Obesity is a huge epidemic throughout the world and scientists are tirelessly looking for ways to combat it. Food addiction is as real as drug addiction and has been shown to work largely through the dopamine reward pathway. It has been found that obese people have a decreased amount of dopamine transduction. The hypothalamus is the integration center and receives all the sensory and peripheral signals. It is the job of the hypothalamus to check for the energy status of the body and signal the CNS to engage in feeding behaviour. Lee A. K. et al., (2010) found that 5 genes involved in the transcription of dopamine (DA) were upregulated in the hypothalamus in obese mice. This suggests that obese people are conditioned to eat more, as their hypothalamus is hyperactive. In addition, John & Kenny (2010) found that the striatal dopamine D2 receptors are downregulated in obese rats. This in conjunction with the increased amount of dopamine in the hypothalamus leads to a feed forward cycle. A normal diet does not satisfy the pleasure threshold for an obese person as their reward circuitry is desensitized and requires highly palatable and fatty food on a regular basis to overcome or reach the threshold. The alterations in the dopamine system in both the reward center and the hypothalamus were as a result of epigenetic changes due to high calorie intake. Combating obesity is especially difficult as the feeding behaviour is mediated by multiple peripheral and central mechanisms. There is no single way to combat obesity and has to be tackled at multiple levels.
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Introduction to diet induced obesity
Diet induced obesity is a result of overeating of highly fatty foods. Regular indulgence in fatty foods results in the desensitization of the reward circuitry. Just as in drug-addiction this hypofunctioning reward circuitry leads the individual to seek even more palatable food. This forms a vicious cycle leading to obesity.
Function of hypothalamus
The hypothalamus monitors the level of nutrients in our blood and the amount of calories we are burning. As the energy levels decrease, the hypothalamus is activated and we feel hungry. An array of different endocrine hormones such as the neuropeptide Y, orexin, melanocortin, insulin, peptide YY, glucagon-like peptide-1 and cholecystokinin are involved in the signaling of nutritional and caloric requirements. Petrovich et al. (2005) gave the first evidence that the amygdala and the prefrontal cortex are involved in the motivational control of appetite as these regions project to the lateral hypothalamus and are activated when a food item is presented; superior activation was seen for palatable foods. In addition, Passamonti et al. 2009 showed that the ventral striatum, amygdala, medial prefrontal, and premotor cortices that are involved in the feeding behaviour have reduced activity in obese humans. The reduced activity between these different regions makes it harder for obese individuals to control their impulses when encountering appetizing food.
Upregulation of dopamine in the hypothalamus
Humans do not indulge in consumption of food merely for survival. It is rather a very rewarding experience and as such involves the dopamine reward pathway. The reward pathway has dopamine neurons that project from the ventral tegmental area (VTA) to the nucleus accumbens. Increased dopamine release from the VTA is seen when indulging in a pleasurable activity i.e. having sex or eating food. In a recent study A. K. Lee et al (2010) showed through the use of microarrays that there is an upregulation of 5 genes in the hypothalamus involved in the availability of dopamine in mice models that were on a high-fat diet. Excess dopamine makes a person more impulsive. It is important to note that the increased impulsivity and the hyperactivity in the hypothalamus make these mice vulnerable to diet induced obesity.
Function of the Ventral Tegmental Area (VTA)
The VTA is a group of neurons in the center of the brain, very close to the midbrain. It receives information from many parts of the brain and is crucial in reward related behaviour. The caveat to this is that the VTA does not receive direct information from any of the external stimuli. Neurons that project to the VTA are widespread but are organized in an elongated formation and run through the core of the brain. This makes it easy for the multiple areas of the brain to access the VTA in a fast and efficient manner. The job of the VTA is to fire dopamine in accordance to how highly it is activated. It cannot identify the type of reward.
Downregulation of the D2 receptors
Dopamine blockers increase the overall energy intake and result in weight gain whereas dopamine agonist result in a decreased amount of energy intake and weight loss. The speculation that a hypofunctioning reward circuitry leads to overeating seen in obese individuals comes from studies that showed that obese rats have a lower level of dopamine and D2 receptor expression compared to lean rats. Using functional magnetic resonance imaging studies Stice, Spoor, Bohon & Small (2008) showed that obese individuals have a lower activation of the reward circuitry when eating highly palatable foods compared to lean individuals. Obese individuals predominantly have the A1 allele of Taq1A that leads to a lesser number of D2 receptors and this results in reduced dopaminergic signaling. Johnson and Kenny (2010) used lentivirus to knockdown striatal D2 receptors to show accelerated compulsive food seeking behaviour.
Epigenetic changes in the dopamine system
The VTA and D2 receptor along with the hypothalamus demonstrate the importance of the dopamine system in obesity. In order to tackle the growing obesity epidemic, understanding the core of the problem is very important. It is often seen that even though obese people want to cut down on their food intake, they simply cannot stop. Z. Vucetic et al. (2012) showed that 2 genes that are expressed in both the hypothalamus and the VTA go through differential methylation as a result of a high fat diet. It was observed that tyrosine hydroxylase (rate limiting enzyme in dopamine synthesis) and dopamine transporter (critical in removing dopamine from the synapse) mRNA’s were significantly increased in the hypothalamus. The opposite was seen for the VTA where the mRNA’s for both these genes were downregulated. This study paves the way forward to link high fat diets and dopamine expression – the mechanism at play. In order combat obesity it was crucial to understand the mechanism behind the changes for a proper intervention. This study also shows the dangerous feed forward cycle at play, as to why obese people on high fat diets keep getting worse. In order to satisfy their hypofunctioning reward circuitry, individuals indulge in highly palatable foods that desensitize the circuit even further.
Consequences of early exposure to fatty foods.
Exposure to a high fat diet early on in life can have significant and long-lasting effects throughout adulthood. In the developed world and most of the developing countries, children are exposed to fatty diets at a very early age due to a culture and prevalence of junk foods. This has directly led to the increase in body mass in adults as they develop a subconscious preference for highly palatable foods. The preference is developed due to the reprogramming of the reward system; reduction in dopamine signalling.
What can be done to fight obesity?
Obesity is caused due to multiple factors and commonly runs in families. Depending on the genetic predisposition and the environment one is exposed to, the risk of obesity can be determined. To fight obesity, scientists are working on new innovative therapies targeting specific areas that are the root cause of obesity. Significant progress has been made in this regard and multiple potential targets have been identified.
- In mice the loss of Akt1 gene protects them from diet-induced obesity, a potential therapy could be to block the production of the mRNA’s from this gene.
- Differential DNA methylation has also been identified in the VTA and hypothalamus that leads to a feed forward cycle due to reduced transduction of the dopamine signaling and increased extracellular dopamine in the hypothalamus. These could be targeted using gene therapy or through drugs.
- Pomc gene mutation leads to obesity at an early age. This gene is dominantly transcribed in the arcuate nucleus of the hypothalamus and the anterior pituitary. The researchers found that restoration of the gene expression lead to prevention of obesity. The efficiency of the gene in preventing obesity was inversely proportional to the age of the mice. It was hypothesized that this was a result of the metabolic changes and increased fat in the mice over time. The study showed the critical importance of dealing with obesity at an early age.
Currently most drugs in the market for obesity target one biological mechanism. Initially these drugs result in weight loss but do not hold up in the long run, due to counter regulation as multiple mechanisms are at play. To successfully target obesity in the long run, the therapies need to target multiple mechanisms ‘polytherapies’. Polytherapy involves a group of targets; it is particularly advantageous as the agents work on more than one mechanism at a time resulting in increased weight loss and a reduced risk of counter regulation. As there is more than one agent, a typical dose is comparatively less than the one used in monotherapy this could potentially lead to reduced side effects.
Fighting obesity requires a complete overhaul of the type of lifestyle one leads. One of the most important things is the determination to loose weight; this helps in the control of the type of food one indulges in. Eating right and exercising regularly are the corner stone of weight loss. These 2 simple steps alone should result in up to 10% loss of weight and prevent health complications that come about as a result of obesity such as hypertension and type 2 diabetes. In cases where lifestyle modifications alone are not enough pharmacological interventions would greatly help as these could target the biological mechanisms directly. In the future with genomic advances, genetic deficiencies could directly be targeted although it is currently possible to do so; the development of safer and precise vectors is warranted.