Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans. Kullmann Stephanie,Heni Martin,Hallschmid Manfred,Fritsche Andreas,Preissl Hubert,Häring Hans-Ulrich Physiological reviews Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance. We also describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders. 10.1152/physrev.00032.2015

Choroid plexus is an additional source of melatonin in the brain. Quintela Telma,Gonçalves Isabel,Silva Marco,Duarte Ana C,Guedes Paula,Andrade Késsia,Freitas Flávia,Talhada Daniela,Albuquerque Tânia,Tavares Sara,Passarinha Luis A,Cipolla-Neto José,Santos Cecília R A Journal of pineal research The cerebrospinal fluid melatonin is released from the pineal gland, directly into the third ventricle, or produced de novo in the brain from extrapineal melatonin sources leading to a melatonin concentration gradient in the cerebrospinal fluid. Despite the interest on this topic, the brain areas capable of producing melatonin are not yet clear. Bearing this in mind, we hypothesized that the choroid plexus (CP) could be one of these melatonin sources. We analyzed and confirmed the presence of the four enzymes required for melatonin synthesis in rat CP and demonstrated that arylalkylamine N-acetyltransferase shows a circadian expression in female and male rat CP. Specifically, this enzyme colocalizes with mitochondria in rat CP epithelial cells, an organelle known to be involved in melatonin function and synthesis. Then, we demonstrated that melatonin is synthesized by porcine CP explants, although without a circadian pattern. In conclusion, our data show that the CP is a local source of melatonin to the central nervous system, probably contributing to its high levels in the cerebrospinal fluid. We believe that in the CP, melatonin might be regulated by its endogenous clock machinery and by the hormonal background. 10.1111/jpi.12528

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Arnold Steven E,Arvanitakis Zoe,Macauley-Rambach Shannon L,Koenig Aaron M,Wang Hoau-Yan,Ahima Rexford S,Craft Suzanne,Gandy Sam,Buettner Christoph,Stoeckel Luke E,Holtzman David M,Nathan David M Nature reviews. Neurology Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of 'brain insulin resistance' and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike. 10.1038/nrneurol.2017.185

Lipocalin-2 protects the brain during inflammatory conditions. Kang S S,Ren Y,Liu C-C,Kurti A,Baker K E,Bu G,Asmann Y,Fryer J D Molecular psychiatry Sepsis is a prevalent health issue that can lead to central nervous system (CNS) inflammation with long-term behavioral and cognitive alterations. Using unbiased proteomic profiling of over 100 different cytokines, we found that Lipocalin-2 (LCN2) was the most substantially elevated protein in the CNS after peripheral administration of lipopolysaccharide (LPS). To determine whether the high level of LCN2 in the CNS is protective or deleterious, we challenged Lcn2 mice with peripheral LPS and determined effects on behavior and neuroinflammation. At a time corresponding to peak LCN2 induction in wild-type (WT) mice injected with LPS, Lcn2 mice challenged with LPS had exacerbated levels of pro-inflammatory cytokines and exhibited significantly worsened behavioral phenotypes. To determine the extent of global inflammatory changes dependent upon LCN2, we performed an RNAseq transcriptomic analysis. Compared with WT mice injected with LPS, Lcn2 mice injected with LPS had unique transcriptional profiles and significantly elevated levels of multiple pro-inflammatory molecules. Several LCN2-dependent pathways were revealed with this analysis including, cytokine and chemokine signaling, nucleotide-binding oligomerization domain-like receptor signaling and Janus kinase-signal transducer and activator of transcription signaling. These findings demonstrate that LCN2 serves as a potent protective factor in the CNS in response to systemic inflammation and may be a potential candidate for limiting sepsis-related CNS sequelae. 10.1038/mp.2016.243

A brain-based pain facilitation mechanism contributes to painful diabetic polyneuropathy. Segerdahl Andrew R,Themistocleous Andreas C,Fido Dean,Bennett David L,Tracey Irene Brain : a journal of neurology The descending pain modulatory system represents one of the oldest and most fundamentally important neurophysiological mechanisms relevant to pain. Extensive work in animals and humans has shown how a functional imbalance between the facilitatory and inhibitory components is linked to exacerbation and maintenance of persistent pain states. Forward translation of these findings into clinical populations is needed to verify the relevance of this imbalance. Diabetic polyneuropathy is one of the most common causes of chronic neuropathic pain; however, the reason why ∼25-30% of patients with diabetes develop pain is not known. The current study used a multimodal clinical neuroimaging approach to interrogate whether the sensory phenotype of painful diabetic polyneuropathy involves altered function of the ventrolateral periaqueductal grey-a key node of the descending pain modulatory system. We found that ventrolateral periaqueductal grey functional connectivity is altered in patients suffering from painful diabetic polyneuropathy; the magnitude of which is correlated to their spontaneous and allodynic pain as well as the magnitude of the cortical response elicited by an experimental tonic heat paradigm. We posit that ventrolateral periaqueductal grey-mediated descending pain modulatory system dysfunction may reflect a brain-based pain facilitation mechanism contributing to painful diabetic polyneuropathy. 10.1093/brain/awx337