periphery) overexpression of DEPTOR prevents high-fat diet-induced obesity, improves glucose metabolism and protects against hepatic steatosis. These phenotypes were associated with a reduction in food intake and feed efficiency and an elevation in oxygen consumption. Strikingly, specific overexpression of DEPTOR in the MBH completely recapitulated these phenotypes. DEPTOR overexpression was associated with an increase in hypothalamic insulin signaling, as illustrated by elevated Akt/PKB activation.
Conclusion: Altogether, these results support a role for MBH DEPTOR in the regulation of energy balance and metabolism.[Hide abstract]
|Blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivityObesity is associated with reactivated liver Notch signaling, which, in turn, increases hepatic insulin resistance, opening up therapeutic avenues for
Notch inhibitors to be repurposed for type 2 diabetes (T2D). Sparling and colleagues demonstrate that Notch likely does not play an active role in
maintenance of adipocyte function or local/systemic insulin sensitivity. On the contrary, γ-secretase appears to sensitize adipocytes to insulin
action, by both biochemical (insulin signaling) and pharmacologic (insulin tolerance testing) proofs. Thus, specific Notch inhibitors are likely to fare
better for treatment of T2D than γ-secretase inhibitors.|
Abstract | PDF
Objective: As the obesity pandemic continues to expand, novel molecular targets to reduce obesity-related insulin resistance and Type 2 Diabetes (T2D) continue to be needed. We have recently shown that obesity is associated with reactivated liver Notch signaling, which, in turn, increases hepatic insulin resistance, opening up therapeutic avenues for Notch inhibitors to be repurposed for T2D. Herein, we tested the systemic effects of γ-secretase inhibitors (GSIs), which prevent endogenous Notch activation, and confirmed these effects through creation and characterization of two different adipocyte-specific Notch loss-of-function mouse models through genetic ablation of the Notch transcriptional effector Rbp-Jk (A-Rbpj) and the obligate γ-secretase component Nicastrin (A-Nicastrin).
Methods: Glucose homeostasis and both local adipose and systemic insulin sensitivity were examined in GSI-treated, A-Rbpj and A-Nicastrin mice, as well as vehicle-treated or control littermates, with complementary in vitro studies in primary hepatocytes and 3T3-L1 adipocytes.
Results: GSI-treatment increases hepatic insulin sensitivity in obese mice but leads to reciprocal lowering of adipose glucose disposal. While A-Rbpj mice show normal body weight, adipose development and mass and unchanged adipose insulin sensitivity as control littermates, A-Nicastrin mice are relatively insulin-resistant, mirroring the GSI effect on adipose insulin action.
Conclusions: Notch signaling is dispensable for normal adipocyte function, but adipocyte-specific γ-secretase blockade reduces adipose insulin sensitivity, suggesting that specific Notch inhibitors would be preferable to GSIs for application in T2D.[Hide abstract]
|IL-13 improves beta-cell survival and protects against IL-1beta-induced beta-cell deathRütti et al. show for the first time that interleukin-13 (IL-13) can directly affect human beta-cell survival and that IL-13 protects beta-cells from interleukin-1beta induced apoptosis, a cytokine known to play an important role in type 2 diabetes. These positive effects are mediated via the IRS2/Akt pathway and the regulation of genes implicated in the cellular stress response. IL-13 may be an important new player in helping beta-cells survive cytokine attack in both major forms of diabetes.|
Abstract | PDF
Objective: IL-13 is a cytokine classically produced by anti-inflammatory T-helper-2 lymphocytes; it is decreased in the circulation of type 2 diabetic patients and impacts positively on liver and skeletal muscle. Although IL-13 can exert positive effects on beta-cell lines, its impact and mode of action on primary beta-cell function and survival remain largely unexplored.
Methods: Beta-cells were cultured for 48 h in the presence of IL-13 alone or in combination with IL-1β or cytokine cocktail (IL-1β, IFNγ, TNFα).
Results: IL-13 protected human and rat beta-cells against cytokine induced death. However, IL-13 was unable to protect from IL-1β impaired glucose stimulated insulin secretion and did not influence NFκB nuclear relocalization induced by IL-1β. IL-13 induced phosphorylation of Akt, increased IRS2 protein expression and counteracted the IL-1β induced regulation of several beta-cell stress response genes.
Conclusions: The prosurvival effects of IL-13 thus appear to be mediated through IRS2/Akt signaling with NFκB independent regulation of gene expression. In addition to previously documented beneficial effects on insulin target tissues, these data suggest that IL-13 may be useful for treatment of type 2 diabetes by preserving beta-cell mass or slowing its rate of decline.[Hide abstract]