RAGE - Towards Understanding Why We Get Fat

(Michael - When reality fails to meet expectations, the problem is not reality.) #1

The summary and overview for the rest of us:

A molecular “trick” that kept our ancient ancestors from starving may now be contributing to the obesity epidemic, a new study finds.

The study (a mouse study, so the usual caveats apply, still very interesting indeed):

Summary

Exquisite regulation of energy homeostasis protects from nutrient deprivation but causes metabolic dysfunction upon nutrient excess. In human and murine adipose tissue, the accumulation of ligands of the receptor for advanced glycation end products (RAGE) accompanies obesity, implicating this receptor in energy metabolism. Here, we demonstrate that mice bearing global- or adipocyte-specific deletion of Ager , the gene encoding RAGE, display superior metabolic recovery after fasting, a cold challenge, or high-fat feeding. The RAGE-dependent mechanisms were traced to suppression of protein kinase A (PKA)-mediated phosphorylation of its key targets, hormone-sensitive lipase and p38 mitogen-activated protein kinase, upon β-adrenergic receptor stimulation—processes that dampen the expression and activity of uncoupling protein 1 (UCP1) and thermogenic programs. This work identifies the innate role of RAGE as a key node in the immunometabolic networks that control responses to nutrient supply and cold challenges, and it unveils opportunities to harness energy expenditure in environmental and metabolic stress.


22%20PM

Why high fat and not just low/zero carbs?
(Polly) #2

Interesting indeed.

(Jane) #3

Importantly, RAGE is much more active during metabolic stress (e.g. starving or overeating) than in everyday function, which suggests it can be safely interfered with through drugs, the authors say.

Of course they want to develop a magic pill to cure obesity! Especially if you have to take it the rest of your life to prevent weight gain - what a goldmine that would be!

Looking at pictures from the 30’s and 40’s where there was definitely a lot of stress fron the Great Depression and so few overweight I personally believe our seed oils cause inflammation and that activates the RAGE molecules.

(Bacon is a many-splendoured thing) #4

It’s worth remembering in this context that obesity is one of the consequences of metabolic dysfunction, not the cause of it.

Dr. Robert Lustig quotes figures in his lectures on sugar and metabolism, to the effect that while about 80% of the obese are also metabolically damaged in other ways, the remaining 20% may be fat but are otherwise healthy The medical term for such people is MHO, “metabolically healthy obese.” The inverse of this is the 40% of normal-weight people who have metabolic disease. Because they are loaded with visceral fat that mostly doesn’t show, the medical term for them is TOFI, “thin on the outside, fat on the inside.”

Dr. Lustig’s most recent lecture suggests that subcutaneous fat, the most visible kind, is not particularly of concern, from the viewpoint of metabolic health. The dangerous kind of fat is visceral, especially liver fat.

(Jane) #5

I can’t remember which thread you posted this on, but you talked about the controversy whether HFCS or seed oils contributed more to the sharp rise in obesity since they were both introduced around the same time. The rise in consumption of both correlate strongly with the rise in obesity.

I did low carb Atkins (but not high fat keto) in 2005 trying to lose weight before my wedding in late December. I didn’t know about seed oils so used canola oil anytime I cooked something needing oil like eggs, sautéing onions, etc.

I started my low carb in March so had plenty of time to lose weight. I lost around 20 lbs (wanted to lose 40) and stalled out, even though I ate very low carb and went to the gym regularly. Looking back, I was eating too often and keeping my insulin high since I didn’t know any better but was frustrating to stall for MONTHS on low carb.

Anyhoo…… thinking about the above argument…… I definitely did not consume HFCS but consumed canola oil so it is possible the inflammation from the canola oil hindered my weight loss in addition to eating too often.

I really think if we outlawed both HCFS and seed oils and quit promoting the lie that saturated fats are bad for you that our overall health would improve greatly in this country.