Pillar 1 - FTO (new thread), page-37

This is a great discussion starter, Titans19.

"does certain FTO variants cause the obesity, or does it cause the hunger creating the obesity?"

From my understanding, the variants of FTO influences key stages in the development of fat. As previously stated, influencing the levels of Ghrelin (which influences hunger levels and ultimately behaviour) and steps of adipogenesis (accumulation of new or larger fat cells). I would like to take a step back and use a currently marketed obesity drug to explain why I think inhibiting FTO is causal in reducing or managing weight gain and/or triggering weight loss. Orlistat works by inhibiting gastric and pancreatic lipases (which are enzymes that break down ingested fat), leading to less uptake of fat from the diet and overall decreasing the intake of fat. An FTO inhibitor could work in quite the same way, as you have the inhibition of FTO, leading to a reduction of Ghrelin (to normal levels), and then the action which is behavioural of reducing food intake and thus calories. It is very clear that energy balance is the key fundamental aspect to consider with weight management, however, when you step back and look at the multifactorial nature of why people put on weight, it is astounding. Below is a figure that demonstrates the interconnected facets of our reality that contribute to weight maintenance (I couldn't find the one that I wanted, needless to say this is basic in comparison to the figure I wanted).



Thus, while your point is quite valid and certainly encouraged, I think that if we are to look at the relationship between a mechanistic pathway and obesity, we first need to see it in context. Orlistat is able to take advantage of a mechanistic pathway within the body and is able to produce millions (and possibly even billions) of dollars of sales each year because the fundamental aspect remains that it works by inhibiting proteins - similar to what Bisantrene is doing.

does the FTO variant increase the chances of cancer, or increase the likelihood of obesity that then increases likelihood of cancer?

This is a great question. And again, I feel like you are simplifying an extremely diverse field of interconnected factors. However, for the sake of simplicity, we shall look specifically at excess fat mass (obesity) and its relationship with cancer outcomes. Cancer development occurs when the DNA becomes damaged, which is then replicated over and over. The DNA damage that may occur has been linked quite consistantly with increased inflammation. What does inflammation and obesity have in common? Quite a lot. Under normal circumstances, the adipose tissue will produce a normal profile of cytokines (anti- and pro-inflammatory markers). However, for obese individuals, with high amounts of adipose tissue and, more importantly, ectopic fat (fat that biologically isn't functioning properly), they produce a very different cytokine profile - very pro-inflammatory. This inflammation has been linked with cancer development for years and inflammation is seen as one of the fundamental catalysts for cell damage. To combat this, the body has anti-inflammatory markers, however, when pro-inflammatory markers are too great, this means that damage can occur more regularly. There are other things that influence cell damage like reactive oxygen species, but I won't go into them here. Thus, I see an extension of your question - is the FTO molecule overexpressed before or after obesity-like fat accumulation has occured and what influence does the FTO protein have on cancer development? I think the relationship between FTO and cancer is quite solid, and I also think that the FTO protein increases the likelihood of obesity and thus cancer. It's like adding fuel to the fire in my opinion.

Also interesting looking into the impact fasting can have on cancer treatments.

Ah, yes. From the reading that I have done, which was up until mid 2020, I did not recall any solid evidence of fasting on overall cancer survival. Essentially cancer patients are starving the cancer cells of carbohydrates (energy), and thus slowing the rate of cancer growth. However, cancer therapies are known for their impact on the body, so I was under the impression fasting was not advised, as it would put your body weight and immune system into a potentially compromised state. I've not read much into what you are saying regarding the FTO protein, so I can take a look at that.