While the balance between calories in and calories out is closely monitored by our brains, our brains tend to ‘think fat’ – meaning that this regulation favors an accumulation of fat stores.  The extent to which our brains ‘think fat’ is very different from person to person – genetics may in fact underlie as much as 70% of human obesity.   So exactly how and why do our brains think fat?

The answer to this question is exquisitely complex, and we are only beginning to get an understanding of what is going on.  We know that there are many nerve cells throughout the brain that sense glucose and fatty acids, and some that can sense amino acids (the building blocks of proteins) as well.  While these nutrient signals may signal us to stop eating, the drive to start eating is much less clear.
Leptin and insulin, hormones that signal us to stop eating, decrease in the fasting state, and it is thought that the withdrawal of these two powerful hormones (as well as an increase in the hunger hormone ghrelin) are the main physiologic stimuli for hunger.
That being said, in human obesity, leptin and insulin levels are both high, yet people with obesity certainly still feel hungry – it appears that people with obesity become resistant to the effects of both leptin and insulin, which also means that these hormones lose their gusto to tell the person that they feel full. 
However, it is much, much more complex than that, as it is not only hunger that drives us to eat.  For example, why can we go all night without food and not be hungry, whereas during the day, we often become hungry just a few hours after the last meal?
There are many factors playing in here, including the circadian (day/night) rhythm of several hormones, as well as social cues to eat.
Although we have the ability to make conscious decisions and choices, many of our actions have a subconscious component that escapes voluntary control.  This is why we might eat a tasty treat like chocolate, even if we are not hungry, even if we recognize the negative consequences of the extra calories.
These subconscious urges are driven by a complex interplay of emotional, sensory, and cognitive information from several parts of the brain.  The rewarding properties of food, which stem from the dopamine system in our brain, are so powerful that they can easily override the neurons involved in sensing nutrients which rather weakly try to send the message that we are full while our dopamine system puts our brain into a state of nirvana.
The next question is, why is it so hard to keep weight off after a person with a weight struggle loses the weight? With short term calorie deficits (=weight loss), leptin and insulin levels fall precipitously, resulting in a powerful drive to eat and regain weight.  To make matters worse, low insulin and leptin levels also lead to a reduction in the body’s energy expenditure (calorie
burn).  This state persists for years in humans, and is only alleviated when the previous body weight is regained.  In other words, our bodies have a metabolic memory, such that our bodies spend potentially the rest of our lives trying to get back to the highest weight we have ever been. 
So why does it seem that our metabolism is set against us?
This is genetically powered and evolutionarily driven – our bodies were designed as super efficient systems to help us keep calories on board so that we would survive a famine.  Our brains
and bodies are so good at this, in fact, that there is much redundancy in this system – if one system promoting weight gain fails or is blocked (eg by an obesity medication), there are backup systems ready to take over and drive weight gain in other ways.  The learning point here is that a single obesity medication, for example, may not be successful in resulting in large amounts of sustained weight loss – multiple targets may need to be approached simultaneously.  This of course depends on the individual, their genetic background, and the myriad of other factors that are playing into their weight struggle.
It seems we have our work cut out for us to find successful ways to treat obesity.

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