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

Abstract

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.

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

“…In line with previous studies [ 32 , 33 , 42 , 43 , 44 ], we did not find any difference in striatal DAT availability between lean subjects and subjects with obesity. However, changes in striatal dopamine D 2/3 receptor availability are particularly pronounced in humans with a BMI > 40 kg/m 2 [ 24 ].…”

“…Data from the present study confirm that subjects with obesity have an increased overall food craving compared to lean subjects, which is caused by an increased loss of control and emotional craving. Next, our data confirm the lack of difference in striatal DAT availability between humans with normal weight and obesity as previously reported [ 32 , 33 , 42 , 43 , 44 ]. We hypothesized that an increase in food craving would be related to a difference in DAT availability.…”

“…As we included only 4 subjects with a BMI > 40 kg/m 2 , we cannot exclude BMI-associated changes in striatal DAT availability occurring with a further progression of obesity to a BMI > 40 kg/m 2 . Moreover, all included subjects were imaged after an overnight fast and we have recently shown that fasting-induced changes in striatal DAT availability may, in part, be explained by peripheral metabolic signals of fasting [ 32 ]. However, this dopaminergic response to fasting did not differ between lean subjects and subjects with obesity and has therefore unlikely confounded our findings [ 32 ].…”

“…Moreover, all included subjects were imaged after an overnight fast and we have recently shown that fasting-induced changes in striatal DAT availability may, in part, be explained by peripheral metabolic signals of fasting [ 32 ]. However, this dopaminergic response to fasting did not differ between lean subjects and subjects with obesity and has therefore unlikely confounded our findings [ 32 ]. In addition, we have earlier reported striatal DAT availability to change in a weight loss-independent, but meal timing-dependent manner in men with obesity following a diet-intervention [ 34 ].…”

“…Subjects participated in molecular neuroimaging studies conducted at the Amsterdam University Medical Centers (Amsterdam UMC, Amsterdam, The Netherlands) between February 2011 and October 2017 [ 31 , 32 , 33 , 34 ]. Subjects were recruited from the general population through local advertisements.…”