UCP2 Regulates Mitochondrial Fission and Ventromedial Nucleus Control of Glucose Responsiveness.

The ventromedial nucleus of the hypothalamus (VMH) plays a critical role in regulating systemic glucose homeostasis. How neurons in this brain area adapt to the changing metabolic environment to regulate circulating glucose levels is ill defined. Here, we show that glucose load results in mitochondrial fission and reduced reactive oxygen species in VMH neurons mediated by dynamin-related peptide 1 (DRP1) under the control of uncoupling protein 2 (UCP2). Probed by genetic manipulations and chemical-genetic control of VMH neuronal circuitry, we unmasked that this mitochondrial adaptation determines the size of the pool of glucose-excited neurons in the VMH and that this process regulates systemic glucose homeostasis. Thus, our data unmasked a critical cellular biological process controlled by mitochondrial dynamics in VMH regulation of systemic glucose homeostasis.

Microglia in Central Control of Metabolism.

Beyond their role as brain immune cells, microglia act as metabolic sensors in response to changes in nutrient availability, thus playing a role in energy homeostasis. This review highlights the evidence and challenges of studying the role of microglia in metabolism regulation.

Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior.

Microglia have been implicated in synapse remodeling by phagocytosis of synaptic elements in the adult brain, but the mechanisms involved in the regulation of this process are ill-defined. By examining microglia-neuronal interaction in the ventral hippocampus, we found a significant reduction in spine synapse number during the light phase of the light/dark cycle accompanied by increased microglia-synapse contacts and an elevated amount of microglial phagocytic inclusions. This was followed by a transient rise in microglial production of reactive oxygen species (ROS) and a concurrent increase in expression of uncoupling protein 2 (Ucp2), a regulator of mitochondrial ROS generation. Conditional ablation of Ucp2 from microglia hindered phasic elimination of spine synapses with consequent accumulations of ROS and lysosome-lipid droplet complexes, which resulted in hippocampal neuronal circuit dysfunctions assessed by electrophysiology, and altered anxiety-like behavior. These observations unmasked a novel and chronotypical interaction between microglia and neurons involved in the control of brain functions.

Hypothalamic POMC neurons promote cannabinoid-induced feeding.

Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for the central regulation of food intake. Here we test whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB1R activity increases feeding, and notably, CB1R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide α-melanocyte-stimulating hormone, and the opioid peptide ß-endorphin. CB1R activation selectively increases ß-endorphin but not α-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids.

POMC Neurons: From Birth to Death.

The hypothalamus is an evolutionarily conserved brain structure that regulates an organism's basic functions, such as homeostasis and reproduction. Several hypothalamic nuclei and neuronal circuits have been the focus of many studies seeking to understand their role in regulating these basic functions. Within the hypothalamic neuronal populations, the arcuate melanocortin system plays a major role in controlling homeostatic functions. The arcuate pro-opiomelanocortin (POMC) neurons in particular have been shown to be critical regulators of metabolism and reproduction because of their projections to several brain areas both in and outside of the hypothalamus, such as autonomic regions of the brain stem and spinal cord. Here, we review and discuss the current understanding of POMC neurons from their development and intracellular regulators to their physiological functions and pathological dysregulation.

Delayed Ocular Motility Restriction After Endoscopic Sinus Surgery in a Patient With Chronic Rhinosinusitis and an Old Medial Orbital Wall Fracture.

The orbital complications of endoscopic sinus surgery, including diplopia and ocular motility restriction, are mainly caused by direct injury to the orbital structures. These complications are rare, but can have catastrophic consequences. Symptoms occur immediately after surgery in most cases. The authors encountered an unusual case of delayed ocular motility restriction after endoscopic sinus surgery in a patient with old medial wall fracture, without direct orbital injury during the procedure. A 77-year-old man with an old medial wall fracture of the right orbit underwent endoscopic sinus surgery for chronic pansinusitis. He complained mild diplopia on right lateral gaze after 2 weeks, which gradually worsened. After 2 months, he exhibited severe lateral gaze movement impairment in the right eye and finally underwent surgical exploration. His symptoms improved after adhesiolysis of the overgrown ethmoid sinus mucosa and periorbital tissue. The authors reported this unusual case and discussed the possible mechanism underlying ocular motility restriction.

Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice.

Prolyl endopeptidase (PREP) has been implicated in neuronal functions. Here we report that hypothalamic PREP is predominantly expressed in the ventromedial nucleus (VMH), where it regulates glucose-induced neuronal activation. PREP knockdown mice (Prep(gt/gt)) exhibited glucose intolerance, decreased fasting insulin, increased fasting glucagon levels, and reduced glucose-induced insulin secretion compared with wild-type controls. Consistent with this, central infusion of a specific PREP inhibitor, S17092, impaired glucose tolerance and decreased insulin levels in wild-type mice. Arguing further for a central mode of action of PREP, isolated pancreatic islets showed no difference in glucose-induced insulin release between Prep(gt/gt) and wild-type mice. Furthermore, hyperinsulinemic euglycemic clamp studies showed no difference between Prep(gt/gt) and wild-type control mice. Central PREP regulation of insulin and glucagon secretion appears to be mediated by the autonomic nervous system because Prep(gt/gt) mice have elevated sympathetic outflow and norepinephrine levels in the pancreas, and propranolol treatment reversed glucose intolerance in these mice. Finally, re-expression of PREP by bilateral VMH injection of adeno-associated virus-PREP reversed the glucose-intolerant phenotype of the Prep(gt/gt) mice. Taken together, our results unmask a previously unknown player in central regulation of glucose metabolism and pancreatic function.

Laser Scanning Confocal Thermoreflectance Microscope for the Backside Thermal Imaging of Microelectronic Devices.

In this paper, we report on a confocal thermoreflectance imaging system that can examine the thermal characteristics of microelectronic devices by penetrating the backside of a device through the substrate. In this system, the local reflectivity variations due to heat generation in the device are measured point by point by a laser scanning confocal microscope capable of eliminating out-of-focus reflections and the thermoreflectance is extracted via Fourier-domain signal processing. In comparison to the conventional widefield thermoreflectance microscope, the proposed laser scanning confocal thermoreflectance microscope improves the thermoreflectance sensitivity by ~23 times and the spatial resolution by ~25% in backside thermoreflectance measurements.

Prolyl Endopeptidase (PREP) is Associated With Male Reproductive Functions and Gamete Physiology in Mice.

Prolyl endopeptidase (PREP) is a serine protease which has been implicated in many biological processes, such as the maturation and degradation of peptide hormones and neuropeptides, learning and memory, cell proliferation and differentiation, and glucose metabolism. A small number of reports have also suggested PREP participation in both male and female reproduction-associated processes. In the present work, we examined PREP distribution in male germ cells and studied the effects of its knockdown (Prep(gt/gt)) on testis and sperm in adult mice. The protein is expressed and localized in elongating spermatids and luminal spermatozoa of wild type (wt) mice, as well as Sertoli, Leydig, and peritubular cells. PREP is also expressed in the head and midpiece of epididymal spermatozoa, whereas the remaining tail region shows a weaker signal. Furthermore, testis weight, histology of seminiferous tubules, and epididymal sperm parameters were assessed in wt and Prep(gt/gt) mice: wild type testes have larger average tubule and lumen diameter; in addition, lumenal composition of seminiferous tubules is dissimilar between wt and Prep(gt/gt), as the percentage of spermiated tubules is much higher in wt. Finally, total sperm count, sperm motility, and normal morphology are also higher in wt than in Prep(gt/gt). These results show for the first time that the expression of PREP could be necessary for a correct reproductive function, and suggest that the enzyme may play a role in mouse spermatogenesis and sperm physiology.

Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses.

Whole-body energy metabolism is regulated by the hypothalamus and has an impact on diverse tissue functions. Here we show that selective knockdown of Sirtuin 1 Sirt1 in hypothalamic Agouti-related peptide-expressing neurons, which renders these cells less responsive to cues of low energy availability, significantly promotes CD4(+) T-cell activation by increasing production of T helper 1 and 17 proinflammatory cytokines via mediation of the sympathetic nervous system. These phenomena were associated with an impaired thymic generation of forkhead box P3 (FoxP3(+)) naturally occurring regulatory T cells and their reduced suppressive capacity in the periphery, which resulted in increased delayed-type hypersensitivity responses and autoimmune disease susceptibility in mice. These observations unmask a previously unsuspected role of hypothalamic feeding circuits in the regulation of adaptive immune response.

A measurement of the maximal forces in plasmonic tweezers.

Plasmonic tweezers that are designed to trap nanoscale objects create many new possibilities for single-molecule targeted studies. Numerous novel designs of plasmonic nanostructures are proposed in order to attain stronger forces and weaker laser intensity. Most experiments have consisted only of immobilization observations--that is, particles stick when the laser is turned on and fall away when the laser is turned off. Studies of the exertable forces were only theoretical. A few studies have experimentally measured trap stiffness. However, as far as we know, no studies have addressed maximal forces. In this paper, we present a new experimental design in which the motion of the trapped particle can be monitored in either parallel or orthogonal directions to the plasmonic structure's symmetric axis. We measured maximal trapping force through such monitoring. Although stiffness would be useful for force-calibration or immobilization purposes, for which most plasmonic tweezers are used, we believe that the maximal endurable force is significant and thus, this paper presents this aspect.

Prolyl endopeptidase-deficient mice have reduced synaptic spine density in the CA1 region of the hippocampus, impaired LTP, and spatial learning and memory.

Prolyl endopeptidase (PREP) is a phylogenetically conserved serine protease and, in humans and rodents, is highly expressed in the brain. Several neuropeptides associated with learning and memory and neurodegenerative disorders have been proposed to be the substrates for PREP, suggesting a possible role for PREP in these processes. However, its physiological function remains elusive. Combining genetic, anatomical, electrophysiological, and behavioral approaches, we show that PREP genetrap mice have decreased synaptic spine density in the CA1 region of the hippocampus, reduced hippocampal long-term potentiation, impaired hippocampal-mediated learning and memory, and reduced growth-associated protein-43 levels when compared with wild-type controls. These observations reveal a role for PREP in mediating hippocampal plasticity and spatial memory formation, with implications for its pharmacological manipulation in diseases related to cognitive impairment.

Melanocortin Signaling Connecting Systemic Metabolism With Mood Disorders.

Obesity and mood disorders are often overlapping pathologies that are prevalent public health concerns. Many studies have indicated a positive correlation between depression and obesity, although weight loss and decreased appetite are also recognized as features of depression. Accordingly, DSM-5 defines two subtypes of depression associated with changes in feeding: melancholic depression, characterized by anhedonia and associated with decreased feeding and appetite; and atypical depression, characterized by fatigue, sleepiness, hyperphagia, and weight gain. The central nervous system plays a key role in the regulation of feeding and mood, thus suggesting that overlapping neuronal circuits may be involved in their modulation. However, these circuits have yet to be completely characterized. The central melanocortin system, a circuitry characterized by the expression of specific peptides (pro-opiomelanocortins, agouti-related protein, and neuropeptide Y) and their melanocortin receptors, has been shown to be a key player in the regulation of feeding. In addition, the melanocortin system has also been shown to affect anxiety and depressive-like behavior, thus suggesting a possible role of the melanocortin system as a biological substrate linking feeding and depression. However, more studies are needed to fully understand this complex system and its role in regulating metabolic and mood disorders. In this review, we will discuss the current literature on the role of the melanocortin system in human and animal models in feeding and mood regulation, providing evidence of the biological interplay between anxiety, major depressive disorders, appetite, and body weight regulation.

UCP2-dependent redox sensing in POMC neurons regulates feeding.

Paradoxically, glucose, the primary driver of satiety, activates a small population of anorexigenic pro-opiomelanocortin (POMC) neurons. Here, we show that lactate levels in the circulation and in the cerebrospinal fluid are elevated in the fed state and the addition of lactate to glucose activates the majority of POMC neurons while increasing cytosolic NADH generation, mitochondrial respiration, and extracellular pyruvate levels. Inhibition of lactate dehydrogenases diminishes mitochondrial respiration, NADH production, and POMC neuronal activity. However, inhibition of the mitochondrial pyruvate carrier has no effect. POMC-specific downregulation of Ucp2 (Ucp2PomcKO), a molecule regulated by fatty acid metabolism and shown to play a role as transporter in the malate-aspartate shuttle, abolishes lactate- and glucose-sensing of POMC neurons. Ucp2PomcKO mice have impaired glucose metabolism and are prone to obesity on a high-fat diet. Altogether, our data show that lactate through redox signaling and blocking mitochondrial glucose utilization activates POMC neurons to regulate feeding and glucose metabolism.

Estrogen-dependent transcription of the NEL-like 2 (NELL2) gene and its role in protection from cell death.

NELL2 (neural tissue-specific epidermal growth factor-like repeat domain-containing protein) is a secreted glycoprotein that is predominantly expressed in neural tissues. We reported previously that NELL2 mRNA abundance in brain is increased by estrogen (E2) treatment and that NELL2 is involved in the E2-dependent organization of a sexually dimorphic nucleus in the preoptic area. In this study we cloned the mouse NELL2 promoter and found it to contain two half-E2 response elements. Electrophoretic mobility shift assays and promoter assays showed that E2 and its receptors (ERalpha and ERbeta) stimulated NELL2 transcription by binding to the two half-E2 response elements. Hippocampal neuroprogenitor HiB5 cells expressing recombinant NELL2 showed increased cell survival under cell death-inducing conditions. Blockade of endogenous synthesis of NELL2 in HiB5 cells abolished the cell survival effect of E2 and resulted in a decrease in phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2). These data suggest that the NELL2 gene is trans-activated by E2 and contributes to mediating the survival promoting effects of E2 via intracellular signaling pathway of ERK.

Role of the Melanocortin System in the Central Regulation of Cardiovascular Functions.

Increasing evidence indicates that the melanocortin system is not only a central player in energy homeostasis, food intake and glucose level regulation, but also in the modulation of cardiovascular functions, such as blood pressure and heart rate. The melanocortins, and in particular α- and γ-MSH, have been shown to exert their cardiovascular activity both at the central nervous system level and in the periphery (e.g., in the adrenal gland), binding their receptors MC3R and MC4R and influencing the activity of the sympathetic nervous system. In addition, some studies have shown that the activation of MC3R and MC4R by their endogenous ligands is able to improve the outcome of cardiovascular diseases, such as myocardial and cerebral ischemia. In this brief review, we will discuss the current knowledge of how the melanocortin system influences essential cardiovascular functions, such as blood pressure and heart rate, and its protective role in ischemic events, with a particular focus on the central regulation of such mechanisms.

Drp1 is required for AgRP neuronal activity and feeding.

The hypothalamic orexigenic Agouti-related peptide (AgRP)-expressing neurons are crucial for the regulation of whole-body energy homeostasis. Here, we show that fasting-induced AgRP neuronal activation is associated with dynamin-related peptide 1 (DRP1)-mediated mitochondrial fission and mitochondrial fatty acid utilization in AgRP neurons. In line with this, mice lacking Dnm1l in adult AgRP neurons (Drp1 cKO) show decreased fasting- or ghrelin-induced AgRP neuronal activity and feeding and exhibited a significant decrease in body weight, fat mass, and feeding accompanied by a significant increase in energy expenditure. In support of the role for mitochondrial fission and fatty acids oxidation, Drp1 cKO mice showed attenuated palmitic acid-induced mitochondrial respiration. Altogether, our data revealed that mitochondrial dynamics and fatty acids oxidation in hypothalamic AgRP neurons is a critical mechanism for AgRP neuronal function and body-weight regulation.

A Sympathetic Treatment for Obesity.

Amphetamine (AMPH), mainly used in the treatment of attention deficit hyperactivity disorder and narcolepsy, has weight loss properties, although with detrimental cardiovascular effects. In this issue, Mahú et al. (2020) describe the effect of a new derivative of AMPH, "PEGyAMPH," a brain-spared anti-obesity drug that alters sympathetic activity without cardiovascular side effects.

MC4R Signaling in Dorsal Raphe Nucleus Controls Feeding, Anxiety, and Depression.

Major depressive disorder is associated with weight loss and decreased appetite; however, the signaling that connects these conditions is unclear. Here, we show that MC4R signaling in the dorsal raphe nucleus (DRN) affects feeding, anxiety, and depression. DRN infusion of α-MSH decreases DRN neuronal activation and feeding. DRN MC4R is expressed in GABAergic PRCP-producing neurons. DRN selective knockdown of PRCP (PrcpDRNKD), an enzyme inactivating α-MSH, decreases feeding and DRN neuronal activation. Interestingly, PrcpDRNKD mice present lower DRN serotonin levels and depressive-like behavior. Similarly, PRCP-ablated MC4R mice (PrcpMC4RKO) show metabolic and behavioral phenotypes comparable to those of PrcpDRNKD mice. Selective PRCP re-expression in DRN MC4R neurons of PrcpMC4RKO mice partially reverses feeding, while fully restoring mood behaviors. Chemogenetic inhibition of DRN MC4R neurons induces anxiety, depression, and reduced feeding, whereas chemogenetic activation reverses these effects. Our results indicate that MC4R signaling in DRN plays a role in feeding, anxiety, and depression.

Stimulation of the molecule 4-1BB enhances host defense against Listeria monocytogenes infection in mice by inducing rapid infiltration and activation of neutrophils and monocytes.

The tumor necrosis factor receptor family molecule 4-1BB (CD137) has diverse roles in adaptive and innate immune responses. However, little is known of its role in bacterial infections. Previously, we showed that 4-1BB-deficient mice have enhanced susceptibility to Listeria monocytogenes infection, and mice pretreated with agonistic anti-4-1BB antibody (3E1) were much more resistant to L. monocytogenes infection than mice treated with control antibody. In this study, we report that stimulating 4-1BB by administering 3E1 in the early phase of L. monocytogenes infection is critical for promoting the survival of mice by inducing rapid infiltration of neutrophils and monocytes into L. monocytogenes-infected livers. The levels of tumor necrosis factor alpha, interleukin 6, and monocyte chemoattractant protein 1 in the livers of 3E1-treated mice increased as early as 30 min postinfection and peaked by 1 to 2 h, while those in mice treated with control antibody started to increase only at 16 h postinfection. Monocytes and neutrophils from the 3E1-treated mice had higher levels of activation markers, phagocytic activity, and reactive oxygen species than those from control mice. In vitro stimulation of 4-1BB induced the production of the inflammatory cytokines/chemokines of neutrophils, but not those of monocytes. These results suggest that 4-1BB stimulation of neutrophils in the early phase of L. monocytogenes infection causes rapid production of inflammatory cytokines/chemokines and that the subsequent infiltration of neutrophils and monocytes is crucial for eliminating the infecting L. monocytogenes.