Communications Cerveau-Périphérie et Contrôle Métabolique / Brain-Periphery Communications in Metabolic Control

Séminaire organisé par Gilles Mithieux (INSERM U855, Lyon, France) et Matthias Tschöp (Helmholtz Zentrum München, Institute for Diabetes and Obesity, Germany) du 16 au 21 avril 2018

Participants

Sébastien Bouret, Jens C. Brüning, Marc Claret, Daniela Cota, Marcelo Dietrich, Ana Domingos, Christina Garcia Caceres, Lora Heisler, Gilles Mithieux, Richard Palmiter, Paul Pfluger, Elena Porro (Cell Press), Matthew Poy, Frank Reimann, Sonja C. Schriever, Randy Seeley, Maud Soty, Matthias Tschöp .

Résumé

Ce séminaire a réuni 18 chercheurs physiologistes et biologistes moléculaires impliqués dans la compréhension de l’homéostasie énergétique et glucidique sous le contrôle du cerveau et du système nerveux périphérique. Plus précisément, le séminaire s’est intéressé aux recherches les plus récentes concernant le rôle des communications cerveau-organe et organes-cerveau dans ces régulations, par l’intermédiaire de communications nerveuses et/ou hormonales. La pertinence de ces recherches dans la compréhension de l’épidémie d’obésité en pleine expansion au plan mondial était une préoccupation commune. Le séminaire rassemblait 3 chercheurs « juniors », 7 jeunes leaders d’équipe récemment établis, 7 leaders d’équipe confirmés et 1 éditeur d’une revue internationale d’excellence en biologie.

Compte-rendu (en anglais)

Matthias Tschöp initiated the seminar by highlighting the key role of the brain and the high heterogeneity of neurons that play a role in energy balance. Matthias considered whether specialized transcriptional regulators may determine permanent changes in the ability of sub-populations of hypothalamic neurons to produce a discrete pattern of specific neuropeptides. He identified transcriptional switches able to program the peptidergic identity of both immature and terminally differentiated hypothalamic neurons, and to promote long-term changes in body weight and glucose control. These findings may lead to the generation of anti-obesity agents controlling hypothalamic neurons activity in a cell-specific fashion.

Cristina García Cáceres showed the importance of astrocytes, which like neurons respond to circulating nutrients and hormones and participate in glucose transport into the brain and tightly cooperate with neurons to efficiently regulate energy metabolism. Cristina’s ongoing studies are based on uncovering the other unknown roles of astrocytes in the control of metabolism. Especially, she found that hypercaloric diet induces neovascularization within the hypothalamus specifically, in both mice and humans. Importantly she identified that astrocytic HIF1α-VEGF signaling is involved in the initiation of this pathologic vascularization during nutritional excess.

Marcelo Dietrich emphasized that ingestive behaviors in mammals always rely on breastfeeding at the beginning of life. It is the milk provided by the mother to the offspring that allows the neonate to thrive. Despite this fundamental importance, we still know little about the mechanisms governing the attachment of the neonate to the mother. Marcelo presented novel findings along this behavioral axis, demonstrating neural mechanisms in the brain of the neonate that are involved in the behavioral attachment to the mother. These novel findings are relevant for the study of ingestive behaviors and the gut-brain communication, as they shed new light on how these intricate mechanisms develop early in life.

Sébastien Bouret’s team is interested in the development of the neuroendocrine systems that control energy homeostasis. Sebastien underlined the large inter-individual disparities between population groups with regard to obesity and that genetics alone cannot explain the obesity epidemics. Sebastien focused on perinatal environment, which can contribute to deleterious health outcomes in adults. Sebastien presented evidence that leptin and ghrelin, two key hormones in energy balance during adult life, can influence hypothalamic development during neonatal periods. He also presented recent data on the importance of axon guidance factors in the development of hypothalamic feeding circuits and in later adult obesity.

Lora Heisler focused on a key precursor of hunger-controlling neuropeptides, the polypeptide proopiomelanocortin (Pomc), within the homeostatic brain regions: the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the solitary tract (NTS). Lora presented 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (Htr2c; 5-HT2CR) agonist lorcaserin (Eisai Pharmaceuticals), a new medication for obesity treatment recently launched in the USA. Using a combination of viral and genetic technology, Lora’s research revealed that lorcaserin suppresses appetite via action at PomcHtr2c signaling within the ARC and NTS on different timescales. These findings reveal a necessary mechanism underpinning the therapeutic benefit of the new obesity medication lorcaserin.

Marc Claret has been interested in hypothalamic nutrient sensing and the role of mitochondria that are implicated in nutrient/energy management and are able to bioenergetically adjust to different metabolic situations through fusion and fission events. Deletion of pro-fusion protein Opa1 in POMC neurons causes an obese phenotype, characterized by hyperphagia and glucose metabolism alterations. This is basically the consequence of altered activation of lipolysis. On the contrary, loss of pro-fusion protein Mfn2 in endothelial cells causes a beneficial phenotype, characterized by leanness, improved glucose metabolism, diet-induced resistance and improved health-span. Marc’s results emphasize the importance of adequate mitochondrial dynamics in prototypical cellular nutrient-sensors upon metabolic control.

Daniela Cota highlighted that energy availability is sensed and then integrated in the context of neuronal activity. How this takes place might give insight on molecular mechanisms involved in the pathophysiology of obesity. Specifically, Daniela presented her data relating to the mTOR pathway and the endocannabinoid signaling on intracellular and intercellular mechanisms engaged in response to energy availability. Notably, she emphasized their impact in the modulation of the activity and function of the hypothalamic POMC neurons, neuronal cells known to play critical roles in the control of energy balance.

Paul Pfluger’s talk on « the enigma that is leptin resistance » stirred lively discussions on the controversial role of adipocyte-derived satiety hormone leptin as endogenous regulator of body weight. By visualizing the transport of leptin into the whole mouse brain via infrared labeling of recombinant leptin combined with delipidation and 3D light-sheet fluorescence microscopy, Paul’s team showed that leptin transport is largely regulated by the choroid plexus, and that despite leptin resistance, diet-induced obese (DIO) mice retain the ability to transport leptin into the brain. These important findings may help reconciling previously discordant observations on brain leptin transport and leptin resistance and should steer the focus of investigators away from leptin transport to concentrate their efforts on other possible causes for leptin resistance.

Sonja C. Schriever focused on dual-specificity phosphatase 8 (Dusp8), a gene recently identified from GWAS studies as a potential novel diabetes type 2 risk gene. Dusp8 is predominantly expressed in the brain and specific for the c-Jun NH2-terminal kinase (Jnk), which is known to escalate the development of diabetes type 2 in obese individuals. The findings of Sonja from murine and human studies presented here demonstrate a functional role of Dusp8 as a hypothalamic rheostat for inflammation, the hypothalamic pituitary adrenal axis feedback control and insulin resistance, and a novel factor that instigates the etiology of type 2 diabetes via a brain-driven mechanism.

Jens Brüning presented new data about the critical regulators that are the functionally antagonistic POMC- and AgRP-expressing hypothalamic neurons, which in addition to their role in food intake coordinately regulate multiple physiological processes according to the energy state, such as glucose metabolism and peripheral insulin sensitivity. In addition to the classical regulation of these neurons, uridine diphosphate (UDP) has been demonstrated by Jens’s team to activate AgRP neurons through the UDP-receptor P2Y6 expressed on AgRP-neurons, and that increased hypothalamic UDP concentrations in obesity thus lead to overactivation of AgRP-neurons in obesity. In conjunction with experiments demonstrating that ablation of P2Y6 selectively from AgRP neurons protects from diet-induced overeating and insulin resistance in mice, this points to the potential to develop P2Y6 antagonists as a novel treatment strategy for obesity and obesity-associated insulin resistance.

Richard Palmiter highlighted that visceral and somatosensory neuronal information is relayed to higher brain regions by glutamatergic neurons that reside in the parabrachial nucleus (PBN) that express calcitonin gene-related peptide (CGRP) and several other neuropeptides. Activation of these CGRP-expressing neurons inhibits feeding and chronic activation of these neurons would lead to starvation. A relevant output of these CGRP-expressing neurons is a projection to the lateral capsule region of the central nucleus of the amygdala onto neurons that express the receptor for CGRP. These neurons are also involved in conditioned taste aversion or fear behaviors (freezing). new data presented by Richard, especially from calcium imaging approach revealed that virtually CGRP neurons are activated by all threats that have been examined. Thus, they serve as a general alarm system for the animal.

Ana Domingos focused on the connection between peripheral sympathetic neurons and adipocytes. Ana previously found this neuro-adipose junction drives lipolysis via norepinephrine (NE) signaling and that the SNS is necessary and sufficient for fat mass reduction. As obesity is a chronic inflammatory state, Ana next wanted to define neuroimmune mechanisms that link inflammation to SNS neurons. She here reported the discovery of Sympathetic neuron-Associated Macrophages (SAMs) that directly regulate the extracellular availability of NE and identified the molecular mechanism by which SAMs import and metabolize NE. Abrogation of the mechanism for the uptake of NE by SAMs increases NE availability, which in turn promotes thermogenesis and browning, and long-term amelioration of obesity independently of food intake. The role of SAMs at steady state and obesity was discussed.

Matthew Poy has been interested in non-coding RNA species including microRNAs (miRNAs). While their diversity and unique expression patterns across different tissues make it challenging, substantial progress in understanding the regulatory role of miRNA in exocytosis and proliferation of the -cell were made. Matthew recently showed neuronal Cadm1 regulates body weight and energy homeostasis via its expression within the hippocampus and hypothalamus. In addition, deletion of Argonaute2, a key mediator of the miRNA pathway, in excitatory neurons of the brain results in increased expression of Cadm1 in the brain. These data suggest a broad role for the miRNA pathway in regulating energy metabolism at both the cellular and systemic level via several tissues including the endocrine pancreas and the central nervous system.

Frank Reimann‘s team focuses on enteroendocrine cells (EECs) scattered throughout the gut epithelium. They respond to the arrival of nutrients in the intestine after a meal and Frank presented data on how this involves electrical activity and integration in glucagon-like peptide-1 (GLP-1) secreting cells. Novel findings included the apparent co-localisation and release of several hormones (GLP-1, peptide-YY and insulin-like peptide-5) from the same vesicles within EECs and the co-release of ATP activating nodose ganglion derived (“vagal afferent”) neurons in co-culture, thus expanding the communication repertoire of the gut-brain axis. Frank pointed the importance of GLP-1 in the altered glucose homeostasis after gastric bypass surgery – a unique group of patients with prophylactic gastrectomy for familial gastric cancer experienced reactive hypoglycemia after an oral glucose tolerance test due to strongly exaggerated GLP-1 and insulin responses, which could be prevented by infusion of the GLP1R antagonist exendin-9.

Randy Seeley emphasized that bariatric surgery remains the most effective treatment for both obesity and type 2 diabetes. While it is still widely viewed as a mechanical manipulation of the GI tract that acts via restriction of the stomach or malabsorption, physiological effects participate in the effects. The most recent works of Randy’s team has focused on HIF-related signaling in the duodenum. Vertical sleeve gastrectomy results in increased HIF2a signaling in the duodenum. Moreover, increasing HIF-signaling by gut-specific deletion of VHL mirrors the VSG-derived metabolic benefits. The promise of finding molecular underpinning for the effects of these surgeries is therapies that are effective as surgery in a less invasive and more scalable manner.

Maud Soty studied intestinal gluconeogenesis (IGN), a peripheral function that positively controls host metabolism via a portal glucose signal to hypothalamic areas involved in the control of energy homeostasis. Maud demonstrated that the beneficial effects of IGN on satiety and glucose control involve 1/ hypothalamic STAT3 phosphorylation independently of the presence of leptin, and 2/ the presence of calcitonin gene-related peptide. Secondly, she showed that the absence of IGN promotes the apparition of hepatic steatosis and inflammation, whereas its induction protects against the development of obesity and these complications. Finally, while IGN deficiency decreases browning in white adipose tissue, IGN induction favours this process and increases body temperature and energy expenditure.

Gilles Mithieux initiated a reflection about the general importance of IGN and portal glucose sensing in the general hypothalamic homeostatic function. Observing that mice with deficient IGN exhibit deficient sensitivity to leptin, while they are not obese, Gilles asked whether the absence of IGN might affect other key functions of the hypothalamus. Preliminary observations of Gilles’s team suggest defects in the reproductive function and in complex behaviors relating to serenity/anxiety in IGN-deficient mice. As a signal initiated upstream of hypothalamus, these data suggest that IGN might have an impact on a large number of functions regulated by the brain, not especially restricted to energy homeostasis.

Elena Porro closed the meeting evoking how the scientific scope of Cell evolves with science and how Cell is interested in publishing in emerging areas of biology. She emphasized that the journal has a very broad view of what a paper might look like, as discoveries are interesting and impactful for different reasons, and papers will not all have « seven figures » or report comprehensive mechanistic insight, for example. Cell considers publishing as a collaborative partnership and wants your experience working with Cell and Cell Press to be as positive as possible. Cell editors are excited to talk to you about your work, and will make every effort to be accessible to you at any time during the editorial process or if you have a question about whether your paper would be a good fit for Cell.