The past 20 years witnessed an enormous leap in understanding of the central regulation of whole-body energy metabolism. Genetic tools have enabled identification of the region-specific expression of ...peripheral metabolic hormone receptors and have identified neuronal circuits that mediate the action of these hormones on behavior and peripheral tissue functions. One of the surprising findings of recent years is the observation that brain circuits involved in metabolism regulation remain plastic through adulthood. In this review, we discuss these findings and focus on the role of neurons and glial cells in the dynamic process of plasticity, which is fundamental to the regulation of physiological and pathological metabolic events.
The sirtuins are a family of highly conserved NAD(+)-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central ...to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD(+) levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease.
SARS-CoV-2 is the cause of a pandemic with growing global mortality. Using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS), we identified 309 host proteins that ...bind the SARS-CoV-2 RNA during active infection. Integration of this data with ChIRP-MS data from three other RNA viruses defined viral specificity of RNA-host protein interactions. Targeted CRISPR screens revealed that the majority of functional RNA-binding proteins protect the host from virus-induced cell death, and comparative CRISPR screens across seven RNA viruses revealed shared and SARS-specific antiviral factors. Finally, by combining the RNA-centric approach and functional CRISPR screens, we demonstrated a physical and functional connection between SARS-CoV-2 and mitochondria, highlighting this organelle as a general platform for antiviral activity. Altogether, these data provide a comprehensive catalog of functional SARS-CoV-2 RNA-host protein interactions, which may inform studies to understand the host-virus interface and nominate host pathways that could be targeted for therapeutic benefit.
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•ChIRP-MS of SARS-CoV-2 RNA identifies viral RNA-host protein interaction networks•Comparative analysis identifies SARS-specific and multi-viral RNA-protein complexes•SARS-CoV-2 interactome-focused CRISPR screens reveal a broad antiviral response•Host mitochondria serve as a general organelle platform for anti-SARS-CoV-2 immunity
Interrogation of SARS-CoV-2 RNA-host protein interaction networks by ChIRP-MS and CRISPR screens, in comparison with other human viruses such as flaviviruses, picornavirus, and rhinovirus, identifies complexes specific to SARS-CoV-2 infection and highlights the role of mitochondria in mediating antiviral immunity.
1 Section of Comparative Medicine and Departments of 2 Obstetrics, Gynecology and Reproductive Sciences and 3 Neurobiology, Yale University School of Medicine, New Haven, Connecticut
Submitted 21 ...November 2007
; accepted in final form 3 March 2008
ABSTRACT
Obesity, characterized by enhanced food intake (hyperphagia) and reduced energy expenditure that results in the accumulation of body fat, is a major risk factor for various diseases, including diabetes, cardiovascular disease, and cancer. In the United States, more than half of adults are overweight, and this number continues to increase. The adipocyte-secreted hormone leptin and its downstream signaling mediators play crucial roles in the regulation of energy balance. Leptin decreases feeding while increasing energy expenditure and permitting energy-intensive neuroendocrine processes, such as reproduction. Thus, leptin also modulates the neuroendocrine reproductive axis. The gonadal steroid hormone estrogen plays a central role in the regulation of reproduction and also contributes to the regulation of energy balance. Estrogen deficiency promotes feeding and weight gain, and estrogen facilitates, and to some extent mimics, some actions of leptin. In this review, we examine the functions of estrogen and leptin in the brain, with a focus on mechanisms by which leptin and estrogen cooperate in the regulation of energy homeostasis.
obesity; metabolism; signal transducer and activator of transcription 3
Address for reprint requests and other correspondence: Q. Gao, Yale Univ. School of Medicine, New Haven, CT 06520 (e-mail: qian.gao{at}yale.edu )
The hypothalamic melanocortin system, which includes neurons that produce pro-opiomelanocortin (POMC)-derived peptides, is a major negative regulator of energy balance. POMC neurons begin to acquire ...their unique properties during neonatal life. The formation of functional neural systems requires massive cytoplasmic remodeling that may involve autophagy, an important intracellular mechanism for the degradation of damaged proteins and organelles. Here we investigated the functional and structural effects of the deletion of an essential autophagy gene, Atg7, in POMC neurons. Lack of Atg7 in POMC neurons caused higher postweaning body weight, increased adiposity, and glucose intolerance. These metabolic impairments were associated with an age-dependent accumulation of ubiquitin/p62-positive aggregates in the hypothalamus and a disruption in the maturation of POMC-containing axonal projections. Together, these data provide direct genetic evidence that Atg7 in POMC neurons is required for normal metabolic regulation and neural development, and they implicate hypothalamic autophagy deficiency in the pathogenesis of obesity.
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► Autophagy is constitutively active in hypothalamic feeding regions ► The loss of Atg7 in POMC neurons causes metabolic defects ► Atg7 is required for the normal maturation of POMC axonal projections
Abstract
Current findings suggest that accumulation of amyloid-β (Aβ) and hyperphosphorylated tau in the brain disrupt synaptic function in hippocampal–cortical neuronal networks leading to ...impairment in cognitive and affective functions in Alzheimer’s disease (AD). Development of new disease-modifying AD drugs are challenging due to the lack of predictive animal models and efficacy assays. In the present study we recorded neural activity in TgF344-AD rats, a transgenic model with a full array of AD pathological features, including age-dependent Aβ accumulation, tauopathy, neuronal loss, and cognitive impairments. Under urethane anesthesia, TgF344-AD rats showed significant age-dependent decline in brainstem-elicited hippocampal theta oscillation and decreased theta-phase gamma-amplitude coupling comparing to their age-matched wild-type counterparts. In freely-behaving condition, the power of hippocampal theta oscillation and gamma power during sharp-wave ripples were significantly lower in TgF344-AD rats. Additionally, these rats showed impaired coherence in both intercortical and hippocampal–cortical network dynamics, and increased incidence of paroxysmal high-voltage spindles, which occur during awake, behaviorally quiescent state. TgF344-AD rats demonstrated impairments in sensory processing, having diminished auditory gating and 40-Hz auditory evoked steady-state response. The observed differences in neurophysiological activities in TgF344-AD rats, which mirror several abnormalities described in AD patients, may be used as promising markers to monitor disease-modifying therapies.
Summary
We present a finite‐element method for the incompressible Navier‐Stokes problem that is locally conservative, energy‐stable, and pressure‐robust on time‐dependent domains. To achieve this, ...the space‐time formulation of the Navier‐Stokes problem is considered. The space‐time domain is partitioned into space‐time slabs, which in turn are partitioned into space‐time simplices. A combined discontinuous Galerkin method across space‐time slabs and space‐time hybridized discontinuous Galerkin method within a space‐time slab results in an approximate velocity field that is H(div)‐conforming and exactly divergence‐free, even on time‐dependent domains. Numerical examples demonstrate the convergence properties and performance of the method.
We present a finite‐element method for the incompressible Navier‐Stokes problem that is locally conservative, energy‐stable, and pressure‐robust on time‐dependent domains. To achieve this, the space‐time formulation of the Navier‐Stokes problem is considered, where the space‐time domain is partitioned into space‐time slabs, which in turn are partitioned into space‐time simplices. A combined discontinuous Galerkin method across space‐time slabs, and space‐time hybridized discontinuous Galerkin method within a space‐time slab, results in an approximate velocity field that is H(div)‐conforming and exactly divergence‐free, even on time‐dependent domains.
Astrocytes represent central regulators of brain glucose metabolism and neuronal function. They have recently been shown to adapt their function in response to alterations in nutritional state ...through responding to the energy state-sensing hormones leptin and insulin. Here, we demonstrate that glucagon-like peptide (GLP)-1 inhibits glucose uptake and promotes β-oxidation in cultured astrocytes. Conversely, postnatal GLP-1 receptor (GLP-1R) deletion in glial fibrillary acidic protein (GFAP)-expressing astrocytes impairs astrocyte mitochondrial integrity and activates an integrated stress response with enhanced fibroblast growth factor (FGF)21 production and increased brain glucose uptake. Accordingly, central neutralization of FGF21 or astrocyte-specific FGF21 inactivation abrogates the improvements in glucose tolerance and learning in mice lacking GLP-1R expression in astrocytes. Collectively, these experiments reveal a role for astrocyte GLP-1R signaling in maintaining mitochondrial integrity, and lack of GLP-1R signaling mounts an adaptive stress response resulting in an improvement of systemic glucose homeostasis and memory formation.
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•GLP-1 inhibits glucose uptake and promotes β-oxidation in cultured astrocytes•Lack of astrocyte GLP-1R in vivo activates a stress response and increases FGF21•Adaptations to astrocyte GLP-1R deletion improve glucose metabolism and memory
Astrocytes regulate brain glucose metabolism and neuronal function. Timper et al. describe a role for astrocyte GLP-1R signaling in maintaining mitochondrial integrity and demonstrate that lack of astrocyte GLP-1R signaling mounts an adaptive stress response to increase astrocyte FGF21 expression resulting in an improvement of systemic glucose homeostasis and memory formation.
Current anti-obesity drugs aim to reduce food intake by either curbing appetite or suppressing the craving for food. However, many of these agents have been associated with severe psychiatric and/or ...cardiovascular side effects, highlighting the need for alternative therapeutic strategies. Emerging knowledge on the role of the hypothalamus in enabling the central nervous system to adapt to the changing environment - by managing peripheral tissue output and by regulating higher brain functions - may facilitate the discovery of new agents that are more effective and have an acceptable benefit-risk profile. Targeting the molecular pathways that mediate the beneficial effects of calorie restriction and exercise may represent an alternative therapeutic approach for the treatment of chronic metabolic disorders such as obesity.
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