Even in countries where obesity used to be so rare: South Africa, South America, East Asia
When talking about obesity, we’re talking about body fat stores, and not all fat is created equal. Hypothesis why visceral fat has detrimental effects
By partitioning, I mean the storage of nutrients into muscle mass (lean mass) and fat stores
Limited stores as glycogen The presence of mixed diet of CHO and lipids drives RQ almost up to 1, indicating that CHO are being exclusively used for tissue oxidation And so eating excess CHO increases body fat stores because it decreases their utilization, and not because it gets converted into lipids. Figure: note that the liver is insulin resistant, and so it continues to increase glucose synthesis as long as CHO intake is high, regardless of the elevations in insulin levels.
If we’re not using our nutrients to make muscle, then we’re storing them in fat…
Now that we’ve looked at intake/nutrients, let’s see what we know about energy expenditure. If we keep up with increased intake, do we gain weight indefinitely? Including exercise level and all other intake The accumulation of fat and increase in body weight seems to increase the energy needs of all body tissues, and not just add to the previous energy needs. The pertinent corrolate to that is weight loss: once a a certain amount of weight loss is achieved, one has to decrease their intake even further just to maintain the new weight, and this is the challenge of all current therapies/diets.
Both diets may have noticeable effects for the first few months, but effects are usually not sustained beyond one year, for the reasons discussed above Exercise may not have a significant effect on weight reduction, but it does prevent significant decline of fat free mass, and it does help maintain weight loss after dietary intervention is over.
Orlistat: inhibits pancreatic lipase, therefore decreasing hydrolysis of ingested fat, side effects are very annoying, but safe
Fluoxetine: very minimal results Bupropion: approved for prevention of wt gain in pts stopping smoking Safety concerns especially with herbs that are sympathomimetic. Physicians should discourage pts from using dietary supplements. TRANSITION
So we see that all the current Rx options are at best modest, and the limiting factor to all is the long term effect. We have seen that despite continued caloric reduction, weight reduction also stabilizes at a certain point. So behavioral changes, diet and exercises cannot be the only determinants of obesity. So what else is playing a part? What has been elucidated since the mid90’s about the ECS, its relation to the neural pathways of food control, and its relation to energy metabolism, insulin the liver and a lot more. Things we did not learn in medical school!
These are all single gene disorders that have been clearly linked to clinical obesity. And this is only a part of the genes that have been identified to play a role in metabolism, suggesting how complex the control of weight is… We will discuss leptin and Melanocortin in more detail later.
What is not seen in the slide: Interaction of the ECS which we will talk about in detail, at each level of this pathway.
The meal ends We will see later that in abnormal conditions, the ECS will kick in, involving the hypothalamus, and prolonging the meal even after satiety signals start
Catabolic pathways: i.e decrease food intake AND increase energy expenditure
Although the idea of an obesity “factor” was there since 1973 when hyperphagic/obese mice’s circulation was linked to normal mice which developed obesity, the discovery was not made until 1994 Even in newborns
Leptin is highly correlated with feeding state
I will discuss human trial of leptin later There is very limited data to support or refute the above, but there have been a few studies that looked at insulin resistance after liposuction (leptin decreased but insulin resistance stayed the same) and supraphysiologic administration of leptin to healthy, obese healthy and obese diabetic patients, inflammatory markers were not different after 3 days (JCEM 2005)
Act on 2 different cell groups in Arc: Orexigenic and Anorexigenic therefore either activating catabolic or anabolic pathways
So, if the system is balanced and has feedback loops for satiety, hunger, initiating and stopping meals, energy preservation and expenditure, what goes wrong?? Maybe some insight from the ECS.
ECS is a relatively new concept since the mid 90’s CB2 receptors mostly populate the immune system
One hypothesis about the function the ECS serves is this.
Cannot find the exact reference, but I know it’s reliable!
So it can be concluded that EC have a role in both initiation of and termination of feeding.
SO the interaction is both ways. ECS modulates adipocyte production of adiponectin and increases fat storage, and the adipocytes try to modulate the ECS by affecting their degradation enzymes and also by producing leptin.
In normal adipocytes, insulin induces expression of degradation enzymes, and decrease synthesis of NAPE but increase synthesis of DAGL In insulin resistant adipocytes, insulin cannot induce expression of degradation enzymes as much as normal cells, and baseline levels of Ecs are higher. The drop in EC in 2C for resistant cells is not sig compared to the healthy adipocytes. Although it appears that DAGL went up with insulin, it eventually declined.
Now we’ve looked at the central effects of ECS, its relation to adipocytes, to the liver and to insulin. Let’s look at its interactions with leptin.
This theory, along with a few others, has been proposed to make sense of all these pathway and all these interactions and how they lead to obesity. Omega 6 polyunsaturated fatty acids
Although I’m sure that this is how you are feeling right now, I still have to talk a little about the therapeutic implication of all this information
Including lipid profile, waist circumference, insulin resistance, metabolic syndrome) NOT FDA approved in USA, but approved in Europe for obesity
Leptin trial: dose escalating, effect only seen with highest dose but study not powered enough to detect subgroup difference in doses, and only the obese subjects were asked to alter their caloric intake.
CV risk for a given BMI goes up independently with waist circumference