Exogenous leptin reverses adaptation to weight reduction

[ItsTheWooo]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=16322796&query_hl=3&itool=pubmed_docsum

Maintenance of a reduced body weight is accompanied by decreased energy expenditure that is due largely to increased skeletal muscle work efficiency. In addition, decreased sympathetic nervous system tone and circulating concentrations of leptin, thyroxine, and triiodothyronine act coordinately to favor weight regain. These "weight-reduced" phenotypes are similar to those of leptin-deficient humans and rodents. We examined metabolic, autonomic, and neuroendocrine phenotypes in 10 inpatient subjects (5 males, 5 females [3 never-obese, 7 obese]) under 3 sets of experimental conditions: (a) maintaining usual weight by ingesting a liquid formula diet; (b) maintaining a 10% reduced weight by ingesting a liquid formula diet; and (c) receiving twice-daily subcutaneous doses of leptin sufficient to restore 8 am circulating leptin concentrations to pre-weight-loss levels and remaining on the same liquid formula diet required to maintain a 10% reduced weight. During leptin administration, energy expenditure, skeletal muscle work efficiency, sympathetic nervous system tone, and circulating concentrations of thyroxine and triiodothyronine returned to pre-weight-loss levels. These responses suggest that the weight-reduced state may be regarded as a condition of relative leptin insufficiency. Prevention of weight regain might be achievable by strategies relevant to reversing this leptin-insufficient state.

[ItsTheWooo]

Kay, doin some research on leptin.

Interest in leptin kinda flopped when it was discovered it wouldn't be the magic pill to solve obesity. It is ineffective and induces leptin resistance.
Sure, giving leptin to a presently obese undieted person is a lot like giving insulin to a T2 diabetic swilling pasta with poor control. It may help, but it just makes the problem worse long run.

But more research shows weight reduced obesity is a state of absolute (from the diet) and relative (due to previously aquired insensitivity) leptin insufficiency. I must wonder, for the obese person who is normal weight/weight reduced, if this state of hypoleptinemia can be pharmacologically treated. Injections and carefully monitored levels of leptin may help restore normal pre-diet metabolic/reproductive function, much the way insulin helps restore normal physiology to a hypoinsulinemic T2 with burned out beta cells.

I suppose so few people actually lose weight and keep it off long enough for there to be enough interest or research in it.

I also do wonder if ignoring the potential theraputic applications of leptin has to do with interest in keeping people weight cycling ($$$). It's much more lucrative to keep us weight cycling or losing weight... so much so that there is no interest left to research helping us keep it off.

[SunnyCarol]

Metabolic Syndrome and Related Disorders

Adipocytokine Changes Caused by Low-Carbohydrate Diet Compared to Conventional Diets in Obesity
Mar 2005, Vol. 3, No. 1: 66-74

Modest weight loss causing a decrease in insulin resistance has been linked to favorable changes in the adipocyte cytokines leptin, adiponectin, and tumor necrosis factor-α (TNF-α), three emerging risk factors of cardiovascular disease. We previously observed a significant reduction in insulin resistance with weight loss in obese subjects on a low-carbohydrate diet. Based on these previous findings, we hypothesize that a low-carbohydrate diet would be more beneficial in changing leptin, TNF-α, and adiponectin than a conventional diet. A total of 75 severely obese (body mass index ≥35 kg/m2) subjects were randomized to instruction of 6 months of a low-carbohydrate diet or a conventional calorie-restricted diet. Serum levels of leptin, TNF-α, TNF-α-soluble receptor 1 (TNF-α SR1), and adiponectin were measured at baseline and after 6 months of dietary intervention. Subjects on low-carbohydrate diets experienced a greater decrease in leptin when compared to conventional dieters (p < 0.001). TNF-α increased significantly in nondiabetic subjects on conventional vs. low-carbohydrate diets (p = 0.003). Adiponectin and TNF-α SR1 change were not significantly different between diets. This is the first study to report the effects of dietary macronutrient alterations on serum adipocytokines in a randomized controlled trial. The greater reduction in insulin resistance and weight on a low-carbohydrate diet, in the short term, translates into greater improvement in leptin but with no significant improvements in TNF-α or adiponectin in patients with moderate to severe obesity after 6 months of dietary intervention

Division of Endocrinology, Department of Medicine, University of Pennsylvania Medical School, Philadelphia, Pennsylvania.
Department of Medicine, Veterans Affairs Medical Center, Philadelphia, Pennsylvania.

[ItsTheWooo]

Subjects on low-carbohydrate diets experienced a greater decrease in leptin when compared to conventional dieters .

Actually it's interesting to see a LC diet does reduce leptin, more than a regular diet, because I had suspected such.

First let me say research shows over eating raises leptin significantly, even if there is no real fat gain (which is probably why cheating helps break stalls).

When I over eat chicken and stay really LC, I experience relatively little reprieve from my "symptoms". I also tend to gain no fat at all, or extremely little. Sometimes I even lose. I mean it does help no doubt but not much.

OTOH if I go to the buffet or something, and eat slightly higher carb, like, chicken with sauce, that kind of thing... then I can tell something REALLY was fixed. The next day I usually feel fantastic and experience none of the usual symptoms of mild metabolic slow down. My hands are warm. My hunger is completely normal. My energy is fabulous. My moods are better, too.
It is, as I felt first starting LC morbidly obese. Of course, I *never* lose then, I often bloat out, and always put on at least a little bit of weight that I need to restrict later to get off.

I think leptin levels are probably controlled by insulin levels somewhat... when insulin acts to put fat in the cell and glycogen in muscles etc.

That leptin levels are reduced more in the severely obese following a LC diet implies the LC diet is better at correcting hyperinsulinemia and the tendency to store energy. If this occurs when normal weight is reached, it is no longer necessarily beneficial then, seeing as evidence shows maintenance of weight loss involves a state of relative (and often absolute) hypoleptinemia.

Perhaps this is why, when I want to restrict food, I do much better if I keep carbs a bit higher. It is just so much easier to lose and not eat a lot then. Seeing as my leptin levels are likely functionally too low most of the time, it's actually easier for me to diet WITH a bit more carbs than pure LC. This is the complete *opposite* of what I experienced when I actually was rather overweight. Although to maintain, strict LC is the easiest, since carbs plus calories seems to overload my body, and I actually feel more tired and hungrier
Another function of leptin is regulating sugar sensitivity; people who've been fasting or are too low weight or have lost a lot of weight really can't handle sugar as well as they should for this reason, *even though* tests will say sugar sensitivity improves it is only in the context of the low cal and/or carb way of eating; when challenged with higher cals and carbs, sugar sensitivity will be worse (until the body replenishes things sufficiently).

[LC FP]

Wooo

It's been said previously on this board that it's easier to lose weight on LC than to maintain the weight loss. (This may be true on any diet I guess). When you say:

Another function of leptin is regulating sugar sensitivity; people who've been fasting or are too low weight or have lost a lot of weight really can't handle sugar as well as they should for this reason

does that explain part of the above? Wen I eat nuts or LC ice cream regularly I start to put on the paunch at a scary pace, eating probably 20% of the carbs I used to eat when I was more insulin resistant. Is it just insulin again, or lack of leptin? I'm confused.

[Dodger]

LC FP,

I think that weight regain is from going back to what caused the excess weight in the first place.

[ItsTheWooo]

Wooo

It's been said previously on this board that it's easier to lose weight on LC than to maintain the weight loss. (This may be true on any diet I guess). When you say:


That's true, but the implication seems to be that this is for purely behavioral reasons (a lifestyle change VS a diet). That might not necessarily be so, at least for some weight reduced people. Speaking personally, my weight is hard to keep off, and it has nothing to do with not wanting to LC (cheating)... I just want to keep eating :lol: . I feel cold often, often tired as well. I am infertile.

If I pack in food at a buffet, at first I feel extremely shaky with eggshell blood sugar. But, then these symptoms go away completely the next day, after the fast of the night. I feel absolutely no irrational hunger, I don't even need to eat really... hands are boiling warm, moods are better, far less apathy more energy etc.
I do think the eating had some kind of "replenishing" effect on my metabolism, and I do think it is through leptin. Over eating does replenish leptin, as under eating depletes it.

does that explain part of the above? Wen I eat nuts or LC ice cream regularly I start to put on the paunch at a scary pace, eating probably 20% of the carbs I used to eat when I was more insulin resistant. Is it just insulin again, or lack of leptin? I'm confused.

Am I understanding you correctly: you start to gain weight rather fast, if you eat foods which are higher in carbs, although still lower in carbs than what you used to eat?

My understanding is that it's always the insulin building fat. However, a relative (or absolute) deficiency in leptin impairs our ability to handle a glucose challenge. So, through a lack of leptin, there is more insulin in response to the same amount of sugar you could previously better handle (because your sugar goes higher, and stays higher longer, your body needs to make more insulin to handle it). This is, of course, assuming everything equal. If other causes of insulin resistance have improved (like excess BF or eating foods that are very high in simple carbohydrates), then so will sugar tolerance. But otherwise, low leptin means glucose intolerance. IR isn't as simple as "one thing" that causes it, it's multifactored, and leptin levels are but one of several relevant factors.

The link between sugar intolerance and leptin is likely brilliant design; the body's way of maximizing whatever nutrition it can find. Low leptin only exists in the fasted, starved, state. It makes perfect sense that it would be a survival advantage to become IR (thus overproduce insulin in response to whatever nutrition found) until leptin were restored (by sufficient weight gain/eating to restore leptin level).
Furthermore, another aspect of low leptin is high cortisol; leptin and cortisol exists on axis (that is, low leptin automatically activates adrenals to make cortisol). Since low leptin always means stress and nutrient scarcity, cortisol helps things along by preparing the body for stress, better making sugar from food, and increasing insulin resistance yet again (again to exploit nutrition and build fat).

This system is all very much self regulating (that is when leptin returns to normal, the fat building will stop) in a healthy person without any diseases or imbalances.

I'm sure it's quite complex (much beyond my understanding or ability to understand) but I do think relative low leptin is one of the main reasons we can regain previously lost weight *so* quickly, much more quickly than we could ever hope to achieve a new high weight in an undieted, fed state.

Here's a really long and complicated reference re: leptin and it's affect on glucose metabolism.
http://www.springerlink.com/media/1f9gxhttrp5h5tpjhq06/contributions/m/l/l/c/mllcm818gkxxwa41.pdf

More evidence that leptin is part of normal glucose tolerance:Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy.
(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=99413717&dopt=Citation)
Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by a paucity of adipose (fat) tissue which is evident at birth and is accompanied by a severe resistance to insulin, leading to hyperinsulinaemia, hyperglycaemia and enlarged fatty liver.
...
Here we show that insulin resistance in our lipodystrophic mice can be overcome by a continuous systemic infusion of low doses of recombinant leptin, an effect that is not mimicked by chronic food restriction. Our results support the idea that leptin modulates insulin sensitivity and glucose disposal independently of its effect on food intake, and that leptin deficiency accounts for the insulin resistance found in CGL.

[deb34]

it's the wooo; could you point me to more information about this quote? please? symptoms of mild metabolic slow down

i'm interested in this as i think, i might have experienced this in the past but had no idea what was goin on...

thanks

Deb34

[Paleoanth]

LC FP,

I think that weight regain is from going back to what caused the excess weight in the first place.

I completely agree.

[LC FP]

My understanding is that it's always the insulin building fat. However, a relative (or absolute) deficiency in leptin impairs our ability to handle a glucose challenge. So, through a lack of leptin, there is more insulin in response to the same amount of sugar you could previously better handle (because your sugar goes higher, and stays higher longer, your body needs to make more insulin to handle it).

Low leptin only exists in the fasted, starved, state.

Furthermore, another aspect of low leptin is high cortisol;... Since low leptin always means stress and nutrient scarcity, cortisol helps things along by preparing the body for stress, better making sugar from food, and increasing insulin resistance yet again (again to exploit nutrition and build fat).

This system is all very much self regulating (that is when leptin returns to normal, the fat building will stop)
Working through all this...

A normal weight never fat person has low insulin, medium leptin and medium cortisol. After eating they have medium insulin, medium leptin and medium cortisol.

A normal weight previously fat person has low insulin, low leptin and high cortisol. After eating they have high insulin, low leptin and high cortisol. The high cortisol drives gluconeogenesis even though the insulin tries to stop it, and the high insulin drives fat storage. So they get fat faster than a normal weight never fat person would, consuming the same diet. Is this what you mean?

If so, I wonder if leptin metabolism can change back towards normal with time? I don't enjoy not eating all the fruit I want, or limiting my nut intake. I guess if I wasn't so lazy I could just exercise more. I wonder if exercise has any effect on leptin..

[ItsTheWooo]

Working through all this...

A normal weight never fat person has low insulin, medium leptin and medium cortisol. After eating they have medium insulin, medium leptin and medium cortisol.

A normal weight previously fat person has low insulin, low leptin and high cortisol. After eating they have high insulin, low leptin and high cortisol. The high cortisol drives gluconeogenesis even though the insulin tries to stop it, and the high insulin drives fat storage. So they get fat faster than a normal weight never fat person would, consuming the same diet. Is this what you mean?

Yes... that is pretty much it, except, leptin / cortisol levels do fluctuate even in weight stable people.

My research is leading me to suspect my original guess was correct - leptin is controlled by insulin acting on the fat cells. So, eating patterns and types of food will affect leptin and cortisol fluctuations in undieted weight stable people (leptin rising with insulin, falling with lulls between food). Reference:
Fasting Insulin Levels Influence Plasma Leptin Levels Independently from the Contribution of Adiposity (http://jcem.endojournals.org/cgi/content/abstract/85/11/4231)

The difference is an undieted , non-weight suppressed person, on average, has relatively higher leptin and lower cortisol, so they aren’t as good at getting fat and keeping on fat if all things are equal.


Keep in mind this is just how metabolism is affected by weight suppression. Even more significant is how leptin affects behavior so as to encourage weight regain and a lack of diet adherence. The presence of sufficient leptin acts on the hypothalamus and inhibits NPY (which makes you hungry as heck) and it activates the POMC (which makes you able to stop eating). Here's a reference:
Fat hormone leptin alters brain architecture and activity, which in turn drives feeding behavior (http://runews.rockefeller.edu/index.php?page=engine&id=51)

If so, I wonder if leptin metabolism can change back towards normal with time?

It may…
It probably depends on a lot of factors, like, how suppressed your weight is (if it is suppressed at all), and eating / lifestyle patterns. Leptin is going to automatically come up a bit when restriction stops and weight is stable (as previously stated, losing fat means eating so as to lower insulin and that means lower leptin).
Amount of fat cells control how “full” each cell at the same amount of fat mass in kg (and this in turn affects leptin level). Time may help us maintain weight, because evidence is extra fat cells die off when insulin levels are low. With less fat cells, there is more fat in each cell assuming unchanged fat mass (thus + leptin). Insulin does more than store fat, it actually causes the growth of new cells, and protects them from death (which is why obesity is implicated in cancer, by way of sugar/insulin). Reducing insulin translates into your body *not* maturing new adipocytes (a process that is accelerated in hyperinsulinemia), and the susceptibility of adipocytes to apoptosis. Bit of evidence:
Decreasing media insulin concentration from 8.5 to 0.85 nM resulted in increased adipocyte apoptosis, whereas high doses of insulin protected adipocytes from TNFalpha-induced apoptosis.” ( http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11414707&dopt=Abstract)

One more thing. It would be good to differentiate between weight reduction from restricting energy, and, weight reduction from simply stopping unhealthful lifestyle behaviors. Like, if you lost weight eating ad lib to hunger, odds are none of this applies to you, because, your weight really isn’t suppressed. It is possible to be overfat, just as it is possible to lose weight and become underfat. By definitions of overfat and underfat, I mean relative to metabolism, not culture (what is overfat for one person, is actually underfat for another).
If weight was lost by eating as much as one wants, not going hungry, or anything of the sort, then it’s very likely metabolism is balanced, insulin and leptin levels are appropriate (whereas before insulin was too HIGH as were leptin levels, producing an overfat state).

I think this is relevant mostly in people who are intake restricted, thus, weight suppressed. Like, for example, a morbidly obese person who’s body is damaged from obesity (aquired leptin resistance/IR), so that their minimum weight is “too high” for their liking… or, a slightly overweight/normal weight person who restricts food to be a more fashionable slender size. It is unfortunate most people who want to be “socially thin” that it will require metabolic suppression by becoming underfat.


I don't enjoy not eating all the fruit I want, or limiting my nut intake. I guess if I wasn't so lazy I could just exercise more. I wonder if exercise has any effect on leptin..
Exercise would probably have a negative effect on leptin, since the only thing that raises leptin is a condition that is conducive to gaining fat (+ insulin). However it has such a positive effect on metabolic rate and sugar metabolism, that it more than negates these effects. So, as a result, with exercise one can tolerate more carbs.

But, it isn't really going to do much to change the other problems associated with low leptin if such symptoms exist (like chronic hunger, adrenal dominance, reduced fertility, reduced thyroid function ). If anything, adding exercise on top of weight reduction from under eating is just going to worsen those symptoms, because the exercise will be dropping insulin and leptin even more.

[LC FP]

Thanks, wooo

This system is so complicated even drug companies are having trouble figuring out how to profit from it.

I think I'll go kill some fat cells!

[ReginaW]

So, through a lack of leptin, there is more insulin in response to the same amount of sugar you could previously better handle (because your sugar goes higher, and stays higher longer, your body needs to make more insulin to handle it). This is, of course, assuming everything equal.

I have to say this is a very interesting thread. I do think something Mike Eades recently wrote about plays into this too....

Following a low-carb diet makes one a little glucose intolerant, which is the reason that the instructions for a glucose tolerance test always include the admonition to eat plenty of carbs in the week before the test. Why? Because all the macronutrients--glucose, fat and protein--are broken down by enzymes during the metabolic process. And all the enzymes necessary for the metabolism of the various macronutrients are made on demand but not immediately. If you are on a high carbohydrate diet, then you will have plenty of enzymes on hand to deal with the carbohydrates you consume. If you switch to a low-carbohydrate diet, it takes a while to manufacture the enzymes in the quantities needed to deal with the extra fat and protein that your metabolic system hadn't been exposed to. This deficiency of protein/fat metabolizing enzymes is the reason people starting a low-carb diet become so easily fatigued--they've got plenty of enzymes on hand to break down carbs, they just don't have the carbs to metabolize. Once they produce the enzymes necessary to deal with the load of protein and fat, which takes a few days, they become low-carb adapted and no longer feel fatigued.

Once people become low-carb adapted--as I hope we all are--then the same thing happens if they go face down in the donuts. They don't have the enzymes on board to deal with the sudden influx of glucose, and, as a consequence, their blood sugar spikes higher than it would on a person eating the same amount of carbohydrate who is already carb adapted.

This paper shows that these carb spikes are not benign. As the paper points out

Risk factors of atherosclerosis such as hypertension, regular smoking, hyperlipidemia, and obesity have been described as being associated with elevated urinary excretion rates of isoprostanes.
Since the best thing we can do for ourselves is limit free radical damage as much as possible, the obvious way to do so is to maintain a constant low level of blood sugar, for which the low-card diet is just the ticket. In view of these recent findings when we're good, we should be very good indeed, but when we're bad maybe we shouldn't be quite so horrid.

April 19, 2006: Low Carb Caveat (http://www.proteinpower.com/drmike/archives/2006/04/)

[ItsTheWooo]

Effect of significant intermediate-term weight loss on serum leptin levels and body composition in severely obese subjects. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=14738675&query_hl=1&itool=pubmed_docsum)

BACKGROUND: Leptin, produced by adipose tissue, signals body fat content to the hypothalamus. Serum leptin levels (SLL), elevated in obese humans, decrease with weight loss. This study investigated the reduction of SLL and fat mass following restrictive bariatric surgery. METHODS: Obese subjects (body mass index [BMI] >35 kg/m2, n=154) undergoing gastric banding (weight-reduced subjects) were investigated for SLL and body composition before surgery and for 2 years after. Overweight subjects matched for fat mass and gender (fat mass-matched overweight controls, n=194) and subjects who had never been obese (normal weight controls, n=158) were studied for comparison. RESULTS: SLL were highest in weight-reduced subjects and decreased with weight loss (P <0.001), remaining elevated compared with normal weight controls (P <0.001) but lower than fat mass-matched overweight controls (women: P <0.04). At 2 years, SLL normalized for fat mass (allowing comparison between various levels of adiposity) were lower in weight-reduced subjects compared with fat mass-matched overweight controls (women: P =0.003), yet were similar for weight-reduced subjects at 2 years compared with normal weight controls despite 14 kg greater fat mass. Relative lean mass of extremities in weight-reduced subjects increased with weight loss (P <0.001). CONCLUSION: SLL decreased after considerable weight loss more than could be accounted for by fat mass or BMI reduction alone. This disproportionate decrease in SLL might point to a mechanism that evolved as adaptation to starvation during times of famine. Thus, post-obese subjects may be at risk of weight-regain due to disproportionately low SLL and increased appetite via the leptin-melanocortin pathway.


Normal weight controls had about equal leptin to the weight reduced people, even though the weight reduced people had more fat mass.
Fat mass matched overweight people had higher leptin than the weight reduced people.
This was observed 2 years after weight loss.

I suppose this is why almost all obese people maintain at an overweight size, and it seems none can achieve normal weight without under eating. Even when we are relatively fatter, our bodies act as if we are thinner.
I also suppose this explains why I experienced such profound adversity at slight underweight., and why I find it extremely hard to maintain this weight (which is thin even by non-dieted people standards, but exceptionally thin possibly underweight to my body)....

The researchers hypothesize why this difference exists:
"This disproportionate decrease in SLL might point to a mechanism that evolved as adaptation to starvation during times of famine. "

Personally I think it's because the weight reduced obese people had more fat cells (excess skin, excess white adipocytes) ... so, level of leptin is disproportionate with what is observed non-weight suppressed people. Leptin level equals controls, even though the weight reduced people were like 30 pounds heavier in fat... leptin was lower than undieted people matched for fat mass.