Metabolic crosstalk: molecular links between glycogen and lipid metabolism in obesity.

Glycogen and lipids are major storage forms of energy that are tightly regulated by hormones and metabolic signals. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen due to increased expression of the glycogenic scaffolding protein PTG/R5. PTG promoter activity was increased and glycogen levels were augmented in mice and cells after activation of the mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target SREBP1. Deletion of the PTG gene in mice prevented HFD-induced hepatic glycogen accumulation. Of note, PTG deletion also blocked hepatic steatosis in HFD-fed mice and reduced the expression of numerous lipogenic genes. Additionally, PTG deletion reduced fasting glucose and insulin levels in obese mice while improving insulin sensitivity, a result of reduced hepatic glucose output. This metabolic crosstalk was due to decreased mTORC1 and SREBP activity in PTG knockout mice or knockdown cells, suggesting a positive feedback loop in which once accumulated, glycogen stimulates the mTORC1/SREBP1 pathway to shift energy storage to lipogenesis. Together, these data reveal a previously unappreciated broad role for glycogen in the control of energy homeostasis

Anisotropy and inflation in Bianchi I brane worlds

After a more general assumption on the influence of the bulk on the brane, we extend some conclusions by Maartens et al. and Santos et al. on the asymptotic behavior of Bianchi I brane worlds. As a consequence of the nonlocal anisotropic stresses induced by the bulk, in most of our models, the brane does not isotropize and the nonlocal energy does not vanish in the limit in which the mean radius goes to infinity. We have also found the intriguing possibility that the inflation due to the cosmological constant might be prevented by the interaction with the bulk. We show that the problem for the mean radius can be completely solved in our models, which include as particular cases those in the references above.Comment: 10 pages, improved discussion on the likeliness of non-isotropization, completed list of references, matches version to appear in Class. Quantum Gra

A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis.

The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-ε and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-ε and TBK1 with amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue-liver axis in mediating the acute metabolic benefits of amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes

Regulation of muscle fiber type and running endurance by PPARdelta

Endurance exercise training can promote an adaptive muscle fiber transformation and an increase of mitochondrial biogenesis by triggering scripted changes in gene expression. However, no transcription factor has yet been identified that can direct this process. We describe the engineering of a mouse capable of continuous running of up to twice the distance of a wild-type littermate. This was achieved by targeted expression of an activated form of peroxisome proliferator-activated receptor delta (PPARdelta) in skeletal muscle, which induces a switch to form increased numbers of type I muscle fibers. Treatment of wild-type mice with PPARdelta agonist elicits a similar type I fiber gene expression profile in muscle. Moreover, these genetically generated fibers confer resistance to obesity with improved metabolic profiles, even in the absence of exercise. These results demonstrate that complex physiologic properties such as fatigue, endurance, and running capacity can be molecularly analyzed and manipulated

Expression and functional analysis of Nr2e3, a photoreceptor-specific nuclear receptor, suggest common mechanisms in retinal development between avians and mammals

The photoreceptor-specific nuclear receptor (PNR; Nr2e3) is a transcription factor important for retinal development. We report here the identification and expression analysis of the avian Nr2e3. Nr2e3 mRNA is expressed in the photoreceptor layer of the neural retina during early stages of chick embryogenesis. Its temporal expression is distinct from that of a related nuclear receptor, Tlx. Chick Nr2e3 recognizes and binds to the same target DNA sequence as its vertebrate orthologs. Functional assays revealed that chick Nr2e3 acts as a transcriptional repressor. Our results suggest that Nr2e3 plays a common role in retinal development in vertebrates

Dependence of Hippocampal Function on ERRγ-Regulated Mitochondrial Metabolism

SummaryNeurons utilize mitochondrial oxidative phosphorylation (OxPhos) to generate energy essential for survival, function, and behavioral output. Unlike most cells that burn both fat and sugar, neurons only burn sugar. Despite its importance, how neurons meet the increased energy demands of complex behaviors such as learning and memory is poorly understood. Here we show that the estrogen-related receptor gamma (ERRγ) orchestrates the expression of a distinct neural gene network promoting mitochondrial oxidative metabolism that reflects the extraordinary neuronal dependence on glucose. ERRγ−/− neurons exhibit decreased metabolic capacity. Impairment of long-term potentiation (LTP) in ERRγ−/− hippocampal slices can be fully rescued by the mitochondrial OxPhos substrate pyruvate, functionally linking the ERRγ knockout metabolic phenotype and memory formation. Consistent with this notion, mice lacking neuronal ERRγ in cerebral cortex and hippocampus exhibit defects in spatial learning and memory. These findings implicate neuronal ERRγ in the metabolic adaptations required for memory formation

OSSOS. IX. Two Objects in Neptune's 9: 1 Resonance - Implications for Resonance Sticking in the Scattering Population

We discuss the detection in the Outer Solar System Origins Survey (OSSOS) of two objects in Neptune's distant 9:1 mean motion resonance at semimajor axis $a\approx~130$~au. Both objects are securely resonant on 10~Myr timescales, with one securely in the 9:1 resonance's leading asymmetric libration island and the other in either the symmetric or trailing asymmetric island. These objects are the largest semimajor axis objects with secure resonant classifications, and their detection in a carefully characterized survey allows for the first robust resonance population estimate beyond 100~au. The detection of these objects implies a 9:1 resonance population of $1.1\times10^4$ objects with $H_r<8.66$ ($D~\gtrsim~100$~km) on similar orbits (95\% confidence range of $\sim0.4-3\times10^4$). Integrations over 4~Gyr of an ensemble of clones spanning these objects' orbit fit uncertainties reveal that they both have median resonance occupation timescales of $\sim1$~Gyr. These timescales are consistent with the hypothesis that these objects originate in the scattering population but became transiently stuck to Neptune's 9:1 resonance within the last $\sim1$~Gyr of solar system evolution. Based on simulations of a model of the current scattering population, we estimate the expected resonance sticking population in the 9:1 resonance to be 1000-4500 objects with $H_r<8.66$; this is marginally consistent with the OSSOS 9:1 population estimate. We conclude that resonance sticking is a plausible explanation for the observed 9:1 population, but we also discuss the possibility of a primordial 9:1 population, which would have interesting implications for the Kuiper belt's dynamical history.Comment: accepted for publication in A

FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours