Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss. In mice with xenografted prostate tumors, elevated MIC-1 levels were also associated with marked weight, fat and lean tissue loss that was mediated by decreased food intake and was reversed by administration of antibody to MIC-1. Additionally, normal mice given systemic MIC-1 and transgenic mice overexpressing MIC-1 showed hypophagia and reduced body weight. MIC-1 mediates its effects by central mechanisms that implicate the hypothalamic transforming growth factor-beta receptor II, extracellular signal-regulated kinases 1 and 2, signal transducer and activator of transcription-3, neuropeptide Y and pro-opiomelanocortin. Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.

Summary Cancer is influenced by its microenvironment, yet broader, environmental effects also play a role but remain poorly defined. We report here that mice living in an enriched housing environment show reduced tumor growth and increased remission. We found this effect in melanoma and colon cancer models, and that it was not caused by physical activity alone. Serum from animals held in an enriched environment (EE) inhibited cancer proliferation in vitro and was markedly lower in leptin. Hypothalamic BDNF was selectively upregulated by EE, its genetic overexpression reduced tumor burden, whereas BDNF knockdown blocked the effect of EE. Mechanistically, we show that hypothalamic BDNF downregulated leptin production in adipocytes via sympathoneural β-adrenergic signaling. These results suggest that genetic or environmental activation of this BDNF/leptin axis may have therapeutic significance for cancer.

Summary Mice lacking the vesicular glutamate transporter-3 (VGLUT3) are congenitally deaf due to loss of glutamate release at the inner hair cell afferent synapse. Cochlear delivery of VGLUT3 using adeno-associated virus-1 (AAV1) leads to transgene expression in only inner hair cells (IHC), despite broader viral uptake. Within two weeks of AAV1-VGLUT3 delivery, acoustic brainstem response (ABR) thresholds normalize, along with partial rescue of the startle response. Lastly, we demonstrate partial reversal of the morphologic changes seen within the afferent IHC ribbon synapse. These findings represent the first successful restoration of hearing by gene replacement in mice, which is an important step towards gene therapy of human deafness.

SUMMARY Living in an enriched environment with complex physical and social stimulation leads to improved cognitive and metabolic health. In white fat, enrichment induced the upregulation of the brown fat cell fate determining gene Prdm16, brown fat specific markers, and genes involved in thermogenesis and β-adrenergic signaling. Moreover, pockets of cells with prototypical brown fat morphology and high UCP1 levels were observed in the white fat of enriched mice associated with resistance to diet-induced obesity. Hypothalamic overexpression of BDNF reproduced the enrichment-associated activation of the brown fat gene program and lean phenotype. Inhibition of BDNF signaling by genetic knockout or dominant negative trkB reversed this phenotype. Our genetic and pharmacologic data suggest a mechanism whereby induction of hypothalamic BDNF expression in response to environmental stimuli leads to selective sympathoneural modulation of white fat to induce “browning” and increased energy dissipation.

SUMMARYAdipocytes undergo considerable volumetric expansion in the setting of obesity. It has been proposed that such marked increases in adipocyte size may be sensed via adipocyte-autonomous mechanisms to mediate size-dependent intracellular signaling. Here, we show that SWELL1 (LRRC8a), a member of the Leucine Rich Repeat Containing protein family, is an essential component of a volume-sensitive ion channel (VRAC) in adipocytes. We find that SWELL1-mediated VRAC is augmented in hypertrophic murine and human adipocytes in the setting of obesity. SWELL1 regulates adipocyte insulin-PI3K-AKT2-GLUT4 signaling, glucose uptake and lipid content via SWELL1 C-terminal leucine-rich repeat domain interactions with GRB2/Cav1. Silencing GRB2 in SWELL1 KO adipocytes rescues insulin-pAKT2 signaling. In vivo, shRNA-mediated SWELL1 knock-down and adipose-targeted SWELL1 knock-out reduce adiposity and adipocyte size in obese mice while impairing systemic glycaemia and insulin-sensitivity. These studies identify SWELL1 as a cell-autonomous sensor of adipocyte size that regulates adipocyte growth, insulin sensitivity and glucose tolerance.

Objective-A prevailing concept in neuroscience has been that the adult mammalian central nervous system is incapable of restorative axon regeneration. Recent evidence, however, has suggested that reactivation of intrinsic cellular programs regulated by Akt/mTor signaling may restore this ability.Methods-To assess this possibility in the brain, we have examined the ability of adenoassociated virus mediated transduction of dopaminergic neurons of the substantia nigra with constitutively active forms of the kinase Akt and the GTPase Rheb to induce re-growth of axons after they have been destroyed by neurotoxin lesion.Results-Both constitutively active myristoylated Akt and hRheb(S16H) induce regrowth of axons from dopaminergic neurons to their target, the striatum. Histological analysis demonstrates that these new axons achieve morphologically accurate reinnervation. In addition, functional reintegration into target circuitry is achieved, as indicated by partial behavioral recovery.Interpretation-We conclude that regrowth of axons within the adult nigro-striatal projection, a system that is prominently affected in Parkinson's disease, can be achieved by activation of Akt/ mTor signaling in surviving endogenous mesencephalic dopaminergic neurons by viral vector transduction.

Axon degeneration is a hallmark of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Such degeneration is not a passive event but rather an active process mediated by mechanisms that are distinct from the canonical pathways of programmed cell death that mediate destruction of the cell soma. Little is known of the diverse mechanisms involved, particularly those of retrograde axon degeneration. We have previously observed in living animal models of degeneration in the nigrostriatal projection that a constitutively active form of the kinase, myristoylated Akt (Myr-Akt), demonstrates an ability to suppress programmed cell death and preserve the soma of dopamine neurons. Here, we show in both neurotoxin and physical injury (axotomy) models that Myr-Akt is also able to preserve dopaminergic axons due to suppression of acute retrograde axon degeneration. This cellular phenotype is associated with increased mammalian target of rapamycin (mTor) activity and can be recapitulated by a constitutively active form of the small GTPase Rheb, an upstream activator of mTor. Axon degeneration in these models is accompanied by the occurrence of macroautophagy, which is suppressed by Myr-Akt. Conditional deletion of the essential autophagy mediator Atg7 in adult mice also achieves striking axon protection in these acute models of retrograde degeneration. The protection afforded by both Myr-Akt and Atg7 deletion is robust and lasting, because it is still observed as protection of both axons and dopaminergic striatal innervation weeks after injury. We conclude that acute retrograde axon degeneration is regulated by Akt/Rheb/mTor signaling pathways.

Hypothalamic BDNF is a key element in the regulation of energy balance. Here we investigated gene transfer of BDNF in rodent models of obesity and diabetes. BDNF led to marked weight loss and alleviation of obesity-associated insulin resistance. To facilitate clinical translation and ensure BDNF expression dialed down as weight loss progressed, we developed a molecular autoregulatory system using a single rAAV vector harboring two expression cassettes, one constitutively driving BDNF, the other a specific microRNA targeting the therapeutic gene controlled by a promoter (agouti related peptide) responsive to the BDNF-induced physiological changes. Hence, as body weight declined, microRNA expression was activated inhibiting transgene expression and, in contrast to the progressive weight loss associated with a non-regulated approach, led to a plateau once significant weight loss was achieved. This strategy mimics the body's endogenous physiological feedback mechanisms thereby resetting the hypothalamic set point to reverse obesity and metabolic syndrome.Obesity confers significant risk for diabetes, cardiovascular disease, stroke and some cancers 1,2 . Obesity and the related condition, metabolic syndrome (or syndrome X) are increasing rapidly worldwide with significant morbidity and mortality and socioeconomic burden 3 . Life style modifications such as exercise and diet as well as approved drugs have limited efficacy. Bariatric surgery can lead to weight loss at the cost of significant morbidity, underscoring the need for a safer and more effective approach.To identify potential molecular therapeutic candidates, we used an environmental paradigm. In our previous studies, physically and socially more complex housing leads to increased neurogenesis, improved learning and memory and resistance to insults [4][5][6] . Moreover, although fed ad libitum on identical diets, such enriched animals gain less weight than standard housing controls with an improved metabolic profile and insulin sensitivity. To further characterize this phenotype we focused on potential regulators in the hypothalamic arcuate nucleus (Arc), a brain region critical to energy balance. Amongst a number of genes screened, we observed a consistent upregulation in BDNF expression at 2, 4 and 9 weeks of enrichment.BDNF has previously been identified as an important component of the hypothalamic pathway that controls body weight and energy homeostasis 7 . Obese phenotypes are found in BDNF heterozygous mice 8 , a conditional knockout model 9 and focal hypothalamic deletion in adult mice 10 . This mature onset obesity is associated with hyperphagia, hyperleptinemia, hyperinsulinemia and hyperglycemia. Moreover in humans similar symptoms are associated