Brain responses to nutrients are severely impaired and not reversed by weight loss in humans with obesity: a randomized crossover study.

Post-ingestive nutrient signals to the brain regulate eating behaviour in rodents, and impaired responses to these signals have been associated with pathological feeding behaviour and obesity. To study this in humans, we performed a single-blinded, randomized, controlled, crossover study in 30 humans with a healthy body weight (females N = 12, males N = 18) and 30 humans with obesity (females N = 18, males N = 12). We assessed the effect of intragastric glucose, lipid and water (noncaloric isovolumetric control) infusions on the primary endpoints cerebral neuronal activity and striatal dopamine release, as well as on the secondary endpoints plasma hormones and glucose, hunger scores and caloric intake. To study whether impaired responses in participants with obesity would be partially reversible with diet-induced weight loss, imaging was repeated after 10% diet-induced weight loss. We show that intragastric glucose and lipid infusions induce orosensory-independent and preference-independent, nutrient-specific cerebral neuronal activity and striatal dopamine release in lean participants. In contrast, participants with obesity have severely impaired brain responses to post-ingestive nutrients. Importantly, the impaired neuronal responses are not restored after diet-induced weight loss. Impaired neuronal responses to nutritional signals may contribute to overeating and obesity, and ongoing resistance to post-ingestive nutrient signals after significant weight loss may in part explain the high rate of weight regain after successful weight loss.

Serotonin, food intake, and obesity.

The role of serotonin in food intake has been studied for decades. Food intake is mainly regulated by two brain circuitries: (i) the homeostatic circuitry, which matches energy intake to energy expenditure, and (ii) the hedonic circuitry, which is involved in rewarding and motivational aspects of energy consumption. In the homeostatic circuitry, serotonergic signaling contributes to the integration of metabolic signals that convey the body's energy status and facilitates the ability to suppress food intake when homeostatic needs have been met. In the hedonic circuitry, serotonergic signaling may reduce reward-related, motivational food consumption. In contrast, peripherally acting serotonin promotes energy absorption and storage. Disturbed serotonergic signaling is associated with obesity, emphasizing the importance to understand the role of serotonergic signaling in food intake. However, unraveling the serotonin-mediated regulation of food intake is complex, as the effects of serotonergic signaling in different brain regions depend on the regional expression of serotonin receptor subtypes and downstream effects via connections to other brain regions. We therefore provide an overview of the effects of serotonergic signaling in brain regions of the homeostatic and hedonic regulatory systems on food intake. Furthermore, we discuss the disturbances in serotonergic signaling in obesity and its potential therapeutic implications.

Striatal Dopamine Transporter Availability Is Not Associated with Food Craving in Lean and Obese Humans; a Molecular Imaging Study.

Brain dopamine signaling is essential for the motivation to eat, and obesity is associated with altered dopaminergic signaling and increased food craving. We used molecular neuroimaging to explore whether striatal dopamine transporter (DAT) availability is associated with craving as measured with the General Food Craving Questionnaire-Trait (G-FCQ-T). We here show that humans with obesity (n = 34) experienced significantly more craving for food compared with lean subjects (n = 32), but food craving did not correlate significantly with striatal DAT availability as assessed with 123I-FP-CIT single-photon emission computed tomography. We conclude that food craving is increased in obesity, but the scores for food craving are not related to changes in striatal DAT availability.

The response to prolonged fasting in hypothalamic serotonin transporter availability is blunted in obesity.

BACKGROUND AND AIMS: Serotonergic and dopaminergic systems in the brain are essential for homeostatic and reward-associated regulation of food intake and systemic energy metabolism. It is largely unknown how fasting influences these systems or if such effects are altered in humans with obesity. We therefore aimed to evaluate the effects of fasting on hypothalamic/thalamic serotonin transporter (SERT) and striatal dopamine transporter (DAT) availability in lean subjects and subjects with obesity. METHODS: In this randomized controlled cross-over trial, we assessed the effects of 12 vs 24 h of fasting on SERT and DAT availability in the hypothalamus/thalamus and striatum, respectively, using SPECT imaging in 10 lean men and 10 men with obesity. RESULTS: As compared with the 12-h fast, a 24-h fast increased hypothalamic SERT availability in lean men, but not in men with obesity. We observed high inter-individual variation in the effects of fasting on thalamic SERT and striatal DAT, with no differences between lean men and those with obesity. In all subjects, fasting-induced increases in circulating free fatty acid (FFA) concentrations were associated with an increase in hypothalamic SERT availability and a decrease in striatal DAT availability. Multiple regression analysis showed that changes in plasma insulin and FFAs together accounted for 44% of the observed variation in striatal DAT availability. CONCLUSION: Lean men respond to prolonged fasting by increasing hypothalamic SERT availability, whereas this response is absent in men with obesity. Inter-individual differences in the adaptations of the cerebral serotonergic and dopaminergic systems to fasting may, in part, be explained by changes in peripheral metabolic signals of fasting, including FFAs and insulin.

The pathogenesis of obesity.

Body fat mass increases when energy intake exceeds energy expenditure. In the long term, a positive energy balance will result in obesity. The worldwide prevalence of obesity has increased dramatically, posing a serious threat to human health. Therefore, insight in the pathogenesis of obesity is important to identify novel prevention and treatment strategies. This review describes the physiology of energy expenditure and energy intake in the context of body weight gain in humans. We focus on the components of energy expenditure and the regulation of energy intake. Finally, we describe rare monogenetic causes leading to an impairment in central regulation of food intake and obesity.

The role of central dopamine and serotonin in human obesity: lessons learned from molecular neuroimaging studies.

Obesity results from an imbalance between energy intake and expenditure, and many studies have aimed to determine why obese individuals continue to (over)consume food under conditions of caloric excess. The two major "neurotransmitter hypotheses" of obesity state that increased food intake is partially driven by decreased dopamine-mediated reward and decreased serotonin-mediated homeostatic feedback in response to food intake. Using molecular neuroimaging studies to visualize and quantify aspects of the central dopamine and serotonin systems in vivo, recent PET and SPECT studies have also implicated alterations in these systems in human obesity. The interpretation of these data, however, is more complex than it may appear. Here, we discuss important characteristics and limitations of current radiotracer methods and use this framework to comprehensively review the available human data on central dopamine and serotonin in obesity. On the basis of the available evidence, we conclude that obesity is associated with decreased central dopaminergic and serotonergic signaling and that future research, especially in long-term follow-up and interventional settings, is needed to advance our understanding of the neuronal pathophysiology of obesity in humans.

The Effect on Treatment Adherence of Administering Drugs as Fixed-Dose Combinations versus as Separate Pills: Systematic Review and Meta-Analysis.

Administering drugs as fixed-dose combinations (FDCs) versus the same active drugs administered as separate pills is assumed to enhance treatment adherence. We synthesized evidence from randomized controlled trials (RCTs) about the effect of FDCs versus separate pills on adherence. We searched PubMed for RCTs comparing a FDC with the same active drugs administered as separate pills, including a quantitative estimate of treatment adherence, without restriction to medical condition. The odds ratio (OR) of optimal adherence with FDCs versus separate pills was used as common effect size and aggregated into a pooled effect estimate using a random effect model with inverse variance weights. Out of 1258 articles screened, only six studies fulfilled inclusion criteria. Across medical conditions, administering drugs as FDC significantly increased the likelihood of optimal adherence (OR 1.33 (95% CI, 1.03-1.71)). Within subgroups of specific medical conditions, the favourable effect of FDCs on adherence was of borderline statistical significance for HIV infection only (OR 1.46 (95% CI, 1.00-2.13)). We observed a remarkable paucity of RCTs comparing the effect on adherence of administering drugs as FDC versus as separate pills. Administering drugs as FDC improved medication adherence. However, this conclusion is based on a limited number of RCTs only.