Brain, nutrition and metabolism: Studies in lean, obese and insulin resistant humans

This thesis describes studies on the effects of obesity, weight loss and meal timing on the human brain and glucose metabolism. We investigated effects of meal timing during a hypocaloric diet and weight loss on brain serotonin transporters (SERT) and dopamine transporters (DAT), neuronal activity patterns and metabolism. In addition, we studied the effect of bright light conditions on glucose and lipid metabolism in lean and obese subjects with type 2 diabetes (T2D). First, we show a trend towards lower hypothalamic SERT binding in obese compared to lean controls and a reduced SERT binding in the diencephalon in obese insulin resistant compared to equally obese insulin sensitive and lean subjects. Second, we show that subjects who consumed most of the calories in the morning during a hypocaloric diet, increased striatal DAT binding and reduced neuronal activation in response to high calorie food pictures in the caudate nucleus, while consuming most of the calories in the evening reduced striatal DAT binding and increased neuronal activation in response to high calorie food pictures in the caudate nucleus. Metabolism and intrahepatic triglyceride content improved after weight loss but without a differential effect of meal timing. Finally, we found that acute exposure to bright light affects glucose metabolism in obese subjects with T2D and lipid metabolism in both, patients with T2D and healthy controls. Taken together, this thesis provides data supporting a clinically relevant interaction between meal timing, body weight loss and the brain, and between light exposure and metabolism

Serotonin Transporter Binding in the Diencephalon Is Reduced in Insulin-Resistant Obese Humans

Background: Altered brain dopaminergic and serotonergic pathways have been shown in obese rodents and humans, but it is unknown whether this is related to obesity per se or to the metabolic derangements associated with obesity. Methods: We performed a case-control study in insulin-sensitive obese (ISO) and insulinresistant obese (IRO) subjects (n = 12) and agematched lean controls (n = 8) and measured serotonin transporter (SERT) binding in the whole diencephalon and specifically in the hypothalamus, as well as dopamine transporter (DAT) binding in the striatum using 123 IFP-CIT single-photon emission computed tomography. We assessed insulin sensitivity using the homeostatic model assessment of insulin resistance. Results: BMI did not differ between the IRO and ISO subjects. SERT binding in the diencephalon was significantly lower in IRO than in ISO subjects, but was not different between lean and obese subjects. SERT binding in the hypothalamus tended to be reduced in obese versus lean subjects, but was not different between IRO and ISO subjects. Striatal DAT binding was similar between lean and obese subjects as well as between ISO and IRO subjects. Conclusions: We conclude that SERT binding in the diencephalon is reduced in insulin-resistant subjects independently of body weight, while hypothalamic SERT binding tends to be lower in obesity, with no difference between insulin-resistant and insulin-sensitive subjects. This suggests that the metabolic perturbations associated with obesity independently affect SERT binding within the diencephalon. (C) 2016 The Author(s) Published by S. Karger AG, Base

Timing of caloric intake during weight loss differentially affects striatal dopamine transporter and thalamic serotonin transporter binding

Recent studies have shown that meal timing throughout the day contributes to maintaining or regaining weight after hypocaloric diets. Although brain serotonin and dopamine are well known to be involved in regulating feeding, it is unknown whether meal timing during energy restriction affects these neurotransmitter systems. We studied the effect of a 4 wk hypocaloric diet with either 50% of daily calories consumed at breakfast (BF group) or at dinner (D group) on hypothalamic and thalamic serotonin transporter (SERT) binding and on striatal dopamine transporter (DAT) binding. The BF and D groups lost a similar amount of weight. Striatal DAT and thalamic SERT binding increased in the BF group, while decreasing in the D group after the diet (Delta DAT 0.37 +/- 0.63 vs. -0.53 +/- 0.77, respectively; P = 0.005; Delta SERT 0.12 +/- 0.25 vs. -0.13 +/- 0.26 respectively, P = 0.032). Additional voxel-based analysis showed an increase in DAT binding in the ventral striatum in the BF group and a decrease in the dorsal striatum in the D group. During weight loss, striatal DAT and thalamic SERT binding increased weight independently when 50% of daily calories were consumed at breakfast, whereas it decreased when caloric intake was highest at dinner. These findings may contribute to the earlier reported favorable effect of meal timing on weight maintenance after hypocaloric diets.-Versteeg, R. I., Schrantee, A., Adriaanse, S. M., Unmehopa, U. A., Booij, J., Reneman, L., Fliers, E., la Fleur, S. E., Serlie, M. J. Timing of caloric intake during weight loss differentially affects striatal dopamine transporter and thalamic serotonin transporter bindin

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

Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans

Hepatic lipid accumulation has been implicated in the development of insulin resistance, but translational evidence in humans is limited. We investigated the relationship between liver fat and tissue-specific insulin sensitivity in 133 obese subjects. Although the presence of hepatic steatosis in obese subjects was associated with hepatic, adipose tissue, and peripheral insulin resistance, we found that intrahepatic triglycerides were not strictly sufficient or essential for hepatic insulin resistance. Thus, to examine the molecular mechanisms that link hepatic steatosis to hepatic insulin resistance, we comprehensively analyzed liver biopsies from a subset of 29 subjects. Here, hepatic cytosolic diacylglycerol content, but not hepatic ceramide content, was increased in subjects with hepatic insulin resistance. Moreover, cytosolic diacylglycerols were strongly associated with hepatic PKCε activation, as reflected by PKCε translocation to the plasma membrane. These results demonstrate the relevance of hepatic diacylglycerol-induced PKCε activation in the pathogenesis of NAFLD-associated hepatic insulin resistance in human