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.
No announcement yet.
Leptin: It probably doesn't do what you think it does.