Invalidation of Microsomal Prostaglandin E Synthase-1 (mPGES-1) Reduces Diet-Induced Low-Grade Inflammation and Adiposity

Chronic low-grade inflammation is known to be linked to obesity, and to occur in the early stages of the disease. This mechanism is complex and involves numerous organs, cells, and cytokines. In this context, inflammation of white adipose tissue seems to play a key role in the development of obesity. Because of its properties, prostaglandin E2 (PGE2), an emblematic inflammatory mediator, has been proposed as an actor linking inflammation and obesity. Indeed, PGE2 is involved in mechanisms that are dysregulated in obesity such as lipolysis and adipogenesis. Microsomal prostaglandin E synthase-1 (mPGES-1) is an enzyme, which specifically catalyzes the final step of PGE2 biosynthesis. Interestingly, mPGES-1 invalidation dramatically alters the production of PGE2 during inflammation. In the present work, we sought to determine whether mPGES-1 could contribute to inflammation associated with obesity. To this end, we analyzed the energy metabolism of mPGES-1 deficient mice (mPGES-1-/-) and littermate controls, fed with a high-fat diet. Our data showed that mPGES-1-/- mice exhibited resistance to diet-induced obesity when compared to wild-type littermates. mPGES-1-/- mice fed with a high-fat diet, showed a lower body weight gain and a reduced adiposity, which were accompanied by a decrease in adipose tissues inflammation. We also observed an increase in energy expenditures in mPGES-1-/- mice fed with a high-fat diet without any changes in activity and browning process. Altogether, these data suggest that mPGES-1 inhibition may prevent diet-induced obesity

Effects of leptin on cat intestinal motility

In a previous study, we established that leptin controls food intake and immune responses by acting on intestinal vagal chemosensitive mechanoreceptors via a functional link with interleukin-1β (Il-1β). Since the control of intestinal motility is one of the main roles of the vagal afferent fibres, we investigated the effects of leptin on intestinal electromyographic (EMG) activity which reflects intestinal motility. For this purpose, the effects of locally injected leptin on small intestine spontaneous EMG activity were studied in 23 anaesthetised cats. The EMG activity was recorded using bipolar electrodes implanted in the proximal small intestine. Leptin and Il-1β (0.1, 1 and 10 μg), administered through the artery irrigating the upper part of the intestine 20 min after cholecystokinin (CCK, 10 μg, i.a.), had significant (P < 0.001) excitatory effects on intestinal EMG activity. The effects of both substances were blocked by the endogenous interleukin-1β receptor antagonist (Il-1ra, 250 μg, i.a.), by atropine (250 μg, i.a.) and by vagotomy. In the absence of CCK, leptin and Il-1β had no effect on intestinal electrical activity. It can therefore be concluded that: (1) leptin is effective only after the previous intervention of CCK, (2) the enhancement of the electrical activity induced by leptin involves Il-1β receptors and the cholinergic excitatory pathway, (3) the modes whereby the leptin-induced enhancement of EMG activity occurs strongly suggest that these effects are due to a long-loop reflex involving intestinal vagal afferent fibres and the parasympathetic nervous system

Glial Modulation of Energy Balance: The Dorsal Vagal Complex Is No Exception

International audienceThe avoidance of being overweight or obese is a daily challenge for a growing number of people. The growing proportion of people suffering from a nutritional imbalance in many parts of the world exemplifies this challenge and emphasizes the need for a better understanding of the mechanisms that regulate nutritional balance. Until recently, research on the central regulation of food intake primarily focused on neuronal signaling, with little attention paid to the role of glial cells. Over the last few decades, our understanding of glial cells has changed dramatically. These cells are increasingly regarded as important neuronal partners, contributing not just to cerebral homeostasis, but also to cerebral signaling. Our understanding of the central regulation of energy balance is part of this (r)evolution. Evidence is accumulating that glial cells play a dynamic role in the modulation of energy balance. In the present review, we summarize recent data indicating that the multifaceted glial compartment of the brainstem dorsal vagal complex (DVC) should be considered in research aimed at identifying feeding-related processes operating at this level

the food contaminant deoxynivalenol provokes metabolic impairments resulting in non-alcoholic fatty liver (NAFL) in mice

International audienceThe ribotoxin deoxynivalenol (DON) is a trichothecene found on cereals responsible for mycotoxicosis in both humans and farm animals. DON toxicity is characterized by reduced food intake, diminished nutritional efficiency and immunologic effects. The present study was designed to further characterize the alterations in energy metabolism induced by DON intoxication. We demonstrated that acute DON intoxication triggered liver steatosis associated with an altered expression of genes related to lipids oxidation, lipogenesis and lipolysis. This steatosis was concomitant to anorexia, hypoglycemia and a paradoxical transient insulin release. DON treatment resulted also in stimulation of central autonomic network regulating sympathetic outflow and adrenaline and glucocorticoids secretion. Furthermore, an increased expression of genes linked to inflammation and reticulum endoplasmic stress was observed in the liver of DON-treated mice. Finally, we propose that lipids mobilization from adipose tissues (AT) induced by DON intoxication drives hepatic steatosis since (1) genes encoding lipolytic enzymes were up-regulated in AT and (2) plasma concentration of triglycerides (TGs) and non-esterified fatty acids were increased during DON intoxication. Altogether, these data demonstrate that DON induced hormonal and metabolic dysregulations associated with a spectrum of hepatic abnormalities, evocative of a non-alcoholic fatty liver disease

Effects of leptin on cat intestinal vagal mechanoreceptors

Vagal afferent nerve fibres are involved in the transmission to the central nervous system of information relating to food intake and immune reactions. Leptin is involved in the control of food intake and has specific receptors in afferent vagal neurones. To investigate the role of these receptors, we studied the effects of leptin on single vagal afferent activities from intestinal mechanoreceptors in anaesthetized cats. The activity of 35 intestinal vagal mechanoreceptors was recorded by means of glass microelectrodes implanted in the nodose ganglion. Leptin (10 μg), administered into the artery irrigating the upper part of the intestine, induced activation in 17 units (P < 0.001), inhibition in 8 units (P < 0.05), and had no effect on 10 units. The excitatory effects of leptin were blocked by the endogenous interleukine-1β receptor antagonist, (Il-1ra, 250 μg, i.a.). Cholecystokinin (CCK, 10 μg, i.a.) induced an activatory response only in the two types of units which were responsive to leptin alone. When leptin was administered after CCK, its excitatory effects were enhanced and its inhibitory effects were blocked, whereas it had no effect on the units which were not affected by leptin alone. The interactions between leptin and CCK are specific ones, since other substances (phenylbiguanide, a serotoninergic agonist; substance P) known to activate the mechanoreceptors did not modify the effects of leptin. These results indicate that leptin appears to play a role in the control of immune responses and food intake via intestinal vagal afferent nerve fibres and that there is a functional link between leptin and Il-1β

Dysregulation of energy balance by trichothecene mycotoxins: mechanisms and prospects

International audienceTrichothecenes are toxic metabolites produced by fungi that constitute a worldwide hazard for agricultural production and both animal and human health. More than 40 countries have introduced regulations or guidelines for food and feed contamination levels of the most prevalent trichothecene, deoxynivalenol (DON), on the basis of its ability to cause growth suppression. With the development of analytical tools, evaluation of food contamination and exposure revealed that a significant proportion of the human population is chronically exposed to DON doses exceeding the provisional maximum tolerable daily dose. Accordingly, a better understanding of trichothecene impact on health is needed. Upon exposure to low or moderate doses, DON and other trichothecenes induce anorexia, vomiting and reduced weight gain. Several recent studies have addressed the mechanisms by which trichothecenes induce these symptoms and revealed a multifaceted action targeting gut, liver and brain and causing dysregulation in neuroendocrine signaling, immune responses, growth hormone axis, and central neurocircuitries involved in energy homeostasis. Newly identified trichothecene toxicosis biomarkers are just beginning to be exploited and already open up new questions on the potential harmful effects of chronic exposure to DON at apparently asymptomatic very low levels. This review summarizes our current understanding of the effects of DON and other trichothecenes on food intake and weight growth

Acute oral metformin enhances satiation and activates brainstem nesfatinergic neurons

International audienceObjective: The study was designed to determine metformin effects on meal pattern, gastric emptying, energy expenditure, and to identify metformin-sensitive neurons and their phenotype. Methods: This study was performed on C57BL/6J and obese/diabetic (db/db) mice. Metformin (300 mg/kg) was administered by oral gavage. Food intake, meal pattern, oxygen consumption (VO2), and carbon dioxide production (VCO2) were obtained using an Oxylet Physiocage System. Gastric emptying assay and real-time RT-PCR from dorsal vagal complex extracts were also performed. C-Fos expression was used as a marker of neuronal activation. Phenotypic characterization of activated neurons was performed using either proopiomelanocortin (POMC)-Tau-Topaz GFP transgenic mice or NUCB2/nesfatin-1 and tyrosine hydroxylase (TH) labeling. Results: Acute per os metformin treatment slowed down gastric emptying, reduced meal size, but not meal number in a leptin-independent manner, and transiently decreased energy expenditure in a leptin-dependent manner. Metformin specifically activated central circuitry within the brainstem, independently of vagal afferents. Finally, while POMC neurons seemed sparsely activated, we report that a high proportion of the c-Fos positive cells were nesfatinergic neurons, some of which coexpressing TH. Conclusions: Altogether, these results show that metformin modifies satiation by activating brainstem circuitry and suggest that NUCB2/nesfatin-1 could be involved in this metformin effec

Acute oral metformin enhances satiation and activates brainstem nesfatinergic neurons

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c-Fos immunoreactivity in the pig brain following deoxynivalenol intoxication: focus on NUCB2/nesfatin-1 expressing neurons

International audienceDeoxynivalenol (DON), produced by the cereal-contaminating Fusarium fungi, is a major trichothecene responsible for mycotoxicoses in farm animals, including swine. The main effect of DON-intoxication is food intake reduction and the consequent body weight loss. The present study aimed to identify brain structures activated during DON intoxication in pigs. To this goal, we used c-Fos staining which constitutes a useful approach to identify activated neurons. We showed that per os administration of Fusarium graminearum extracts (containing the equivalent of 1mg DON per kg of body weight) induced an increase in c-Fos immunoreactivity in several central structures, including the ventrolateral medulla (VLM), dorsal vagal complex (DVC), paraventricular nucleus of the hypothalamus (PVN), arcuate nucleus (Arc), supraoptic nucleus (SON) and amygdala (CeA). Moreover, we coupled c-Fos staining with phenotypic markers detection in order to specify the neuronal populations activated during DON intoxication. This phenotypic characterization revealed the activation of catecholaminergic but not of serotoninergic neurons in response to the toxin. In this context, we also paid a particular attention to NUCB2/nesfatin-1 positive cells, since nesfatin-1 is known to exert a satiety effect. We report here, for the first time in the pig brain, the presence of NUCB2/nesfatin-1 neurons in the VLM, DVC, PVN, Arc and SON, and their activation during DON intoxication. Taken together, these data show that DON stimulates the main structures involved in food intake in pigs and suggest that catecholaminergic and NUCB2/nesfatin-1 neurons could contribute in the anorexigenic effects of the mycotoxin

The food born mycotoxin deoxynivalenol induces low-grade inflammation in mice in the absence of observed-adverse effects

International audienceScope: Deoxynivalenol (DON) is the most common fungi toxin contaminating cereals and cereal-derived products. High consumption of DON is implicated in mycotoxicoses and causes a set of symptoms including diarrhea, vomiting, reduced weight gain or immunologic effects. However, such clinical intoxications are rare in humans, who are most frequently, exposed to low DON doses without developing acute symptoms. The adverse effect of chronically consumed low DON doses can not be totally excluded. Using a mouse model, we evaluated the impact on inflammatory status of subchronic administration of DON given at doses comparable to the daily human consumption. Methods and results: The inflammatory status was evaluated in mice receiving 1, 2.5 or 25 mg/kg bw/day DON during a 10 or 30 days period. The systemic interleukin-1 beta (IL-1b) concentrations were evaluated by Elisa and inflammatory biomarker mRNA expressions were quantified by qPCR within brain structures and peripheral organs. While DON intake failed to modify physiological markers, we observed a systemic IL-1b increase and a modulation of pro-inflammatory gene expression in brain structures, liver, duodenum and adipose tissue. Conclusion: We bring here the first evidence that subchronic DON intake, at doses that match daily human intake, induces, in a murine model, a central and peripheral low grade inflammatio