Obesity and the Brain: Implications for the Surgeon

| July 22, 2011 | 0 Comments

by Kimberley E. Steele, MD, FACS; Thomas H. Magnuson, MD, FACS; Anne O. Lidor MD, MPH, FACS; Dean F. Wong, MD; and Michael A. Schweitzer, MD, FACS

Drs. Steele, Magnuson, Lidor, and Schweitzer are all from the Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Dr. Wong is from the Department of Neuroradiology, The Johns Hopkins University School of Medicine.

Funding: The pilot study mentioned is this article was funded by a grant in 2006–2007 from the AWS and Ethicon Endosurgery Fellowship Award.

Financial Disclosure: The authors report no financial diclosures relevant to the content of this article.

Bariatric Times. 2011;8(7):12–13

Each year, the number of patients with morbid obesity in the United States increases alarmingly. When traditional weight loss methods fail, the only successful alternative is bariatric surgery. However, despite the indisputable effectiveness of bariatric surgery, there remain those who have less successful weight loss than others. This cannot be attributed entirely to the type of procedure itself but may in fact be more complicated and involve genetics and neurochemical factors. In this article, we review the work that has been done to date on the neurotransmitter dopamine and how it may relate to the bariatric surgical population.

The number of people with morbid obesity in the United States is increasing at an alarming rate. When traditional weight loss methods fail, the best alternative is usually bariatric surgery. But why do some bariatric patients have more successful weight loss than others? Despite the indisputable effectiveness of bariatric surgery in the aggregate, there remains significant inter-individual variability in the treatment response.[1] This difference cannot be attributed entirely to the type of procedure (i.e. restrictive vs. malabsorptive) that the patient undergoes. Something much more complicated, involving both genetics and environment and mediated through neurochemical factors, is at play.

It is well known that caloric intake is regulated by the brain, notably the hypothalamus. Our subconscious mind, as it were, informs us of when and how much to eat. For millennia, these brain mechanisms have prevented starvation and ensured the continuance of our species.

Unfortunately, what was adaptive in the relatively calorie-restricted environment of the past has become a liability in our current obesogenic environment, with its abundance of inexpensive, highly caloric, and generously portioned foods. In this environment, it is difficult at times for almost all of us to resist the urge to overeat. But for the individual with a genetic predisposition to obesity, this abundance of food can fuel an addiction that is potentially as harmful as cigarettes, alcohol, or cocaine.

Neurochemical Mechanisms in the Bariatric Patient
Research in neuroscience has revealed that a common mediator of many addictive behaviors is the neurotransmitter dopamine, which some have termed the pleasure molecule. Dopamine is the primary regulator of eating behavior[2] and is released in response to both appropriate and excessive eating.[3] Abnormal regulation of this molecule may explain why individuals with obesity tend to eat more carbohydrate and energy-dense foods than their nonobese counterparts. If an individual carries a genetically reduced sensitivity to dopamine, he or she may require excessive reward stimulation—in effect, a “fix”—just to feel normal. For certain individuals, this may take the form of overeating, resulting in obesity, while others may manifest a tendency toward compulsive gambling, shopping, or other behaviors. The relevance for the bariatric surgeon is that understanding of these neurochemical mechanisms may shed light on why some patients fail weight loss surgery. A diagnostic test, if it can be found, that would predict which patients were predisposed to fail would be an important tool for the bariatric surgeon, enabling customized pre-operative planning and postoperative care.

Recent efforts at understanding the brain mechanisms of reward behavior have made use of positron-emission computed tomography (PET). PET is a nuclear medicine imaging technique that can display dynamic neurochemical changes in the brain. As such, it is considered a “functional” imaging modality, offering information beyond what can be gathered by strictly anatomic imaging, such as a computed tomography (CT) scan. In the clinical setting, PET imaging is well known for its role in differentiating actively metabolizing metastatic disease from other tissues. But in research centers, PET imaging has also been instrumental in the elucidation of central dopaminergic pathways and their relation to reward-based behaviors.[4]

Obesity and Dopamine
In 2001, Dr. Gene-Jack Wang used PET imaging to demonstrate that patients with obesity had reduced dopamine receptor availability when compared to controls, and that there was an inverse linear relationship between dopamine receptor availability and body mass index (BMI); that is, the higher the BMI, the lower the dopaminergic activity.[5] Two hypotheses have been proposed to explain this relationship. The first is that individuals with obesity are born with a primary deficiency in dopamine receptors, with an associated under stimulation of dopaminergic reward circuits. This is thought to result in overeating as a compensatory mechanism. The second explanation is that dopaminergic receptor activity is initially normal, but becomes down-regulated as a result of chronic over stimulation of dopaminergic pathways in individuals with obesity, in a manner analogous to the insulin insensitivity seen in such patients.

Bariatric surgical patients present us with a uniquely valuable resource to determine which of these hypotheses is correct. If obesity is characterized by a primary dopamine receptor deficiency, one would expect that this deficiency would not improve substantially following gastric bypass surgery. On the other hand, if decreased receptor density is due to receptor down regulation, the marked weight loss produced by gastric bypass surgery could be expected to result in increased receptor availability, as food intake is decreased and the attendant chronic dopaminergic overstimulation is alleviated.

Research to Practice
Our group studied five female subjects ranging in age from 20 to 38 years old, all of whom underwent laparoscopic Roux-en Y gastric bypass (RYGB).[6] The mean BMI was 45kg/m2. These subjects underwent pre-operative brain magnetic resonance imaging (MRI), as well as PET imaging with the injection of [11C] raclopride, a radioligand for D2/D3 receptors. Five regions of interest were studied, including the ventral striatum, anterior putamen, posterior putamen, anterior caudate nucleus, and posterior caudate nucleus. Six weeks after undergoing standard RYGB, each subject was weighed. The average weight loss six weeks following surgery was 25.4lbs. The five patients then underwent postoperative PET imaging with [11C] raclopride. We found that dopamine D2 receptor availability, measured as [11C] raclopride binding, increased in female patients who lost weight following RYGB. These findings were consistent with Wang et al[5] in showing an inverse relationship between BMI and dopamine receptor availability. Since previous work had been limited to comparisons of obese subjects with matched controls, the question of whether decreased dopamine D2 receptor availability was a cause or effect of increased BMI remained unclear. Our data, though limited to only five subjects, did suggest that dopamine receptor binding potential increases in response to weight loss, implying that decreased receptor density is a consequence and not a cause of obesity, and thus, arguing against the concept that obesity is caused by a primary deficiency of dopamine receptors.
One year following our study, Dunn et al[7] published the only other study reporting dopamine receptor availability after RYGB. Five female subjects, age 41 to 52 years old with a mean BMI of 43kg/m2, were enrolled in the study. Four subjects underwent RYGB and one subject underwent laparoscopic sleeve gastrectomy (LSG). A very similar PET protocol was utilized, except that the radioligand [18 f] fallypride was used instead of [11C] raclopride. To our surprise, they obtained the opposite of our results: dopamine D2 receptor availability decreased following bariatric surgery. While both protocols were very similar, there were some differences that may have accounted for discrepant findings. The most likely contributing factor was a difference in age. The mean age in Dunn’s study was 14 years greater than ours. Age is known to affect the dopaminergic response. As middle age approaches, estrogen and progesterone levels decrease, and this is associated with less D2 receptor expression and function.[8]

Furthermore, both our study and Dunn’s study were limited by small sample size, so larger studies are needed.

Indeed, it may turn out that both of the hypotheses regarding dopamine could be correct. Some individuals might carry a genetic deficiency in dopamine receptors, while others might develop down regulation of receptors due to overstimulation. A further understanding of these neurochemical mechanisms may have important implications for both surgical and nonsurgical management of obesity, including the selection of patients for different surgical procedures and the prediction of long-term outcomes following bariatric surgery. Ultimately, we hope that PET imaging of the brain will one day serve as a useful guide in the management of the bariatric surgical patient.

1.    Melton-Meaux GB, Steele KE, Schweitzer MA, et al. Suboptimal weight loss after gastric bypass surgery: correlation of demographics, co-morbidities, and insurance status with outcomes. J Gastrointest Surg. 2008;12(2):250–255.
2.    Chau DT, Roth RM, Green AI. The neural circuitry of reward and its relevance to psychiatric disorders. Curr Psychiatry Rep. 2004;6:391–99.
3.    Comings DE, Blum K. Reward deficiency syndrome: genetic aspects of behavioral disorders. Prog Brain Res. 2000;126:325–341.
4.    Volkow ND, Fowler JS, Wang GJ, Telang BF. Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology. 2009;56 (Suppl 1):3–8. Epub 2008 Jun 3.
5.    Wang GJ, Volkow ND, Logan J, et al. Brain dopamine and obesity. Lancet. 2001;3:354–357.
6.    Steele KE, Prokopowicz GP, Schweitzer MA, et al. Alterartions of central dopamine receptors before and after gastric bypass surgery. Obes Surg. 2010;20:369–374.
7.    Dunn JP, Cowan RL, Volkow ND, et al. Decreased dopamine type 2 receptor availability after bariatric surgery: preliminary findings. Brain Research. 2010;123–130.
8.    Bazzett TJ, Becker JB. Sex differences in the rapid and acute effects of estrogen on striatal D2 dopamine receptor binding. Brain Res. 1994;637:163–172.

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