Blunted Brain Energy Consumption Relates to Insula Atrophy and Impaired Glucose Tolerance in Obesity

Abstract

Brain energy consumption induced by electrical stimulation increases systemic glucose tolerance in normalweight men. In obesity, fundamental reductions in brain energy levels, gray matter density, and cortical metabolism, as well as chronically impaired glucose tolerance, suggest that disturbed neuroenergetic regulation may be involved in the development of overweight and obesity. Here, we induced neuronal excitation by anodal transcranial direct current stimulation versus sham, examined cerebral energy consumption with 31 P magnetic resonance spectroscopy, and determined systemic glucose uptake by euglycemic-hyperinsulinemic glucose clamp in 15 normal-weight and 15 obese participants. We demonstrate blunted brain energy consumption and impaired systemic glucose uptake in obese compared with normal-weight volunteers, indicating neuroenergetic dysregulation in obese humans. Broadening our understanding of reduced multifocal gray matter volumes in obesity, our findings show that reduced appetite-and taste-processing area morphometry is associated with decreased brain energy levels. Specifically, gray matter volumes of the insula relate to brain energy content in obese participants. Overall, our results imply that a diminished cerebral energy supply may underlie the decline in brain areas assigned to food intake regulation and therefore the development of obesity.The incidence and prevalence of obesity have been escalating worldwide, and obesity has already reached epidemic proportions (1,2). This frightening development, in conjunction with the urgent need to replace more-or-less inefficient treatment strategies, has resulted in the development of new pathophysiological concepts of obesity. There is currently a growing consensus that this disease involves dysregulation within brain areas assigned to control food intake behavior and systemic energy homeostasis (3,4). Data show that complex neuronal pathways with reciprocal connections between the hypothalamus, brainstem, and higher cortical centers control appetite and food intake behavior (5), whereas afferent inputs from the periphery as well as efferent signals to peripheral organs regulate energy homeostasis (6). At large, appetite perception, food intake behavior, and energy homeostasis are synchronized in the hypothalamus as the cerebral "appetite center" (3,4). In this context, lower levels of high-energy phosphates (i.e., ATP and phosphocreatine [PCr]), have been detected in obese compared with normal-weight humans (7), which suggests a relationship between brain energy supply and body weight regulation. Supporting this view is the finding that cerebral ATP and PCr levels predict the amount of calories subsequently consumed (8). Moreover, brain energy consumption by electrical stimulation increases glucose tolerance in normal-weight men (9). On this basis, we aimed to test

Double transcranial direct current stimulation of the brain increases cerebral energy levels and systemic glucose tolerance in men

“…It is not possible to confirm whether the influence of tDCS is direct/indirect or excitatory/inhibitory in the present study. Nevertheless, the repeatedly observed increased high‐energy phosphates and glucose infusion rates upon tDCS following an identical stimulation protocol indicate neuronal excitatory rather than inhibitory effects.…”

“…On the days of experimental testing, participants were instructed to fast for at least 16 hours. Baseline blood samples of glucose, insulin, C‐peptide, adrenocorticotrophic hormone (ACTH) and cortisol were taken, followed by a standard hyperinsulinaemic‐euglycaemic glucose clamp procedure to investigate systemic glucose tolerance as described previously . After a euglycaemic plateau in the range 4.5‐5.5 mmol L −1 had been reached, baseline blood samples were taken and the first 31 P magnetic resonance spectra were recorded.…”

Blunted rise in brain glucose levels during hyperglycemia in adults with obesity and T2DM

“…Because only steady-state levels of glucose were measured, it is not possible to know if the differences resulted from decreased transport of glucose across the BBB or increased rates of glucose utilization. However, given the large body of evidence that obesity is associated with relative cerebral hypometabolism (18,19,28), increased cerebral glucose utilization among obese and T2DM individuals appears unlikely, thus suggesting decreases in transport activity are driving the observed changes.…”

Gray matter alterations and correlation of nutritional intake with the gray matter volume in prediabetes

“…Our finding in ACC differs from the results of previous studies in obesity, which mostly found a correlation of carbohydrate intake with changes in the insula. [40,41] A previous study of anorexia nervosa patients also revealed that GMV alterations in the ACC likely represent the pathophysiology underlying the dysregulation of food intake. [42] The decelerated loss of GMV has been found to be associated with intensive glycemic treatment in diabetes.…”