Neuro-Imaging: PET in the Diagnosis of Obesity

  • Fig. 1.: [11C] DASB PET images, co-registered with the individual MRI images.Fig. 1.: [11C] DASB PET images, co-registered with the individual MRI images.
  • Fig. 1.: [11C] DASB PET images, co-registered with the individual MRI images.
  • Fig. 2.: Activated brown adipose tissue (BAT), as can be found with the aid of PET and radioactively labeled glucose ([18F]FDG) even with lean adults (A), here in comparison with a patient with a high body mass index (BMI) without BAT activation, B) as a possible new treatment target.

Overweight and obesity are increasing throughout the world. The main reasons for this are overeating and the availability of appetizing food which are high in calories, as well as psychological factors such as coping with stress and emotional eating.

The biological relationships between obesity and abnormal eating behavior are largely unknown. Imaging methods such as functional magnetic resonance tomography (fMRI) and positron emissiontomography (PET) with markers for the blood flow and glucose consumption enable recording of regional changes in the context of different eating behavior. These differences in eating behavior during the intake of food as well as the subsequent activation of certain areas of the dopaminerbrain (neuronal response) are based on a series of homeostatic and hedonistic mechanisms. Such mechanisms integrate (peripheral) signals (e.g. hormones such as the adipokines, ghrelin and insulin) for the maintenance of the energy balance and various aspects of motivation, reinforcement and reward. The neuronal response to eating factor is also dependent on several internal and external factors such as the social environment, stress, personality traits as well as genetic composition. These stimuli trigger cognitive control mechanisms, which in total are important for the intake of food and the fulfillment of endogenous requirements.

What Causes Appetite?
This is primarily controlled by the prefrontal cortex; however, functional imaging studies have found other areas of the brain which are responsible for certain functions associated with the intake and valuation of food [1]. For example the amygdala is a key region for an increased stimulus response and conditioning. Here, stress conditions cause a reduction in inhibitory control and an increase in anxiety and avoidance behavior [2,3]. The hypothalamus is one of the most important structures for the integration of peripheral signals and hunger. Other regions of the brain which are involved in the reward system of the brain, such as the nucleus accumbens and the ventral tegmental area are activated by eating.

With the development of highly selective radioactively labelled tracers for certain receptors of the brain it has become possible to quantify their availability with PET in vivo and to examine changes to these structures in the case of eating disorders and overweight/obesity.

The diffuse modulatory systems of the brain which utilize the neurotransmitters dopamine, serotonin, noradrenaline and acetylcholine are considered to be significant. With PET, the regional distribution of synaptic integrity, density of structures and binding potential can be investigated.

Previous Results

Up to now, the best analyzed system is the (mesolimbic) dopaminergic system, which plays an important role in the motivation for eating and for reward aspects [5] and which is regulated by the neuropeptides, ghrelin [6] as well as insulin [7]. Eating, in particular the consumption of food which is rich in sugar and fat act as a natural reward substance (which is necessary for survival) as well as conditioning stimulus, and thus lead to increased dopaminergic activity, not only during the availability of food, but also in its expectation and satiety [5]. Dopamine communicates an urge to eat. Disturbances to dopaminergic transmission are linked to corresponding changes in eating behavior. Both preclinical experiments as well as PET studies consistently demonstrate a reduced function of postsynaptic D2 receptors in the striatum and an associated reduced activity in the medial and ventral prefrontal regions, probably as amanifestation of a reduced topdown control [5]. As such changes of the D2 receptor status are not only found in the case of obesity and so-called „binge eating", but rather in various substance dependence disorders, it is currently being discussed whether obesity should be categorized as an addictive disorder. This has a direct effect on the evaluation of obesity as an illness. By means of PET it was recently demonstrated, that the adipokine leptin also influences the central dopaminergic transmission [8]. Changes on the presynaptic side, i.e. of the dopamine transporter, have not been seen up tonow [9], however they are probably only relevant in the case of manifest obesity [10].

The second monoaminergic transmitter, which has already been investigated on the basis of somewhat larger cohorts, is serotonin. The serotonergic system, a widely distributed network of neurons, has a wide range of very important autonomic functions such as the regulation of waking and sleeping, sexual behavior, as well as the regulation of appetite. Serotonin is associated with certain moods and emotional behavior. Here, particularly the serotonin transporter (SERT) is the target structure of modern antidepressants and of the combined SERT and noradrenaline reuptake inhibitorappetite supperssant sibutramine (Reductil) which has been off the market since 2010 due to cardiovascular side effects. For investigations of the SERT, carbon-11 labelled DASB, an established, highly selective radioactive tracer is available, which has already been used in the PET studies of many neuro-psychiatric disorders [11] with (Fig. 1). Our own initial investigations [11C] DASB and PET suggest that there is an increase in SERT availability with an increased body mass index (BMI) [12], which was also confirmed as a trend in an Europeanmulti-center study of healthy test candidates with an alternative monoaminergic marker for single photonemission computer tomography (SPECT) [13]. On the other hand, other PET investigations with [11C] DASB show an opposite trend towards lower values in the case of increased BMI [14]. However, all of these cohorts lacked persons with severe obesity, so that all of the results are preliminary. Studies, in which test candidates with a high BMI are compared with controls of normal weight, are at present being carried out in the Integrated Research and Treatment Center (IFB) Adiposity Diseases at the Medical University Leipzig [15].

Noradrenaline and Acetylcholine
Specific radioactive tracers are now available for the two other brain modulatory systems. The noradrenergic transporter as the presynaptic part of the noradrenergic system, which is important in the stress response can be investigated in vivo with the reboxetine derivate [11C]MRB [16]. For the acetylcholine receptors (AChR), in particular the α4β2-nAChR nicotine AChR (nAChR), whichis most widely present in the brain, radiolig ands such as 2-[18F]A85380 or [18F] Flubatine [17], which was developed in Leipzig are available. In addition, further neurotransmitters systems such as the opioid system or endocannabinoids (CB) are of great interest for the homeostatic regulation of food intake, as ultimately with the rimonabant (Acomplia) an appetite reducing medication was approved, whose target structureare the CB1 receptors in the brain. Due to the severe psychiatric side effects such as depression and suicidal moods, which in turn demonstrate the association of adipositas with psychological co-morbidities, the medication was however taken off the market in 2008. Both opiodergic as well as CB receptors can be imaged with PET and selective radiolig ands, whereby at present μ-opioid receptor is becoming the focus of attention as a pharmacological treatment target, not only for adipositas, but also for other eating disorders. Initial PET studies on μ-opioidreceptors with [11C] Carfentanil are showed changes in the fronto-striatal areas, the reward and limbic system for adipositas [18].

Neuroreceptor PET investigations can not only be used for monitoring new pharmacological treatments, but also prior to interventions such as leptin substitution therapy or bariatric surgery (e.g. for stomach bypass operations). With the aid of these methods it may be possible to identify patients who would especially benefit from the particular treatment. For this purpose, the combination of PET with structural fMRI - at nowadays even with simultaneous measurements with new hybrid devices such as are available e.g. in Leipzig, Germany - is beneficial.

In summary, neuro-imaging with PET or SPECT and radioactively labelled, highly selective tracers offers the possibility to further research the biological underpinnings of over-eating and obesity, to directly investigated quantitative neurochemical changes in vivo and to generate new hypotheses on origin of obesity and eating disorders. New technologies such as combined PETMRT devices also enable the study of neuronal activation and changes to neurotransmission under stimulation (e.g. when eating chocolate) and to derive new treatment options or develop new therapies. Here it is important to link the neuronal changes to neuro-psychological, endocrinological (stress, peripheral hormones) and genetic parameters, in order to disentangle the cause and result of obesity and to further characterize the phenotype. A future field of research will be to examine the interaction between hormone signal from the intestine, the microbiome, otheraxis signals, the the brown adipose tissue (BAT) (Fig. 2) and changes in the brain.

This work on neuro-imaging in obesity and the BAT was supported by the Bundesministerium für Bildung und Forschung (BMBF, Research ref. No.: 01EO1001) and the Deutsche Forschungsgemeinschaft (DFG-SPP 1629 „Thyroid Trans Act"). We are also grateful to Prof. Dr. Marianne Patt for her careful checking of the manuscript and her critical comments, as well as Karen Steinhoff for the provision of the image material of the BAT.

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[3] Roozendaal B. et al.: Nat. Rev. Neurosci. 10, 423-433 (2009)
[4] Horvath T. L.: Nat Neurosci. 8, 561-565 (2005)
[5] Volkow N. D. et al.: Trends Cogn. Sci. 15, 37-46 (2011)
[6] Skibicka K. P. et al.: Peptides 32, 2265-2273 (2011)
[7] Könner A. C. et al.: Cell Metab. 13, 720-728 (2011)
[8] Burghardt P. R. et al.: J. Neurosci. 32, 15369-15376 (2012)
[9] van de Giessen E. et al.: Neuroimage 64, 61-67 (2013)
[10] Narayanaswami V. et al.: Int. J. Obes. (Lond) (2012)

Further literature is available from the authors.





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