Corinne Leloup

1 Changes in brain activity associated with deleterious metabolic effects of non-caloric sweeteners (NCS) have been demonstrated in humans, particularly when their intake is concomitant with that of glucose. Here, we have focused on hypothalamic glucose sensing in rats, detecting increases in circulating glucose levels and in turn triggering various physiological controls. The identification of sweet-taste receptors in the hypothalamus has suggested that they participate in glucosensing mechanism, but the existence of a dialogue between different pathways has never been studied. Here, we tested the acute effects of hypothalamic glucosensing combined with a NCS (sucralose or acesulfame potassium (aceK)), the latter binding only to sweet-taste receptors, without producing energy. Our working hypothesis was that the concomitance of two contradictory signals (energetic, sweet glucose vs. non-energetic, sweet NCS) could be responsible for deleterious physiological effects. After validation that sweet taste receptors and their signaling expressions were indeed present in the rat hypothalamus, insulin secretion induced by hypothalamic glucosensing (increased glucose level) in the presence of sucralose and aceK was examined. Insulin release was reduced compared to glucose alone, while the two NCS alone have no effect. Regarding the satiety-inducing effect of glucose, concomitant injection of each NCS with glucose produced the opposite effect to that observed with glucose alone, with food intake being increased, an effect also present with NCS injected alone. Using the GT1-7 hypothalamic cell line expressing sweet-taste receptors, we showed that the ATP concentration which normally increases with rising glucose levels was dose-dependently decreased in the presence of NCS, an effect which is inhibited in the presence of gurmarin, a specific inhibitor of sweet-taste receptors. The increase in ROS production in response to rising glucose levels was enhanced in the presence of NCS, an effect that was blocked in the presence of gurmarin. In both cases, NCS have an inhibitory effect on stimulated mitochondrial respiration. Taken together, these results suggest that NCS via sweet-taste receptors interfere with mitochondrial signaling and/or energy production during hypothalamic glucose sensing.

Aims: Part of hypothalamic (mediobasal hypothalamus [MBH]) neurons detect changes in blood glucose levels that in turn coordinate the vagal control of insulin secretion. This control cascade requires the production of mitochondrial reactive oxygen species (mROS), which is altered in models of obesity and insulin resistance. Obese, insulin-resistant Zücker rats are characterized by hypothalamic hypersensitivity to glucose. This initiates an abnormal vagus-induced insulin secretion, associated with an overproduction of mROS in response to a low glucose dose. Here, we hypothesized that ghrelin, known to buffer reactive oxygen species (ROS) via mitochondrial function, may be a major component of the hypothalamic glucose hypersensitivity in the hypoghrelinemic obese Zücker rat. Results: Hypothalamic glucose hypersensitivity-induced insulin secretion of Zücker obese rats was reversed by ghrelin pretreatment. The overproduction of MBH mROS in response to a low glucose load no longer occurred in obese rats that had previously received the cerebral ghrelin infusion. This decrease in mROS production was accompanied by a normalization of oxidative phosphorylation (OXPHOS). Conversely, blocking the action of ghrelin with a growth hormone secretagogue receptor antagonist in a model of hyperghrelinemia (fasted rats) completely restored hypothalamic glucose sensing-induced insulin secretion that was almost absent in this physiological situation. Accordingly, ROS signaling and mitochondrial activity were increased by the ghrelin receptor antagonist. Innovation: These results demonstrate for the first time that ghrelin addressed only to the brain could have a protective effect on the defective control of insulin secretion in the insulin-resistant, hypoghrelinemic obese subject. Conclusions: Ghrelin, through its action on OXPHOS, modulates mROS signaling in response to cerebral hyperglycemia and the consequent vagal control of insulin secretion. In insulin-resistant obese states, brain hypoghrelinemia could be responsible for the nervous defect in insulin secretion.

Background: The need for early diagnosis biomarkers in Alzheimer’s disease (AD) is growing. Only few studies have reported gustatory dysfunctions in AD using subjective taste tests. Objective: The main purpose of the study was to explore gustatory functions using subjective taste tests and recordings of gustatory evoked potentials (GEPs) for sucrose solution in patients with minor or major cognitive impairment (CI) linked to AD, and to compare them with healthy controls. The secondary objective was to evaluate the relationships between GEPs and the results of cognitive assessments and fasting blood samples. Methods: A total of 45 subjects (15 healthy subjects, 15 minor CI patients, 15 major CI patients) were included to compare their gustatory functions and brain activity by recording GEPs in response to a sucrose stimulation. CI groups were combined in second analyses in order to keep a high power in the study. Correlations were made with cognitive scores and hormone levels (ghrelin, leptin, insulin, serotonin). Results: Increased P1 latencies and reduced N1 amplitudes were observed in minor or major patients compared to controls. GEPs were undetectable in 6 major and 4 minor CI patients. Thresholds for sucrose detection were significantly higher in the major CI group than in controls or the minor CI group. No correlation was found with hormone levels. Conclusions: The cortical processing of sensory taste information seems to be altered in patients with minor or major CI linked to AD. This disturbance was identifiable with subjective taste tests only later, at the major CI stage.

Obesity results from a temporary or prolonged positive energy balance due to an alteration in the homeostatic feedback of energy balance. Food, with its discriminative and hedonic qualities, is a key element of reward-based energy intake. An alteration in the brain reward system for highly palatable energy-rich foods, comprised of fat and carbohydrates, could be one of the main factors involved in the development of obesity by increasing the attractiveness and consumption of fat-rich foods. This would induce, in turn, a decrease in the taste of fat. A better understanding of the altered reward system in obesity may open the door to a new era for the diagnosis, management and treatment of this disease.

Although diet interventions are mostly related to metabolic disorders, nowadays they are used in a wide variety of pathologies. From diabetes and obesity to cardiovascular diseases, to cancer or neurological disorders and stroke, nutritional recommendations are applied to almost all diseases. Among such disorders, metabolic disturbances and brain function and/or diseases have recently been shown to be linked. Indeed, numerous neurological functions are often associated with perturbations of whole-body energy homeostasis. In this regard, specific diets are used in various neurological conditions, such as epilepsy, stroke, or seizure recovery. In addition, Alzheimer’s disease and Autism Spectrum Disorders are also considered to be putatively improved by diet interventions. Glycemic index diets are a novel developed indicator expected to anticipate the changes in blood glucose induced by specific foods and how they can affect various physiological functions. Several results have provided indications of the efficiency of low-glycemic index diets in weight management and insulin sensitivity, but also cognitive function, epilepsy treatment, stroke, and neurodegenerative diseases. Overall, studies involving the glycemic index can provide new insights into the relationship between energy homeostasis regulation and brain function or related disorders. Therefore, in this review, we will summarize the main evidence on glycemic index involvement in brain mechanisms of energy homeostasis regulation.

Although diet interventions are mostly related to metabolic disorders, nowadays they are used in wide variety of pathologies. From diabetes and obesity to cardiovascular diseases, through cancer or neurological disorders and stroke, nutritional recommendations applied to almost all diseases. Among those disorders, metabolic disturbances and brain function and/or diseases have recently been shown to be linked. Indeed, numerous neurological functions are often associated with perturbations of whole-body energy homeostasis. In this regard, specific diets are used in various neurological conditions such as epilepsy, stroke, or seizure recovery. In addition, Alzheimer’s disease or Autism Spectrum Disorders are also considered as putatively improved by diet intervention. Glycemic index diets are a novel developed indicator expected to anticipate the changes in blood glucose induced by specific foods, and how they can affect various physiological function. Several results provide indications of efficiency of low glycemic index diets in weight management, insulin sensitivity, but also cognitive function, epilepsy treatment, stroke, or neurodegenerative diseases. Overall, studies involving glycemic index could provide new insight in the relationship between energy homeostasis regulation and brain function or related disorders. Therefore, in this review we will summarize main evidences on glycemic index involvement in brain mechanisms of energy homeostasis regulation.

Small intestinal bacterial overgrowth (SIBO) is a common complication of bariatric surgery. Digestive decontamination treatments with oral antibiotic therapy vary and are not codified. This retrospective study was conducted to analyse the characteristics of bariatric surgery patients who underwent a glucose breath test (GBT) and to analyse the effectiveness of the antibiotic decontamination therapy.

Aspartame and Stevia are widely substituted for sugar. Little is known about cerebral activation in response to low-caloric sweeteners in comparison with high-caloric sugar, whereas these molecules lead to different metabolic effects. We aimed to compare gustatory evoked potentials (GEPs) obtained in response to sucrose solution in young, healthy subjects, with GEPs obtained in response to aspartame and Stevia. Twenty healthy volunteers were randomly stimulated with three solutions of similar intensities of sweetness: Sucrose 10 g/100 mL of water, aspartame 0.05 g/100 mL, and Stevia 0.03 g/100 mL. GEPs were recorded with EEG (Electroencephalogram) electrodes. Hedonic values of each solution were evaluated using the visual analog scale (VAS). The main result was that P1 latencies of GEPs were significantly shorter when subjects were stimulated by the sucrose solution than when they were stimulated by either the aspartame or the Stevia one. P1 latencies were also significantly shorter when subjects were stimulated by the aspartame solution than the Stevia one. No significant correlation was noted between GEP parameters and hedonic values marked by VAS. Although sucrose, aspartame, and Stevia lead to the same taste perception, cerebral activation by these three sweet solutions are different according to GEPs recording. Besides differences of taste receptors and cerebral areas activated by these substances, neural plasticity, and change in synaptic connections related to sweet innate preference and sweet conditioning, could be the best hypothesis to explain the differences in cerebral gustatory processing after sucrose and sweeteners activation.