Leptin: It probably doesn't do what you think it does. page 2

[pklopp]

Welcome back

Very clear analogy, and I'm very much looking forward to the next instalments!

Thank you ... Sorry about dropping off the face of the earth, but I started reading that monster leptin thread about a year ago and it took until now to finish it ...

-PK

[otzi]

Great Bro-Science, but I would suggest going to Google Scholar, type in some keywords like, Leptin, Obesity, Leptin-resistance, etc... Then sort the hits to 2011 and newer, uncheck the 'patents' button and see what you get, then read some of the studies. You will see things related to Leptin resistance as the real problem. Leptin doesn't matter, it's the leptin receptors that matter. Just like in diabetes, insulin isn't the problem--just the result, it's the insulin receptors that are out of whack. I just pulled this from Google Scholar for instance.

The hormone leptin, secreted predominantly from adipose tissue, plays a crucial role in the regulation of numerous neuroendocrine functions, from energy homeostasis to reproduction. Genetic deficiency as a consequence of leptin or leptin receptor mutations, although rare in humans, leads to early onset of chronic hyperphagia and massive obesity. In most human obesity, however, leptin levels are chronically elevated. Under these conditions of persistent hyperleptinaemia, leptin resistance develops, and signalling through the leptin receptor is curtailed, fuelling further weight gain. Here, we review the role of leptin receptors in the regulation of feeding and obesity development. Leptin receptors are found in each of the major components of the CNS “feeding” circuitry—the brainstem, hypothalamus and distributed reward centres. Through these receptors, leptin exerts influences on signalling and integration within these circuits to alter feeding behaviours. Although some progress is now being made with peptide analogues, the leptin receptor has not proved to be amenable to small molecule pharmacological intervention to date. Where clinical benefit from recombinant leptin administration has been achieved, this has been under circumstances of complete endogenous leptin deficiency or relative hypoleptinaemia such as in lipodystrophy.
Keywords Leptin – Leptin receptors – Obesity

[Drea6681]

thank you. Day two of my leptin reset and I am walking away. I'm sorry, I just don't think 6 slices of bacon, 4 eggs, and lots of butter is healthy unless you spend 5 hours at the gym.

[activia]

thank you. Day two of my leptin reset and I am walking away. I'm sorry, I just don't think 6 slices of bacon, 4 eggs, and lots of butter is healthy unless you spend 5 hours at the gym.

I dont see a problem with bacon/eggs/nor butter. I dont see why this would equate to 5 hours in the gym either. Fat on its own does not make you fat. I have had that for breakfast many times.

I just think there is no way that we would know the exact diet that would increase leptin receptors.. Is it worthy of an experiment if you are stuck? Sure thing.. as long as you feel good doing it. However, it certainly doesnt make Dr. Kruse an all knowledgeable being.. I heard him on the Paleo Summit and was like WTF what planet do you live on?

[dbalch]

In my estimation the interplay of hormones is so far beyond our grasp at this current juncture that this is the actual reason paleo makes the only sense as for how to eat and live.

Exactly, for me paleo is the ultimate "keep it simple, stupid" philosophy of diet.

[Dave Mayo]

I am not a big fan of looking for a smoking gun, there are probably multiple smoking guns wrt obesity. I like to look at the hypothalamus as a detective trying to solve a case. A good detective like the hypothalamus will look at all of the evidence and come to a conclusion, and leptin isn't the only evidence. For one, there are so many more hormones related to appetite such as ghrelin, PYY, CCK, and others that pinpointing a single culprit is unlikely. Second, the hypothalamus doesn't only use hormones as evidence, it senses substrate and we also have to consider food reward centers in the brains as other possible culprits. Case in point, Malonyl CoA. Hypothalamic malonyl CoA plays a key role in lipogenesis and high levels of Malonyl CoA signal to the brain that energy is sufficient. It also increases faty acid oxidation and mitochondrial biogenesis. An increased level of ketones tends to increase Malonyl CoA which would certainly provide support for what we see in decreased appetite with a paleo/ketogenic diet, so you can't really say that improved leptin signaling is solely responsible for the benefits of a paleo diet. If you are eating a ton of carbs circulating malonyl CoA would drop because it would be used to synthesize fatty acids as that is it's primary function. I don't think the point is leptin resistance causes this and low Malonyl CoA causes that and PYY does this, it's that we are sending mixed signals to our hypothalamus and whatever is given priority is leading the hypothalamus to decide the evidence is pointing to a low energy state. If the responsibility of leptin is to tell the hypothalamus energy levels are good and it ignores that signal, either something else is perceived as a better indicator of energy balance or the system is broken, but we don't know which it is. It could very well be that leptin sensitivity is the culprit, but it could just as well be that something else that is associated with leptin levels is the culprit. As is said in these circles time and time again, correlation doesn't show causality.

[activia]

^^ Agree 100%

[Anonymouse]

First off, I'll say I agree with you partially. It is hard to say that leptin is the culprit for all of our problems given the complexity of our biochemistry. But leptin resistance due to high blood sugar is a real phenomenon, and, phrased in your analogy, could mean that the fuel gauge on your car is broken. It would trick you into thinking you don't have any fuel and you may overflow your tank in response, leading to car obesity.

[Analog6]

Thanks so much PK. I read the leptin reset parameters and they just ran up the red flags in my mind as being a bit illogical. Love the fuel light analogy and you have made real sense to me.

[Martha]

I don't think anyone really understands most of what happens in the body or why, and honestly I don't think we really need to. We just need to eat real food.

I absolutely agree. The human organism is so complex it is likely we will never understand all the cascade effects of tweaking this or that macro to achieve some poorly understood "benefit." To believe otherwise is pure hubris, IMO. It is what has turned us into a nation of serial pill-poppers who constantly need the next pill to undo the damage the first pill did.