Why Hyperleptinaemia is Not Leptin Resistance

Yesterday, I posted about the presentation of Columbia University’s Rudy Leibel on how losing weight results in a hypometabolic and orexogenic response mediated largely by a fall in plasma leptin levels that, as a rule, accompany any attempt at reducing fat stores.

This post elicited a number of responses that I will try to address in this follow-up post.

Several readers wanted to know whether there is a way to readjust your ‘leptin sensitivity’ so that the brain no longer wants to restore body weight to pre-weight loss levels.

The short answer is ‘no’. Although there are several proposed strategies (special diets, refeeding days, exercise strategies, etc.) floating around in the popular literature, there is very little scientific evidence that this can actually be done. The sad fact is that anyone, who has ever lost weight, has to continue with efforts to keep it off – this includes people who have had bariatric surgery, who if they ever decide to reverse their surgery – will rapidly gain their weight back (even after years of keeping it off). This, by the way, is why bariatric surgery has to be seen as a definitive and permanent solution and why temporary devices like gastric balloons, which have to be eventually removed, are not a permanent treatment for obesity.

Another reader wanted to know, that if this was true, why some people are successful in maintaining long-term weight loss.

The answer to this is that these individuals somehow manage to continue their efforts (whatever those may be) in the long-term. The best studied group of individuals who have succeeded in the long-term are perhaps those represented by the National Weight Control Registry, who, using various strategies manage to reduce their caloric intake to about 1400 KCal (the same amount that is effectively eaten by successful post-bariatric surgery patients) combined with considerable amounts of exercise (upto 400 KCal worth every day). Such ongoing efforts are clearly beyond what most people can do without completely changing their lives. So, what the NWC participants actually demonstrate, is not so much that sustaining weight loss is possible but rather that this requires an almost ‘superhuman’ effort (some would say ‘obsession’) – indeed the NWC registrants represent a rare minority of people attempting to lose weight by diet and exercise alone (the NWC registry has a few thousand registrants compared to the tens of millions who try losing weight every year).

Finally, some readers wondered about ‘leptin resistance’, a term often used to describe the fact that obese people apparently need higher circulating levels of leptin (hyperleptinaemia) to suppress their appetite and burn more calories than lean people.

In his talk, Leibel made clear that ‘resistance’ may not be the best way to describe this phenomenon.

Rather, he preferred to refer to an elevated leptin ‘threshold’, implying that there is an upward shift in the levels of leptin required to suppress the orexogenic and hypometabolic response elicited by caloric restriction.

Leibel prefers the term threshold, because even in people with a high threshold (i.e. obesity), once you have administered enough leptin to restore baseline levels and suppress the orexogenic response that follows weight loss, there is no further decrease in appetite, even at higher leptin doses. This is why simply injecting additional leptin into a person who is at their usual weight (i.e. prior to weight loss) has little to no effect on appetite, which incidentally, is exactly why leptin does not produce weight loss and would not meet thergulatory criteria for as a weight-loss drug (the rare exception being in individuals who are born with a genetic lack of leptin).

Perhaps the difference between ‘resistance’ and ‘threshold’ can best be understood by comparing leptin to insulin. In people who are resistant to insulin (e.g. patients with type 2 diabetes), you can ‘overcome’ this resistance by simply injecting increasing amounts of insulin. Even in the most insulin-resistant individual, you can eventually lower blood glucose levels by injecting more insulin – if you inject too much, these individuals will experience hypoglycemia, i.e. experience the physiological impact of too much insulin.

In contrast, the hypometabolic and orexogenic state following weight loss will respond to leptin injections only up to a dose that is just high enough to restore pre-weight-loss levels (the threshold level) – adding additional leptin will not increase metabolism or suppress appetite further.

Thus, while people with insulin resistance will respond to increasing doses of insulin to the point of hypoglycemic shock, people with an elevated leptin threshold will achieve a maximum metabolic and anorexogenic response (albeit at higher levels than people with a lower threshold) beyond which leptin has no further effect.

This may seem like a ‘semantic’ distinction but from a treatment perspective (and the science behind it), this difference is substantial and explains why high doses of insulin can always be used to treat diabetes even in the most insulin-resistant individual whereas leptin only works upto the point where it restores levels to the respective (pre-weight loss) threshold.

Obviously, the key question is why some people have a higher leptin threshold or rather why this threshold (that can also be thought of as the famous ‘set point’) only seems to move in one direction (namely to higher levels) and then becomes permanent (unless it is moved to even higher levels by weight gain).

As Leibel explained, the reason that this leptin threshold appears permanent, may be due to the fact that it becomes ‘hardwired’ into the brain – a process that is essentially irreversible (perhaps with the exception of patients with cancer cachexia). It is therefore perhaps not surprising that it actually takes neurosurgery (in animal experiments) to ‘reverse’ this threshold – an approach that is clearly not feasible in humans.

Several readers also asked whether leptin is available and whether it works in humans to help keep weight off – more on this topic tomorrow.

In the meantime, here is a link to a previous post on Leibels ‘Threshold Theory‘.

Edmonton, Alberta