In the previous installments of this series the basics of leptin were laid out in detail. However, as I am sure you are aware, it has been quite some time since the last article in this series was published. In that time there has been an explosion of new research. This new research has begun to shed light on leptin’s interplay with various systems in the body. So in this installment we are going to delve much deeper into leptin’s effects. Specifically we are going to discuss how leptin’s direct interaction with various tissues promotes weight loss. However keep in mind that in this installment we are only going to be dealing with leptin’s direct effects on tissues. Much of leptin’s punch occurs because of downstream signals and various changes regulated by leptin’s interaction with the brain and nervous system. So keep that in mind as you read this article. Leptin’s powerful central effects cannot be denied. However to understand how it accomplishes some of this I have tried to ignore any systemic effects in this article. In the next installment we will delve deeper into leptin’s powerful systemic effects. So without further delay…I give you, “Leptin: the Next Big Thing Pt. IV.”

Leptin and Adipose Tissue

When discussing leptin’s effects on fat loss it seems only logical that we should start our discussion with the white adipose cell, a.k.a. fat cells. If you have taken the time to look in to some of the research on leptin and fat cells you would be awestruck. Visions of fat cells shriveling up like raisins in the sun would dance through your head. Seriously, some of these studies are littered with things that seem almost magical—such as fat cells eating away at there own lipid storage depots and spilling glycerol out in to the blood stream (1). Imagine if all you had to do was get a shot of leptin to transform your fat cells in to fat-burning machines. Unfortunately this is one of those times where people don’t behave like rats. Or more specifically, human fat cells behave nothing like mouse or rat fat cells when treated with leptin. When white fat cells extracted from our favorite scientific pet, the rodent, are incubated with a serum of leptin they become quite lipolytic (3,4,5,6). This is not the case with human fat cells however. Treating human white adipose cell lines with leptin does not induce lipolysis; nor does it reduce insulin’s attenuation of lipolysis (2,7).

The story does not end there however. Luckily it seems that leptin does have some positive effects on human white adipose tissue. Namely, leptin is very anti-lipogenic. It has been shown to lower the amount of human fatty acid synthase (FAS) and sterol regulatory element-binding protein (SREBP) (8). This is further validated by in vivo research conducted on the obese. The obese have plenty of leptin as you already know and the obese have been shown to have lower levels of FAS and SERBP.

Additionally, leptin has a rather remarkable affect on Perosixome Proliferator-Activated Receptor-gamma (PPAR-gamma). PPAR-gamma is an orphan nuclear receptor that is activated when poly-unsaturated fatty acids (PUFA) bind to it. In many ways PPAR-gamma is the master control switch for fat storage. When PPAR-gamma is activated it causes a host of enzymes to be created. The majority of these enzymes serve two purposes. First they promote the esterification of fatty acids, creating triacylglycerides (TAG). Secondly they promote the formation of lipid droplets form TAG. Unfortunately, when leptin was administered to mice it increased the cellular expression of PPAR-gamma by 70-80% (9).

All of this does make sense when you examine it however. Leptin is a multi-function hormone. It serves as an anti-starvation hormone as well as a long-term signal of energy reserves. Well, relatively long term, when compared to neurotransmitters. So it makes sense that leptin would indeed reduce lipogenic enzymes as it is signaling to other cells that there are plenty of caloric reserves, and that the body needn’t bother storing more.

Leptin’s effects on PPAR-gamma activity also makes sense. Specifically this activity is one of the signals that leads pre-adipocytes to differentiate in to full fledged fat cells. Since leptin is signaling that there is ample stored fuel, it logically follows that it would be alerting the pre-fat cells that there may be a need for more fat cells to store these incoming calories because the current cells are already full. This is further validated by studies showing that when pre-adipocytes are incubated in supraphysiological levels of leptin they do indeed differentiate into full-fledged fat cells. Of course, this only happens at extremely high leptin levels such as those seen in the obese.

In normal individuals PPAR-gamma and leptin seem to operate in a negative feedback loop. Leptin signaling at the fat cell upregulates PPAR-gamma as previously stated, however PPAR-gamma activation dramatically lowers leptin production. Thus it would seem that in normal individuals the relationship between leptin and PPAR-gamma is used to evenly distribute nutrients to all of the adipose tissue in the body; it is a sort of short-term regulator of how much fuel each cell should receive.

Additionally, leptin has some positive effects on human adipose tissue, specifically related to insulin stimulated glucose uptake. There are several studies that show leptin to lower glucose uptake in fat cells. This would be of benefit as it would reduce the energy supplied to your fat cells, thus forcing them to use fatty acids to meet their energy demands. Some of the evidence in this category is mixed, however much of that can be attributed to the fact that differing levels of leptin were used in the studies.

The relationship is an “inverted U.” In other words leptin’s effects in this respect appear maximally at low and high leptin concentrations. This makes sense after further examination. When leptin concentration is very low this is a signal that one is in a state of starvation. By reducing glucose uptake into adipose, you make that available to other tissues such as the brain and muscles, which are deemed more important. So, at low concentrations, leptin acts on adipose tissue to prioritize nutrient usage. At very high concentrations this is also to be expected. You see both leptin and insulin have cross talk in their signaling cascade. In other words leptin resistance leads to insulin resistance and insulin resistance leads to leptin resistance. So when one has incredibly high leptin levels it is only logical that insulin sensitivity would suffer, and insulin stimulated glucose uptake would decrease.

So at the very least it would seem that leptin’s effects on human adipose tissue is a mixed bag. Its effects are primarily beneficial, however they are disappointing compared to early animal research. Still, there are many questions left unanswered. In a very rigorous investigation of the current literature, your humble author found that there are approximately 2.34567 gazillion studies on leptin and rodent fat cells. There are however, only a handful conducted on human cell lines. This means that there is still much investigation to be done and hopefully future research will shed some light leptin’s role in the human adipose cellular lifecycle.

Now, you’re probably saying, "But Spook, I read the previous articles, I know leptin is good for fat loss. Are you trying to tell me leptin doesn’t promote fat loss? Did your parents pick you up by the soft spot as a child? Did you fry your brain on In-Rage? Or are you just a commy bastard?" No, no, and no on all accounts. Don't fret; leptin is indeed marvelous for fat loss, at least in the already lean. To understand why, we must look beyond our fat cells. That is exactly what we are going to do in the rest of this article as we examine leptin’s direct effects on the numerous systems of the human body.

Leptin and Muscle Tissue

One way in which leptin aids in fat loss is by its direct effects on skeletal and cardiovascular muscle. Muscle cells express the long form leptin receptor (Ob-R). This is the receptor that is responsible for initiating leptin’s signaling cascade through the JAK pathway when it interacts with various tissues. In very simple terms, leptin causes your muscle cells to utilize fat instead of carbohydrates for energy. To properly address this phenomenon we must digress for a moment to briefly describe the system that regulates substrate utilization at the cellular level.

Inside the muscle cells in your body are small organelles called mitochondria. The mitochondria create the majority of the energy our cells need to operate, in the form of ATP. For various reasons that are to complex to delve in to in this article, our mitochondria tend to use mostly fat or mostly carbohydrates for energy production, but they tend not to use both of them at the same time. This issue is an interesting one that I hope to provide a full examination of in the future, but for now you will just have to take your humble author’s word for it. In essence, your cells will use fat or carbohydrates but not both at the same time.

The choice of fuel selection is controlled in large part by a protein called, acetyl-CoA carboxylase (ACC) (10). On the surface of the mitochondria’s membrane is another protein called carnitine palmitoyl transferase (CPT). You can think of CPT as a doorway for long chain fatty acids to get inside the mitochondria. If CPT can't get those long chain fatty acids in to the mitochondria, then they can't be oxidized (11). CPT transfers a fatty acid in to the mitochondria by binding to the acyl end of a fatty acid acyl complex. Essentially, there is this substance called acytal-CoA that is floating around in your cells. When it comes time to burn fat the acytal-CoA is grafted on to the end of a fatty acid, forming an acyal-FAT complex. CPT latches on to the acyl part and transports the fat into the mitochondria to create around 140 ATP molecules per fatty acid. ACC creates a product called malonyl-CoA by acting on acytal-CoA. Malonyl-CoA is a competitive inhibitor of the acyal-FAT complex. It binds to CPT, thus preventing CPT from doing its job of transporting the real fat into the mitochondria.

As you can see, if we wish for our cells to keep burning fat, we need to make sure there is as little malonyl-CoA as possible. To keep malonyl-CoA content low we need to stop ACC from creating this compound. Luckily our body has a way of doing just that. There is yet another protein called AMP-Activated Protein Kinase (AMPK). This proteins job is to deactivate ACC. In other words:

AMPK activation = ACC deactivation = less malonyl-CoA = more fat oxidation.
AMPK deactivation = ACC activation = more malonyl-CoA = less fat oxidation.

Great, this is just what we were looking for. Now we are ready to see how leptin affects these enzymes and optimizes fatty acid oxidation.

When skeletal muscle was incubated in a serum with leptin, AMP-activated protein kinase (AMPK) was activated (12,13). When AMPK is activated it inhibits ACC thus reducing malonyl-CoA. This reduction in malonyl-CoA frees CPT to do its thing and transfer long chain fatty acids in to the mitochondria where they can be used to produce ATP. Additionally, chronic leptin administration not only activated AMPK but also increased the amount of AMPK in muscle cells. So you can see this is of great benefit. This also makes sense from a physiological perspective, as leptin is signaling the rest of the body that there is ample fuel stored in your fat cells. This signal lets the muscle know that there is ample fat so it should use fat as its primary energy source.

Leptin’s activation of AMPK and concurrent increase of AMPK concentration also promotes a lean physique through mechanisms other than just short-term usage of fat for fuel. Chronic AMPK activation is also implicated in the mechanisms responsible for several of the adaptations muscles undergo in response to chronic exercise. Specifically, chronic AMPK activation upregulates a protein called nuclear respiratory factor-1 (NRF-1). NRF-1 is one of the primary proteins involved in mitochondrial neobiogenesis (16,18). In other words chronic AMPK activation causes cells to grow more mitochondria, thereby increasing ones oxidative potential. Clearly AMPK is not the only protein involved in mitochondrial biogenesis, but it does play a key role.

This behavior is to be expected. You see when you first start a bout of exercise (as in the first few seconds of the first muscle contraction) there is a sharp increase in demand for ATP. This demand cannot be met by oxidative phosphorylation in the mitochondria. So there is a very temporary but very real energy deficit. As AMP-Activated Protein Kinase's (AMPK) name implies it activated by Adenosine Mono-Phosphate (AMP). More specifically, it’s activated by the AMP/ATP ratio. Or even more simply: AMPK is activated when there is an energy deficit. This temporary deficit activates AMPK, which then promotes NRF-1 and PGC-1 production, leading to mitochondrial biogenesis. The entire process of mitochondrial biogenesis is not yet completely understood, but this is certainly an area of interest and something to keep one’s eye on.

AMPK activation also increases cellular concentration of GLUT4 protein (18). The GLUT family of proteins is responsible for transporting carbohydrates into cells. Activation of AMPK may therefore help lower insulin resistance. AMPK is so important for GLUT regulation that its role cannot be overstated. Mice that have their AMPK artificially deactivated are known as “lazy mice” for a reason—there skeletal muscle cannot maintain a store of glycogen and they become incredibly fatigued with even the slightest exertion (19).

Additionally AMPK activation results in the upregulation of Fatty Acid Translocase (FAT/CD36). This protein is to fat as GLUT is to carbohydrates. Its function is to transport free fatty acids across the cellular membrane where they can be used as fuel (12).

An entire article could easily be written about all of AMPK’s various functions. However, considering this article is about leptin and not AMPK we will have to just leave it the explanation where it stands, as further exploration into AMPK is beyond the scope of this article.

Leptin further enhances metabolism by activating the Krebs (TCA) cycle in muscle, as well as pyruvate-dehydrogenase (PDH). PDH is the bridge linking pyruvate decarboxylation to the citric acid cycle. To my knowledge it is not known at this time if this is a direct effect or an indirect one brought about by increased mitochondrial uncoupling (15). Leptin also appears to promote fat oxidation and increased oxygen utilization by some yet undiscovered mechanisms. Specifically, leptin administration induced a large increase in both fat oxidation and oxygen consumption without effecting glucose utilization, AMPK, or ACC in cardiac muscle (14). So, it appears as though all of the pieces of the puzzle have yet to be uncovered.

Furthermore, leptin enhances fatty acid oxidation through some mechanism related to PPAR-alpha. PPAR-alpha is for the most part the opposite of PPAR-gamma. PPAR-alpha, when activated, causes a host of enzymes to be created that elevate fatty acid oxidation. In in vivo studies, PPAR-alpha seems to be linked to leptin’s effects by a yet to be determined mechanism. Specifically, leptin administration to rats increases PPAR-alpha content as well as CPT; it also lowers intra-cellular TAG stored in the muscles and liver. Additionally leptin lowered the amount of ACC present in said tissues.

Clearly this is a near perfect scenario. Leptin is literally priming the pump for fat oxidation to take place. This link between PPAR-alpha and leptin can be verified by experiments conducted on PPAR-alpha knockout mice. When leptin is administered—even at incredibly high level—to these special mice they fail to respond. No increase in fat oxidation, no weight loss, no decrease in ACC, and no decrease in cellular TAG.

Now that’s much better news isn't it? You can officially stop plotting my assassination now, thank you.

Leptin and the Thyroid

Before we dive in and start discussing leptin’s profound effects on the thyroid system, let me first give a very brief review of the hypothalamus-pituitary-thyroid axis.

That wonderful little control center in your brain, the hypothalamus, releases a protein called Thyrotropin-Releasing Hormone (TRH). TRH wanders over to the pituitary gland and causes it to release another hormone called Thyrotropin or Thyroid Stimulating Hormone, but for the remainder of this article we will simply refer to it as TSH. TSH is then relayed to the thyroid gland where the thyroid gland secretes—you guessed it—thyroid hormone.

With that out of the way, we can now discuss leptin’s effects on the thyroid hormone control system. Before I do however, I would like to caution the reader to pay extra close attention to this section and to read it very carefully. I have no idea why but for some reason leptin and the thyroid system have not been discussed in detail in any bodybuilding literature that I am aware of. The reason that I advise you to pay close attention in this section is that, in my opinion, leptin is not some side line player that has only a small effect on the thyroid. It is my contention that leptin is a key player in this system. It may even be the single most important factor governing thyroid hormone levels in healthy individuals.

First let us discuss leptin’s effects on the hypothalamus. When leptin initiates its signal cascade at the hypothalamus it increases TRH output (20). This increase in TRH should cause a concurrent increase in TSH at the pituitary; it should lead to higher levels of thyroid hormone in the blood stream. The literature confirms this as elevated leptin levels are associated with elevated thyroid hormone levels as well. But guess what: that not at all how it works. Now let’s dive deeper in to this system to see why leptin is such a key player in determining thyroid hormone levels (21).

It is true that leptin causes TRH to be released from the hypothalamus. Where things get strange is leptin’s effects on the pituitary gland. As stated previously, one would think that increased TRH results in increased TSH. But this is not the case when one takes leptin’s role in to account. In actuality, the higher the leptin levels are, the lower the level of TSH. This is confusing, I know; it is true however (22). Normally lower TSH means lower thyroid hormone levels—at least in the long run in healthy people. In the short term however TSH and thyroid hormone operate in a negative feedback loop. When thyroid hormone levels get high it causes TSH to go down. When TSH gets too low thyroid hormone levels drop and TSH goes back up. Thus it was thought that TRH is really the main control since TSH and thyroid hormone levels are constantly in oppositional flux.

Leptin throws a monkey wrench into this supposition, however. Specifically, leptin is directly suppressive to TSH release in the pituitary. In fact, it has even been hypothesized that since the pituitary gland creates leptin of its own this is one avenue through which it lowers its own TSH output.

Leptin’s effects on the thyroid gland itself are also very interesting. When leptin signals at the thyroid gland it causes thyroid hormone to be released (23). As you can see this is a pretty complicated relationship. To reiterate: Leptin is positive at the thyroid gland and hypothalamus but negative at the pituitary. This strange relationship is why leptin is such a key player in the control of thyroid hormone levels. Essentially, leptin somewhat overrides the ‘normal’ control system, controlling and in many ways ultimately determining thyroid hormone levels. To shed some light on this paradox, lets stop looking at in vitro research and examine some in vivo studies to see how this really works.

Normally when in caloric restriction, leptin levels and thyroid hormone levels drop. Supplemental leptin administration, given at a replacement dose, brings thyroid hormone levels back within a normal range (24). In a very interesting study rats were starved at 10% below there maintenance calorie levels and monitored for an extended period. During this time—as you would expect—leptin, T3, and T4 levels were all reduced. The researchers then administered the rats with just enough leptin to get them back to their previous pre-dieting levels. As you would expect, thyroid hormone levels returned to normal.

What is interesting is that in a related study, researchers monitored rats that were given supplemental leptin. In these rats TSH was remarkably reduced yet T3/T4 levels were significantly elevated (22). The only viable explanation is that leptin short-circuits the normal negative feedback-loop between the pituitary and the thyroid gland. Essentially, leptin takes control of the thyroid gland and determines the amount of thyroid hormone released.

The link between TSH and leptin is even stronger than one might imagine. TSH not only signals the thyroid gland to make thyroid hormone, it also signals adipose tissue to make leptin (25). It is very potent I might add. In one study researchers took human adipose tissue from elective surgery patients and incubated it with TSH. TSH powerfully stimulated leptin release comparable to that seen by glucose and insulin. Now, that probably comes as a surprise. It appears leptin and TSH operate in a negative feedback loop similar to TSH and thyroid hormone. There is very strong evidence to support this supposition. TSH and leptin blood levels follow the exact same diurnal rhythm. In fact they are so synchronous that there peak blood levels coincide. So it would seem that this negative feedback loop between the two is very efficient and quite powerful (26).

So at this point I think it’s safe to say that leptin is very important for the regulation of the hypothalamus-pituitary-thyroid axis. Further more, it provides some direct insight as to why leptin levels don’t plummet to next to nothing when one’s calories are reduced. You see in the absence of the “feed signal,” TSH output increases due to the drop in thyroid hormone, which in turn serves as a very potent signal to the adipose to secrete leptin.

I know this was a lot of information to take in at once. I suggest you reread it again as, in your humble author’s opinion, the link between thyroid hormones and leptin cannot be overstated.
Of Things to Come

Well that’s all for now. Take some time and ponder the ramifications of all of this. In the next installment of this series we will examine leptin’s effects on various parts of the brain and nervous system, and how it relates to fat loss. This is where things will really start to become interesting, as much of leptin’s power does not come from interacting with various body tissues. Leptin’s primary source of influence comes from its interaction with the brain and the central nervous system. Leptin’s systemic indirect effects are vitally important to its function. These indirect effects are the reason you get the munchies and the reason you can barely get your ass out of bed in the morning while dieting. So tune in next time for the exciting conclusion. Same Spook channel; Same Spook time.

References:

(1) J Biol Chem 1999 Jun 18;274(25):17541
Novel form of lipolysis induced by leptin.
Wang MY, Lee Y, Unger RH.

(2) Horm Res 2002;58(2):88-93
In vitro effects of leptin on human adipocyte metabolism.
Elimam A, Kamel A, Marcus C.

(3) Am J Physiol Endocrinol Metab 2002 Mar;282(3):E593-600
Fatty acid oxidation and triacylglycerol hydrolysis are enhanced after chronic leptin treatment in rats.
Steinberg GR, Bonen A, Dyck DJ.

(4) Cell Signal 2001 Nov;13(11):827-33
Modulation of the leptin-induced white adipose tissue lipolysis by nitric oxide.
Fruhbeck G, Gomez-Ambrosi J.

(5) FASEB J 2001 Feb;15(2):333-40
Leptin-induced lipolysis opposes the tonic inhibition of endogenous adenosine in white adipocytes.
Fruhbeck G, Gomez-Ambrosi J, Salvador J.

(6) J Clin Invest 1997 Dec 1;100(11):2858-64
Direct effects of leptin on brown and white adipose tissue.
Siegrist-Kaiser CA, Pauli V, Juge-Aubry CE, Boss O, Pernin A, Chin WW, Cusin I, Rohner-Jeanrenaud F, Burger AG, Zapf J, Meier CA.

(7) Int J Obes Relat Metab Disord 2001 Oct;25(10):1465
Effects of leptin on the differentiation and metabolism of human adipocytes.
Aprath-Husmann I, Rohrig K, Gottschling-Zeller H, Skurk T, Scriba D, Birgel M, Hauner H.

(8) Am J Physiol Endocrinol Metab 2002 Jan;282(1):E46-51
Increased hepatic lipogenesis but decreased expression of lipogenic gene in adipose tissue in human obesity.
Diraison F, Dusserre E, Vidal H, Sothier M, Beylot M.

(9) Biochem Biophys Res Commun 1998 May 29;246(3):660-7
Leptin regulation of peroxisome proliferator-activated receptor-gamma, tumor necrosis factor, and uncoupling protein-2 expression in adipose tissues.
Qian H, Hausman GJ, Compton MM, Azain MJ, Hartzell DL, Baile CA.

(10) Ann N Y Acad Sci 2002 Jun;967:217-35
Regulation of fat metabolism in skeletal muscle.
Jeukendrup AE.

(11) Am J Physiol Endocrinol Metab 2002 Jul;283(1):E66-72
Exercise training increases lipid metabolism gene expression in human skeletal muscle.
Tunstall RJ, Mehan KA, Wadley GD, Collier GR, Bonen A, Hargreaves M, Cameron-Smith D.

(12) Biochem Soc Trans 2003 Feb;31(Pt 1):196-201
Role of AMP-activated protein kinase in leptin-induced fatty acid oxidation in muscle.
Minokoshi Y, Kahn BB.

(13) Am J Physiol Endocrinol Metab 2003 Mar;284(3):E648-54
AMPK expression and phosphorylation are increased in rodent muscle after chronic leptin treatment.
Steinberg GR, Rush JW, Dyck DJ.

(14) Biol Chem 2002 Aug 16;277(33):29424
Leptin activates cardiac fatty acid oxidation independent of changes in the AMP-activated protein kinase-acetyl-CoA carboxylase-malonyl-CoA axis.
Atkinson LL, Fischer MA, Lopaschuk GD.

(15) Front Biosci 2001 Jan 1;6:D90-7
The response of skeletal muscle to leptin.
Ceddia RB, William WN Jr, Curi R.

(16) Proc Natl Acad Sci U S A 2002 Dec 10;99(25):15983-7
AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation.
Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI.

(17) Am J Physiol Endocrinol Metab 2001 Dec;281(6):E1340-6
Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis.
Bergeron R, Ren JM, Cadman KS, Moore IK, Perret P, Pypaert M, Young LH, Semenkovich CF, Shulman GI.

(18) Am J Physiol Endocrinol Metab 2002 May;282(5):E1008-13
Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca(2+).
Ojuka EO, Jones TE, Nolte LA, Chen M, Wamhoff BR, Sturek M, Holloszy JO.

(19) Biochem Soc Trans 2003 Feb;31(Pt 1):236-41
Selective suppression of AMP-activated protein kinase in skeletal muscle: update on 'lazy mice'.
Mu J, Barton ER, Birnbaum MJ.

(20) J Clin Invest 2001 Jan;107(1):111-20
Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling.
Harris M, Aschkenasi C, Elias CF, Chandrankunnel A, Nillni EA, Bjoorbaek C, Elmquist JK, Flier JS, Hollenberg AN.

(21) Clin Endocrinol Metab 2002 May;87(5):2391
Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones.
Rosenbaum M, Murphy EM, Heymsfield SB, Matthews DE, Leibel RL.

(22) J Endocrinol 2002 Jul;174(1):121
The role of leptin in the regulation of TSH secretion in the fed state: in vivo and in vitro studies.
Ortiga-Carvalho TM, Oliveira KJ, Soares BA, Pazos-Moura CC.

(23) Int J Mol Med 2002 Jan;9(1):31
Rat thyroid gland expresses the long form of leptin receptors, and leptin stimulates the function of the gland in euthyroid non-fasted animals.
Nowak KW, Kaczmarek P, Mackowiak P, Ziolkowska A, Albertin G, Ginda WJ, Trejter M, Nussdorfer GG, Malendowicz LK.

(24) Clin Endocrinol Metab 2002 May;87(5):2391
Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones.
Rosenbaum M, Murphy EM, Heymsfield SB, Matthews DE, Leibel RL.

(25) J Endocrinol 2003 Jan;176(1):7-12
TSH stimulates leptin secretion by a direct effect on adipocytes.
Menendez C, Baldelli R, Camina JP, Escudero B, Peino R, Dieguez C, Casanueva FF.

(26) J Clin Endocrinol Metab 2001 Jul;86(7):3284
Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling.
Harris M, Aschkenasi C, Elias CF, Chandrankunnel A, Nillni EA, Bjoorbaek C, Elmquist JK, Flier JS, Hollenberg AN.