Exercise therapy for chronic pain: How does exercise change the limbic brain function?

We are exposed to various external and internal threats which might hurt us. The role of taking flexible and appropriate actions against threats is played by "the limbic system" and at the heart of it there is the ventral tegmental area and nucleus accumbens (brain reward system). Pain-related fear causes excessive excitation of amygdala, which in turn causes the suppression of medial prefrontal cortex, leading to chronification of pain. Since the limbic system of chronic pain patients is functionally impaired, they are maladaptive to their situations, unable to take goal-directed behavior and are easily caught by fear-avoidance thinking. We describe the neural mechanisms how exercise activates the brain reward system and enables chronic pain patients to take goal-directed behavior and overcome fear-avoidance thinking. A key to getting out from chronic pain state is to take advantage of the behavioral switching function of the basal nucleus of amygdala. We show that exercise activates positive neurons in this nucleus which project to the nucleus accumbens and promote reward behavior. We also describe fear conditioning and extinction are affected by exercise. In chronic pain patients, the fear response to pain is enhanced and the extinction of fear memories is impaired, so it is difficult to get out of "fear-avoidance thinking". Prolonged avoidance of movement and physical inactivity exacerbate pain and have detrimental effects on the musculoskeletal and cardiovascular systems. Based on the recent findings on multiple bran networks, we propose a well-balanced exercise prescription considering the adherence and pacing of exercise practice. We conclude that therapies targeting the mesocortico-limbic system, such as exercise therapy and cognitive behavioral therapy, may become promising tools in the fight against chronic pain.

Three weeks of exercise therapy altered brain functional connectivity in fibromyalgia inpatients.

Background: Fibromyalgia (FM) is a chronic pain syndrome characterized by widespread pain, tenderness, and fatigue. Patients with FM have no effective medication so far, and their activity of daily living and quality of life are remarkably impaired. Therefore, new therapeutic approaches are awaited. Recently, exercise therapy has been gathering much attention as a promising treatment for FM. However, the underlying mechanisms are not fully understood, particularly, in the central nervous system, including the brain. Therefore, we investigated functional connectivity changes and their relationship with clinical improvement in patients with FM after exercise therapy to investigate the underlying mechanisms in the brain using resting-state fMRI (rs-fMRI) and functional connectivity (FC) analysis. Methods: Seventeen patients with FM participated in this study. They underwent a 3-week exercise therapy on in-patient basis and a 5-min rs-fMRI scan before and after the exercise therapy. We compared the FC strength of sensorimotor regions and the mesocortico-limbic system between two scans. We also performed a multiple regression analysis to examine the relationship between pre-post differences in FC strength and improvement of patients' clinical symptoms or motor abilities. Results: Patients with FM showed significant improvement in clinical symptoms and motor abilities. They also showed a significant pre-post difference in FC of the anterior cingulate cortex and a significant correlation between pre-post FC changes and improvement of clinical symptoms and motor abilities. Although sensorimotor regions tended to be related to the improvement of general disease severity and depression, brain regions belonging to the mesocortico-limbic system tended to be related to the improvement of motor abilities. Conclusion: Our 3-week exercise therapy could ameliorate clinical symptoms and motor abilities of patients with FM, and lead to FC changes in sensorimotor regions and brain regions belonging to the mesocortico-limbic system. Furthermore, these changes were related to improvement of clinical symptoms and motor abilities. Our findings suggest that, as predicted by previous animal studies, spontaneous brain activities modified by exercise therapy, including the mesocortico-limbic system, improve clinical symptoms in patients with FM.

Voluntary running-induced activation of ventral hippocampal GABAergic interneurons contributes to exercise-induced hypoalgesia in neuropathic pain model mice.

The exact mechanism of exercise-induced hypoalgesia (EIH) in exercise therapy to improve chronic pain has not been fully clarified. Recent studies have suggested the importance of the ventral hippocampus (vHPC) in inducing chronic pain. We investigated the effects of voluntary running (VR) on FosB+ cells and GABAergic interneurons (parvalbumin-positive [PV+] and somatostatin-positive [SOM+]) in the vHPC-CA1 in neuropathic pain (NPP) model mice. VR significantly improved thermal hyperalgesia in the NPP model. The number of the FosB+ cells was significantly higher in partial sciatic nerve ligation-sedentary mice than in Sham and Naive mice, whereas VR significantly suppressed the FosB+ cells in the vHPC-CA1. Furthermore, VR significantly increased the proportion of activated PV+ and SOM+ interneurons in the vHPC-CA1, and tracer experiments indicated that approximately 24% of neurons projecting from the vHPC-CA1 to the basolateral nucleus of amygdala were activated in NPP mice. These results indicate that feedforward suppression of the activated neurons via VR-induced activation of GABAergic interneurons in the vHPC-CA1 may be a mechanism to produce EIH effects, and suggested that disappearance of negative emotions such as fear and anxiety by VR may play a critical role in improving chronic pain.

Exercise-induced increase in M2 macrophages accelerates wound healing in young mice.

Moderate-intensity exercise performed during wound healing has been reported to decrease inflammatory cytokines and chemokines and accelerate wound healing. However, its effect on macrophage phenotype and the mechanism by which exercise accelerates wound healing remain unclear. The purpose of this study was to investigate the effect of exercise on macrophage phenotype during wound healing and to clarify the relationship between angiogenesis and wound healing. 12-week-old male C57BL/6J mice were divided into sedentary (n = 6) and exercise groups (n = 6). The exercise group performed moderate-intensity treadmill running exercise (9.0 m/min, 60 min) for 10 days. Double immunofluorescence analysis was performed using F4/80+ inducible nitric oxide synthase (iNOS)+ for M1 macrophages, F4/80+ transforming growth factor-beta (TGF-ß)1+ for M2 macrophages, and CD31+ alpha smooth muscle actin (α-SMA)+ for angiogenesis. The exercise group showed significantly accelerated wound healing compared with the sedentary group. From early wound healing onward, exercise significantly inhibited M1 macrophage infiltration and increased M2 macrophage count. Exercise also significantly increased angiogenesis. Furthermore, the M2 macrophage phenotype was significantly correlated with angiogenesis in the exercise group, indicating that M2 macrophages and angiogenesis are related to accelerated wound healing. These findings suggest that moderate-intensity exercise increases TGF-ß1 derived from M2 macrophages, which may be associated with enhanced angiogenesis and wound healing in young mice.

Brain Mechanisms of Exercise-Induced Hypoalgesia: To Find a Way Out from "Fear-Avoidance Belief".

It is well known that exercise produces analgesic effects (exercise-induced hypoalgesia (EIH)) in animal models and chronic pain patients, but the brain mechanisms underlying these EIH effects, especially concerning the emotional aspects of pain, are not yet fully understood. In this review, we describe drastic changes in the mesocorticolimbic system of the brain which permit the induction of EIH effects. The amygdala (Amyg) is a critical node for the regulation of emotions, such as fear and anxiety, which are closely associated with chronic pain. In our recent studies using neuropathic pain (NPP) model mice, we extensively examined the association between the Amyg and EIH effects. We found that voluntary exercise (VE) activated glutamate (Glu) neurons in the medial basal Amyg projecting to the nucleus accumbens (NAc) lateral shell, while it almost completely suppressed NPP-induced activation of GABA neurons in the central nucleus of the Amyg (CeA). Furthermore, VE significantly inhibited activation of pyramidal neurons in the ventral hippocampus-CA1 region, which play important roles in contextual fear conditioning and the retrieval of fear memory. This review describes novel information concerning the brain mechanisms underlying EIH effects as a result of overcoming the fear-avoidance belief of chronic pain.

Tumor suppression and improvement in immune systems by specific activation of dopamine D1-receptor-expressing neurons in the nucleus accumbens.

Recent research has suggested that the mesolimbic dopamine network that mainly terminates in the nucleus accumbens may positively control the peripheral immune system. The activation of dopamine receptors in neurons in the nucleus accumbens by the release of endogenous dopamine is thus expected to contribute to efferent immune regulation. As in the stimulation of Gs-coupled dopamine D1-receptors or Gi-coupled D2-receptors by endogenous dopamine, we investigated whether specific stimulation of dopamine D1-receptor-expressing neurons or inhibition of dopamine D2-receptor-expressing neurons in the nucleus accumbens could produce anti-tumor effects and improve the immune system in transgenic mice using pharmacogenetic techniques. Repeated stimulation of D1-receptor-expressing neurons in either the medial shell, lateral shell or core regions of the nucleus accumbens significantly decreased tumor volume under a state of tumor transplantation, whereas repeated suppression of D2-receptor-expressing neurons in these areas had no effect on this event. The number of splenic CD8+ T cells was significantly increased following repeated stimulation of D1-receptor-expressing neurons in the nucleus accumbens of mice with tumor transplantation. Furthermore, this stimulation produced a significant reduction in the population of splenic CD8+ T cells that expressed immune checkpoint-related inhibitory receptors, PD-1, TIM-3 and LAG-3. These findings suggest that repeated stimulation of D1-receptor-expressing neurons (probably D1-receptor-expressing medium spiny neurons) in the nucleus accumbens suppressed tumor progression and improved the immune system by suppressing the exhaustion of splenic CD8+ T cells.

Relief of neuropathic pain by cell-specific manipulation of nucleus accumbens dopamine D1- and D2-receptor-expressing neurons.

Emerging evidence suggests that the mesolimbic dopaminergic network plays a role in the modulation of pain. As chronic pain conditions are associated with hypodopaminergic tone in the nucleus accumbens (NAc), we evaluated the effects of increasing signaling at dopamine D1/D2-expressing neurons in the NAc neurons in a model of neuropathic pain induced by partial ligation of sciatic nerve. Bilateral microinjection of either the selective D1-receptor (Gs-coupled) agonist Chloro-APB or the selective D2-receptor (Gi-coupled) agonist quinpirole into the NAc partially reversed nerve injury-induced thermal allodynia. Either optical stimulation of D1-receptor-expressing neurons or optical suppression of D2-receptor-expressing neurons in both the inner and outer substructures of the NAc also transiently, but significantly, restored nerve injury-induced allodynia. Under neuropathic pain-like condition, specific facilitation of terminals of D1-receptor-expressing NAc neurons projecting to the VTA revealed a feedforward-like antinociceptive circuit. Additionally, functional suppression of cholinergic interneurons that negatively and positively control the activity of D1- and D2-receptor-expressing neurons, respectively, also transiently elicited anti-allodynic effects in nerve injured animals. These findings suggest that comprehensive activation of D1-receptor-expressing neurons and integrated suppression of D2-receptor-expressing neurons in the NAc may lead to a significant relief of neuropathic pain.

Plastic changes in amygdala subregions by voluntary running contribute to exercise-induced hypoalgesia in neuropathic pain model mice.

Physical exercise has been established as a low-cost, safe, and effective way to manage chronic pain, but exact mechanisms underlying such exercise-induced hypoalgesia (EIH) are not fully understood. Since a growing body of evidence implicated the amygdala (Amyg) as a critical node in emotional affective aspects of chronic pain, we hypothesized that the Amyg may play important roles to produce EIH effects. Here, using partial sciatic nerve ligation (PSL) model mice, we investigated the effects of voluntary running (VR) on the basal amygdala (BA) and the central nuclei of amygdala (CeA). The present study indicated that VR significantly improved heat hyperalgesia which was exacerbated in PSL-Sedentary mice, and that a significant positive correlation was detected between total running distances after PSL-surgery and thermal withdrawal latency. The number of activated glutamate (Glu) neurons in the medal BA (medBA) was significantly increased in PSL-Runner mice, while those were increased in the lateral BA in sedentary mice. Furthermore, in all subdivisions of the CeA, the number of activated gamma-aminobutyric acid (GABA) neurons was dramatically increased in PSL-Sedentary mice, but these numbers were significantly decreased in PSL-Runner mice. In addition, a tracer experiment demonstrated a marked increase in activated Glu neurons in the medBA projecting into the nucleus accumbens lateral shell in runner mice. Thus, our results suggest that VR may not only produce suppression of the negative emotion such as fear and anxiety closely related with pain chronification, but also promote pleasant emotion and hypoalgesia. Therefore, we conclude that EIH effects may be produced, at least in part, via such plastic changes in the Amyg.

Activation of mesolimbic reward system via laterodorsal tegmental nucleus and hypothalamus in exercise-induced hypoalgesia.

Ventral tegmental area (VTA) dopamine (DA) neurons are the primary source of dopamine in target structures that constitute the mesolimbic reward system. Previous studies demonstrated that voluntary wheel running (VWR) by neuropathic pain (NPP) model mice produces exercise-induced hypoalgesia (EIH), and that activation of mesolimbic reward system may lead to EIH. However, the neuronal mechanism by which the mesolimbic reward system is activated by VWR is unknown. Here, we found that VWR produces EIH effects and reverses the marked reduction in activated lateral VTA (lVTA)-DA neurons induced by NPP. The proportions of activated laterodorsal tegmental nucleus (LDT)-cholinergic and lateral hypothalamus-orexin neurons were significantly enhanced by VWR. Retrograde tracing and dual immunostaining revealed that VWR activates lVTA-projecting LDT-cholinergic/non-cholinergic and lateral hypothalamic area (LHA)-orexin/non-orexin neurons. Therefore, EIH effects may be produced, at least in part, by activation of the mesolimbic reward system via activation of LDT and LHA neurons.

Bilateral increases in ERK activation at the spinomedullary junction region by acute masseter muscle injury during temporomandibular joint inflammation in the rats.

We determined the role of persistent monoarthritis of temporomandibular joint region (TMJ) on bilateral masseter muscle (MM) nociception in male rats using orofacial nocifensive behaviors, phosphorylated extracellular signal-regulated kinase and Fos induction at the trigeminal subnucleus caudalis/upper cervical spinal cord (Vc/C2) region in response to formalin injection to the MM region. TMJ inflammation was induced by local injection of CFA into the left TMJ region. Orofacial nocifensive behaviors evoked by formalin injection ipsilateral or contralateral to the TMJ inflammation appeared to be increased at 1-14 days or at 1, 10 and 14 days after induction of TMJ inflammation, respectively, while increases in behavioral duration were seen mainly in the late phase rather than the early phase. The number of pERK positive cells was investigated in superficial laminae at the Vc/C2 region at 3, 10, 20, 60 and 80 min after MM stimulation with formalin at 14 days after TMJ inflammation. TMJ-inflamed rats displayed greater responses of pERK expression by the ipsilateral MM stimulation at 3-60 min, while contralateral MM stimulation increased pERK expression at 3, 10 and 20 min compared to non-CFA rats. Fos expression by MM stimulation was increased at 14 days after induction of TMJ inflammation regardless of the affected side. These findings showed that persistent TMJ inflammation for 10 and 14 days is sufficient to enhance MM nociception indicated by behaviors and neural responses in superficial laminae at the Vc/C2 region.

Exercise-induced hypoalgesia: potential mechanisms in animal models of neuropathic pain.

Physical exercise, such as forced treadmill running and swimming, can sufficiently improve mechanical allodynia and heat hyperalgesia in animal models of neuropathic pain (NPP), including partial sciatic nerve ligation, chronic constriction injury, and spinal nerve ligation models. Thus, physical exercise has been established as a low-cost, safe, and effective way to manage NPP conditions, but the exact mechanisms underlying such exercise-induced hypoalgesia (EIH) are not fully understood. A growing body of evidence has identified several factors that work at different levels of the nervous system as playing important roles in producing EIH in animal models of NPP. The objective of this review is to provide an overview of key players associated with EIH, and then to discuss our current understanding of the mechanisms underlying EIH. Relevant studies have demonstrated that physical exercise can dramatically alter the levels of inflammatory cytokines, neurotrophins, neurotransmitters, endogenous opioids, and histone acetylation at various sites in the nervous system, such as injured peripheral nerves, dorsal root ganglia, and spinal dorsal horn in animal models of NPP, thereby contributing to the production of EIH. These results suggest that EIH is produced through multiple cellular and molecular events in the pain pathway.

A new aspect of chronic pain as a lifestyle-related disease.

Physical exercise has been established as a low-cost, safe, and effective way to manage chronic intractable pain. We investigated the underlying mechanisms of exercise-induced hypoalgesia (EIH) using a mouse model of neuropathic pain (NPP). Epigenetic changes in activated microglia and maintained GABA synthesis in the spinal dorsal horn may contribute to EIH. Voluntary exercise (VE), a strong reward for animals, also induced EIH, which may be due in part to the activation of dopamine (DA) neurons in the ventral tegmental area (VTA). VE increases the expression of pCREB in dopaminergic neurons in the VTA, which would enhance dopamine production, and thereby contributes to the activation of the mesolimbic reward system in NPP model mice. We demonstrated that neurons in the laterodorsal tegmental and pedunculopontine tegmental nuclei, a major input source of rewarding stimuli to the VTA, were activated by exercise. Chronic pain is at least partly attributed to sedentary and inactive lifestyle as indicated by the Fear-avoidance model. Therefore, chronic pain could be recognized as a lifestyle-related disease. Physical activity/inactivity may be determined by genetic/epigenetic and neural factors encoded in our brain. The hypothalamus and reward system is closely related in the axis of food intake, energy metabolism and physical activity. Understanding the interactions between the mesolimbic DA system and the hypothalamus that sense and regulate energy balance is thus of significant importance. For example, proopiomelanocortin neurons and melanocortin 4 receptors may play a role in connecting these two systems. Therefore, in a certain sense, chronic pain and obesity may share common behavioral and neural pathology, i.e. physical inactivity, as a result of inactivation of the mesolimbic DA system. Exercise and increasing physical activity in daily life may be important in treating and preventing chronic pain, a life-style related disease.

Involvement of mesolimbic dopaminergic network in neuropathic pain relief by treadmill exercise: A study for specific neural control with Gi-DREADD in mice.

BACKGROUND: Exercise alleviates pain and it is a central component of treatment strategy for chronic pain in clinical setting. However, little is known about mechanism of this exercise-induced hypoalgesia. The mesolimbic dopaminergic network plays a role in positive emotions to rewards including motivation and pleasure. Pain negatively modulates these emotions, but appropriate exercise is considered to activate the dopaminergic network. We investigated possible involvement of this network as a mechanism of exercise-induced hypoalgesia. METHODS: In the present study, we developed a protocol of treadmill exercise, which was able to recover pain threshold under partial sciatic nerve ligation in mice, and investigated involvement of the dopaminergic reward network in exercise-induced hypoalgesia. To temporally suppress a neural activation during exercise, a genetically modified inhibitory G-protein-coupled receptor, hM4Di, was specifically expressed on dopaminergic pathway from the ventral tegmental area to the nucleus accumbens. RESULTS: The chemogenetic-specific neural suppression by Gi-DREADD system dramatically offset the effect of exercise-induced hypoalgesia in transgenic mice with hM4Di expressed on the ventral tegmental area dopamine neurons. Additionally, anti-exercise-induced hypoalgesia effect was significantly observed under the suppression of neurons projecting out of the ventral tegmental area to the nucleus accumbens as well. CONCLUSION: Our findings suggest that the dopaminergic pathway from the ventral tegmental area to the nucleus accumbens is involved in the anti-nociception under low-intensity exercise under a neuropathic pain-like state.

Improvements in impaired GABA and GAD65/67 production in the spinal dorsal horn contribute to exercise-induced hypoalgesia in a mouse model of neuropathic pain.

BACKGROUND: Physical exercise effectively attenuates neuropathic pain, and multiple events including the inhibition of activated glial cells in the spinal dorsal horn, activation of the descending pain inhibitory system, and reductions in pro-inflammatory cytokines in injured peripheral nerves may contribute to exercise-induced hypoalgesia. Since fewer GABAergic hypoalgesic interneurons exist in the dorsal horn in neuropathic pain model animals, the recovery of impaired GABAergic inhibition in the dorsal horn may improve pain behavior. We herein determined whether the production of gamma-aminobutyric acid (GABA) and glutamic acid decarboxylase (GAD) in the dorsal horn is restored by treadmill running and contributes to exercise-induced hypoalgesia in neuropathic pain model mice. C57BL/6 J mice underwent partial sciatic nerve ligation (PSL). PSL-Runner mice ran on a treadmill at 7 m/min for 60 min/day, 5 days/week, from two days after PSL. RESULTS: Mechanical allodynia and heat hyperalgesia developed in PSL-Sedentary mice but were significantly attenuated in PSL-Runner mice. PSL markedly decreased GABA and GAD65/67 levels in neuropils in the ipsilateral dorsal horn, while treadmill running inhibited these reductions. GABA+ neuronal nuclei+ interneuron numbers in the ipsilateral dorsal horn were significantly decreased in PSL-Sedentary mice but not in PSL-Runner mice. Pain behavior thresholds positively correlated with GABA and GAD65/67 levels and GABAergic interneuron numbers in the ipsilateral dorsal horns of PSL-Sedentary and -Runner mice. CONCLUSIONS: Treadmill running prevented PSL-induced reductions in GAD65/67 production, and, thus, GABA levels may be retained in interneurons and neuropils in the superficial dorsal horn. Therefore, improvements in impaired GABAergic inhibition may be involved in exercise-induced hypoalgesia.

Histone Acetylation in Microglia Contributes to Exercise-Induced Hypoalgesia in Neuropathic Pain Model Mice.

UNLABELLED: Physical exercise can attenuate neuropathic pain (NPP), but the exact mechanism underlying exercise-induced hypoalgesia (EIH) remains unclear. Recent studies have shown that histone hyperacetylation via pharmacological inhibition of histone deacetylases in the spinal cord attenuates NPP, and that histone acetylation may lead to the production of analgesic factors including interleukin 10. We intended to clarify whether histone acetylation in microglia in the spinal dorsal horn contributes to EIH in NPP model mice. C57BL/6J mice underwent partial sciatic nerve ligation (PSL) and PSL- and sham-runner mice ran on a treadmill at a speed of 7 m/min for 60 min/d, 5 days per week, from 2 days after the surgery. PSL-sedentary mice developed mechanical allodynia and heat hyperalgesia, but such behaviors were significantly attenuated in PSL-runner mice. In immunofluorescence analysis, PSL surgery markedly increased the number of histone deacetylase 1-positive/CD11b-positive microglia in the ipsilateral superficial dorsal horn, and they were significantly decreased by treadmill-running. Moreover, the number of microglia with nuclear expression of acetylated H3K9 in the ipsilateral superficial dorsal horn was maintained at low levels in PSL-sedentary mice, but running exercise significantly increased them. Therefore, we conclude that the epigenetic modification that causes hyperacetylation of H3K9 in activated microglia may play a role in producing EIH. PERSPECTIVE: This article presents the importance of epigenetic modification in microglia in producing EIH. The current research is not only helpful for developing novel nonpharmacological therapy for NPP, but will also enhance our understanding of the mechanisms and availability of exercise in our daily life.

Deficiency of oncostatin M receptor ß (OSMRß) exacerbates high-fat diet-induced obesity and related metabolic disorders in mice.

Oncostatin M (OSM) belongs to the IL-6 family of cytokines and has diverse biological effects, including the modulation of inflammatory responses. In the present study we analyzed the roles of OSM signaling in obesity and related metabolic disorders. Under a high-fat diet condition, OSM receptor ß subunit-deficient (OSMRß(-/-)) mice exhibited increases in body weight and food intake compared with those observed in WT mice. In addition, adipose tissue inflammation, insulin resistance, and hepatic steatosis were more severe in OSMRß(-/-) mice than in wild-type (WT) mice. These metabolic phenotypes did not improve when OSMRß(-/-) mice were pair-fed with WT mice, suggesting that the effects of OSM signaling on these phenotypes are independent of the increases in the body weight and food intake. In the liver of OSMRß(-/-) mice, the insulin-induced phosphorylation of p70 S6 kinase remained intact, whereas insulin-induced FOXO1 phosphorylation was impaired. In addition, OSMRß(-/-) mice displayed a higher expression of genes related to de novo lipogenesis in the liver than WT mice. Furthermore, treatment of genetically obese ob/ob mice with OSM improved insulin resistance, adipose tissue inflammation, and hepatic steatosis. Intraportal administration of OSM into ob/ob mice activated STAT3 and increased the expression of long-chain acyl-CoA synthetase (ACSL) 3 and ACSL5 with decreased expression of fatty acid synthase in the liver, suggesting that OSM directly induces lipolysis and suppresses lipogenesis in the liver of obese mice. These findings suggest that defects in OSM signaling promote the deterioration of high-fat diet-induced obesity and related metabolic disorders.

[The present status and attempts toward the achievement of gender equality in the JAA].

The proportion of female members in The Japanese Association of Anatomists (JAA) is 18% with the proportion of female members higher among the young generation (20-30 Y.O.; 34.8%, 30-40 Y.O.; 26.8%). However, the number of female members in the Board of Directors has been zero or one (0 or 6%) for many years. More than two female members are necessary on the Board to promote the diversity in the management of the JAA. The numbers of female members in other committees has shown gradual increase in recent years. A substantial increase in female faculty members including professors in each university and school will support the future development of the anatomical research field and the association. We have made the first great step by setting up the committee on promotion of gender equality in JAA in March, 2011. In the next year, JAA became a member of Japan Inter-Society Liaison Association Committee for Promoting Equal Participation of Men and Women in Science and Engineering (EPMEWSE). Our committee's activity includes holding workshops and seminars at the annual meetings to promote gender equality in the research field and to encourage mutual support and friendship, not only among women members but also among all members.

Lack of oncostatin M receptor ß leads to adipose tissue inflammation and insulin resistance by switching macrophage phenotype.

Oncostatin M (OSM), a member of the IL-6 family of cytokines, plays important roles in a variety of biological functions, including inflammatory responses. However, the roles of OSM in metabolic diseases are unknown. We herein analyzed the metabolic parameters of OSM receptor ß subunit-deficient (OSMRß(-/-)) mice under normal diet conditions. At 32 weeks of age, OSMRß(-/-) mice exhibited mature-onset obesity, severer hepatic steatosis, and insulin resistance. Surprisingly, insulin resistance without obesity was observed in OSMRß(-/-) mice at 16 weeks of age, suggesting that insulin resistance precedes obesity in OSMRß(-/-) mice. Both OSM and OSMRß were expressed strongly in the adipose tissue and little in some other metabolic organs, including the liver and skeletal muscle. In addition, OSMRß is mainly expressed in the adipose tissue macrophages (ATMs) but not in adipocytes. In OSMRß(-/-) mice, the ATMs were polarized to M1 phenotypes with the augmentation of adipose tissue inflammation. Treatment of OSMRß(-/-) mice with an anti-inflammatory agent, sodium salicylate, improved insulin resistance. In addition, the stimulation of a macrophage cell line, RAW264.7, and peritoneal exudate macrophages with OSM resulted in the increased expression of M2 markers, IL-10, arginase-1, and CD206. Furthermore, treatment of C57BL/6J mice with OSM increased insulin sensitivity and polarized the phenotypes of ATMs to M2. Thus, OSM suppresses the development of insulin resistance at least in part through the polarization of the macrophage phenotypes to M2, and OSMRß(-/-) mice provide a unique mouse model of metabolic diseases.