Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3�6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55 of the global rise in mean BMI from 1985 to 2017�and more than 80 in some low- and middle-income regions�was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing�and in some countries reversal�of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories. © 2019, The Author(s)

Activation of glial cells in the cervical spinal cord and in the trigeminal ganglion following induction of inflammatory pain

It is now well known that glial cells in the central and peripheral nervous system do not merely provide nutrients and trophic support to pain-transducing neurons, but rather directly participate to the genesis and maintenance of chronic pain, through their functional cross-talk with neuronal cells. Thus, the overall aim of the present work was to study the contribution of glial cells in the spinal-trigeminal system to the development and maintenance of inflammatory pain, and to verify whether the purinergic system might be a part of the complex and still largely unknown molecular network at the basis of the neuron-to-glia communication. We therefore set up a sub-chronic inflammatory model in vivo, characterized by inflammatory pain and trigeminal hypersensitivity, by injecting complete Freund adjuvant (CFA) into the temporomandibular joint (TMJ) of rats. Glial cell (i.e., astrocytes and miroglia in the spinal cord and satellite glial cells in the trigeminal ganglion) activation was then evaluated in the spinal-trigeminal system by immunohistochemistry. CFA-injected animals showed ipsilateral mechanical allodynia and TMJ edema. In the ipsilateral trigeminal ganglion, a highly significant increase in the number of reactive satellite glial cells encircling neurons was also observed, paralleled by activation of resident macrophages. Seventy-two hours after CFA injection, activated microglial cells were evident in the ipsilateral trigeminal subnucleus caudalis and in the cervical dorsal horn, with a significant up-regulation of Iba1 immunoreactivity. Conversely, no signs of reactive astrogliosis were detected, indicating no role for spinal astrocytes in pain transmission, at least at these early time points. Since the purinergic system has been implicated in the activation of microglial cells during neuropathic pain, we have also evaluated the expression of the microglial-specific P2Y12 receptor subtype. No upregulation was detected following induction of TMJ inflammation, suggesting that any possible role of P2Y12 receptor in this specific model of inflammatory pain does not involve changes in its expression. We are now evaluating the pro- or anti-algogenic role of other P2Y receptors through their selective inhibition in vivo. Our data suggest that specific glial cell populations might represent innovative targets for controlling pain during trigeminal nerve sensitization, such as during migraine attacks

Dopaminergic input to GABAergic neurons in the rostral agranular insular cortex of the rat

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Role of P2Y purinergic receptors in neuron-glia signaling in trigeminal ganglia: involvement in pain transmission

During chronic pain conditions, a cross-communication between sensory neurons and satellite glial cells (SGCs) within the trigeminal ganglia (TG), contributes to the development of hyperalgesia and allodynia. Since the purinergic system plays a special role in neuron-to-glia signalling, our purpose is to study in vitro and in vivo the involvement of G protein-coupled P2Y receptors in TG pain transmission. By using primary mixed TG cultures we previously showed that the proinflammatory mediator bradykinin (BK) potentiated purinergic P2Y receptors expressed by SGCs. Since BK receptors were functional in neurons only and BK was ineffective on neuron-free SGCs cultures, we hypothesized that the neuronal release of a soluble molecule was responsible of BK effects on SGCs. We identified this molecule as the calcitonin gene related peptide (CGRP), since its levels were markedly increased by BK application, and the CGRP antagonist, CGRP8-37, inhibited BK-induced effects on P2Y receptors. Interestingly, we found an increased CGRP release in cultures from a genetic mouse model of familial hemiplegic migraine, suggesting that the cross-talk with the purinergic system could be even more important in pathological conditions. To delve into the role of specific P2Y receptor subtypes in pain transmission, we set up a chronic inflammatory model in rat based on the injection of the complete Freund adjuvant (CFA) into the temporo mandibular joint (TMJ). The development of inflammation was confirmed by Evans blue dye extravasation in the ipsilateral TMJ, and by the increased orofacial pain sensitivity. Immunohistochemistry showed a significant GFAP upregulation on SGCs in the ipsilateral TG after CFA injection, as well as microglial activation in the ipsilateral medulla oblongata. We are now planning to selectively target specific P2Y receptors in vivo to evaluate their pro- or anti-algogenic role for the development of innovative analgesic drugs

Purinergic neuron/glia communication in the spinal-trigeminal system in vitro and in vivo: implications for basic mechanisms of pain transmission

It is now known that glial cells directly participate to the genesis and maintenance of chronic pain, both in the central and in the peripheral nervous system, through their functional cross-talk with pain-transducing neurons [1]. The whole molecular network at the basis of this neuron-to-glia communication is still largely unknown, and the purinergic system is likely to play a key role in close conjunction with other pain-transducing systems [2, 3]. Therefore, we decided to study the contribution of the G protein-coupled P2Y purinergic receptors in pain transmission in the spinal-trigeminal system both in vitro and in vivo. In primary mixed trigeminal cultures, we showed that the pro-algogenic molecule bradykinin potentiates P2Y receptors expressed by satellite glial cells (SGCs) [4] through the neuronal release of calcitonin gene related peptide (CGRP), which in turn activates the ERK1/2 pathways in SGCs [5]. Interestingly, in cultures from a genetic mouse model of familial hemiplegic migraine we observed an increased CGRP release and an up-regulation in the number of SGCs showing functional P2Y receptors, suggesting that the role of the purinergic system in neuron-glia crosstalk is even more important under pathological conditions [5]. To study the pro- or anti-algogenic role of specific P2Y receptor subtypes in vivo, we next set up a sub-chronic inflammatory model in vivo by injecting complete Freund adjuvant (CFA) into the temporomandibular joint (TMJ). CFA-injected animals showed mechanical allodynia and TMJ edema, accompanied by a strong increase in the number of reactive SGCs and resident macrophages in the TG, and by microglial activation in the ipsilateral medulla oblongata [6]. We are now evaluating the pro- or anti-algogenic role of specific P2Y-receptor subtypes in pain transduction. Overall, our results suggest that P2Y receptors on glial cells might represent innovative targets for the development of effective analgesic drugs. References [1] M. Takeda, M. Takahashi, S. Matsumoto. Contribution of the activation of satellite glia in sensory ganglia to pathological pain. Neuroscience Biobehavioural Reviews, 33, 784-792, 2009. [2] D. Donnelly-Roberts, S. McGaraughty, C.C. Shieh, P. Honore, M.F. Jarvis. Painful purinergic receptors. Journal of Pharmacology and Experimental Therapeutics, 324, 409-415, 2009. [3] G. Villa, M. Fumagalli, C. Verderio, M.P. Abbracchio, S. Ceruti. Expression and contribution of satellite glial cells purinoceptors to pain transmission in sensory ganglia: an update. Neuron Glia Biol, 6, 31-42, 2010. [4] S. Ceruti, M. Fumagalli, G. Villa, C. Verderio, M.P. Abbracchio. Purinoceptor-mediated calcium signaling in primary neuron-glia trigeminal cultures. Cell Calcium, 43, 576-90, 2008. [5] S. Ceruti, G. Villa, M. Fumagalli, L. Colombo, G. Magni, M. Zanardelli, E. Fabbretti, C. Verderio, A.M. van den Maagdenberg, A. Nistri, M.P. Abbracchio. Calcitonin Gene-Related Peptide-Mediated Enhancement of Purinergic Neuron/Glia Communication by the Algogenic Factor Bradykinin in Mouse Trigeminal Ganglia from Wild-Type and R192Q Cav2.1 Knock-In Mice: Implications for Basic Mechanisms of Migraine Pain. J Neurosci, 31, 3638-3649, 2011. [6] G. Villa, S. Ceruti, M. Zanardelli, G. Magni, L. Jasmin, P.T. Ohara, M.P. Abbracchio. Temporomandibular join inflammation activates glial and immune cells in both the trigeminal ganglia and the spinal trigeminal nucleus. Mol Pain, 6, 89, 2010