Leptin, the BASICS

[natron]

Leptin
With all this new talk about leptin, I thought it appropriate to open a discussion about this wonderful hormone. Yes, I said hormone. Okay, I know what you’re thinking. Fat cells aren’t endocrine. Well, are you in for a surprise. With a better understanding of leptin you’ll soon realize adipose are more than just a storage site for pizza and nachos… much more. In fact, to a bodybuilder leptin is probably as important as insulin or testosterone! Got your attention yet?
Leptin, discovered in 1994, comes from the Greek leptos (meaning thin). It is a product of the ob gene and is expressed primarily in white adipose tissue. Okay, enough science (for now). Increased leptin signalling leads to decreased food intake, increased energy expenditure, and increased thermogenesis. All this leads to weightloss!
The real problem with leptin comes when you ‘hit the wall’ while dieting. Everyone knows what I’m talking about here. At first, you start melting off the pounds with hardly any effort at all. Then, things get harder. It seems your cardio has to double and you’re eating nothing but lettuce and tuna but you’re barely making any progress at all. It’s like your body is fighting you and every calorie is an all-out war. Blame leptin! Fasting results in reduction of circulating leptin levels. Since leptin has a role in hunger and fat storage, less leptin results in being more hungry and retaining more fat. I’m assuming everyone who’s tried a diet has experienced both of these occurrences.
The effects of leptin are mediated both periphery and centrally. Peripherally, leptin directly stimulates energy expenditure. Centrally, leptin acts on the hypothalamus to affect metabolism and eating behavior. I’ll elaborate on this later.
Although this is my major concern, I feel obligated to mention that the effects of leptin are not limited to weight management. Leptin is also involved in regulation of blood pressure, angiogenesis, brain and bone development and wound healing. It also plays various roles in the immune system. Nevertheless, I will concentrate on its role in energy homeostasis for the majority of this summary; because that’s where my interests lay.
Leptin: The Science

So what’s the science that started this whole leptin craze? First, it was shown that animals that lacked the gene to make leptin (ob/ob mice), and mice that lacked the receptor that leptin works through (db/db mice) had decreased energy expenditure, morbid obesity and insulin resistance. It was soon discovered that administering leptin either I.V. or I.P. to ob/ob mice decreased food intake and increased energy expenditure. This proved two things: 1) leptin is involved in eating behaviour and energy expenditure; and 2) these outcomes at least partially result from effects of leptin on the brain.
Cool Facts

Leptin synthesis is greater in subcutaneous fat than in visceral fat. Since women have more subcutaneous fat, this is one reason they have higher leptin levels… I wonder if that’s why they eat less? Hmm…..
Testosterone may increase leptin sensitivity (but possibly lowers expression). The net effect appears to be positive and this is a possible explanation for the beneficial effects of androgen therapy on fat loss in obese men. So keep poppin’ that trib while you’re cutting.
Control of Leptin Levels

Leptin production is controlled by a variety of factors on the transcriptional level. Translation: certain things make you produce more and certain things reduce production. Leptin is increased by insulin, acute infection, and proinflammatory cytokines. In contrast, cold exposure, adrenergic stimulation, growth hormone, thyroid hormone, melatonin, testosterone, and smoking decrease leptin. Yet another reason smoking is bad for your health. There is also evidence that Vitamin E (400-1200IU/day), Zinc (25-50mg/day) and nicotine increase leptin. The LeptoGen supplements are designed with the purpose of increasing leptin expression.
Is Leptin the Cure for Obesity?

So does this mean that leptin is a miracle cure for obesity? Sadly, no. The majority of obese individuals do not have problems in the leptin gene. Instead, the problem resides in leptin-resistance. In fact, most obese individuals actually have increased leptin levels. It is still not known at what steps of the pathway leptin resistance occurs.
In mice, leptin deficiency is associated with increases appetite, reduced metabolic rate and relative activity. This leads to a phenotype with a variety of endocrine abnormalities and infertility. Leptin replacement reversed most of these abnormalities. In humans, leptin replacement in leptin-deficient humans returns appetite to normal with associated weightloss.
So what happens in obese individuals? We know that administering more leptin does nothing to fix the problem. Does this mean leptin has no possible benefit in weightloss? Actually, no. In the obese, leptin levels are actually elevated. However, the problem lies in that these individuals are leptin resistant. This means their bodies don’t respond to leptin normally, or that greater amounts of leptin are required to illicit a response. Possible mechanisms of resistance include defective brain transport and impaired leptin signalling. In the obese, leptin levels are higher, but transport into the brain (or degradation once there) seems to be a major problem. Receptor problems and problems in leptin signalling are also definite possibilities. Still don’t think obesity has a genetic component?
Either way, if you’re reading this ‘article’ then this probably doesn’t apply to you. Your primary concern would most likely be the drop in leptin associated with dieting. Resistance is probably not an issue. For you, strategies to increase leptin during times of caloric restriction (ie. cutting) would be highly beneficial.
Peripheral Effects

Leptin directly affects energy metabolism in the periphery. Leptin activates AMPK (and increases expression) in skeletal muscle, thus inhibiting ACC. This favors fat burning over storage. AMPK is also implemented in NRF-1 activation, thereby increasing mitochondrial proliferation. More mitochondria means an increased ability to burn fat. In addition, AMPK increases GLUT expression, leading to increased insulin sensitivity (to see why this is good, read Insulin: Friend and/or Foe). Two other important enzymes regulated by leptin are FAS and SREBP. Leptin decreases their expression, thus lessening the ability of the fat cell to store fat. As a note, some effects of leptin appear to be mediated via PPAR alpha (a transcription factor I have a particular interest in). However, the majority of the effects seem to be mediated via the central nervous system.
Central Effects

It seems the greatest effects of leptin are on your noggin… I mean, your head. This is apparent from studies showing leptin had no effect when sympathetic output was prevented. Having limited experience with brain physiology, I can honestly say I’m often reluctant to admit its importance. Maybe it’s because I associate it to psychology (lets just say I’m not a fan). Nevertheless, we are talking brain physiology here… not psychology.
The effects of leptin on the brain are thought to result from transcriptional control in the hypothalamus. For the science geeks, this is mediated through the leptin receptor (Ob-Rb) and the JAK-STAT pathway. Leptin is known to decrease expression of orexigenic (read “makes me hungry”) peptides such as NPY and increasing anorexigenic (think anorexic) peptides such as alpha-MSH, CRH and CART. Sympathetic output and temperature regulation are also affected.
When dieting, especially when severely limiting carbohydrate intake, leptin levels drop. This is due to reduced glucose uptake into adipose negatively affecting leptin synthesis. In carbohydrate restrictive diets, leptin levels drop even lower because of the beneficial effect of insulin on leptin levels. So what we have is a situation where leptin and insulin are low. It doesn’t take Einstein to figure out that this is counterproductive for both fat-loss and muscle gain. Still, there’s even more to it than that. Low leptin levels (and also low insulin) have negative effects on the hypothalamus. In the ARC region of the hypothalamus, this results in increased NPY and AgRP and also to decreased POMC and CART. The effect of this (both directly and indirectly via the PVN) is to increase food intake (read carbohydrate cravings) and to decrease sympathetic output. Since sympathetic output increases energy expenditure, the overall effect is to increase your intake of calories and decrease calories burned. Still, it doesn’t stop there. The decrease in POMC and CART (and again the PVN) also have effects on the hypophysis. The end result of this is increased cortisol, decreased thyroid hormone, decreased sex steroids (read less testosterone), and less growth hormone release. Wow, that’s exactly what you DON’T want. Translation: starvation causes your body to conserve energy and increase your appetite. If you’ve read the leptin series you’ll have a different understanding of the mechanism. Understandably, it’s a much more complicated process than I’ve presented and much is still unknown. Still, I think the above mechanism is relatively accurate.
So, if we could maintain leptin levels (and keep insulin levels in check – see insulin post) while dieting, wouldn’t that be a miracle? Enter LeptiGen.

What Else Can you Do?

This is where the idea of a cheat meal (or refeed) came about. Obviously, this is only of significance after a period of dieting has caused a decrease in leptin levels. Since glucose is the major stimulant for leptin production, it’s no wonder this is the most important ingredient in a well-planned refeed. Par Deus recommends calories on the refeed day(s) to be 20-50% above maintenance. The higher the calories, the shorter the refeed. Put simply, you want to shovel in carbs, and simple carbs at that. Good choices are glucose, Maltodextrin and starches. Fructose appears to be useless. Due to the effects of insulin on leptin production, the higher the GI (or, more correctly, Insulin Index) the better.
In a less strict diet, there are alternative ways to ensure sufficient leptin. Believe me or not, spiking your insulin levels a couple of times earlier in the day (not just post workout) could actually help in weightloss. However, I wouldn’t recommend doing this more than twice daily (excluding post-workout). And, as I’ve explained in my insulin post, DO NOT spike your insulin late in the evening unless it’s post-workout.
Leptin is also under control of your body’s daily rhythms. It is lowest in the morning and highest late evening. Since levels increase after eating, it is possible that eating during the night (ie. wake up and eat) could have benefits. However, this has not been studied in depth so I’ll leave this to your own discretion… but a protein shake in the middle of the night is a good idea either way.
Bottom Line

Leptin…

• Decreases energy intake;
• Increases lipolysis (breaking down of fat);
• Decreases lipogenesis (building fat);
• Decreases appetite; and
• Increases insulin sensitivity.

All this results in beneficial effects to muscle gain and fat loss.

[natron]

wonderful articles written by Caled Stone aka Par Deus

http://www.mindandmuscle.net/articles/CalebStone/leptin

http://www.mindandmuscle.net/article...bStone/leptin2

http://www.mindandmuscle.net/article..._stone/leptin3

http://www.mindandmuscle.net/articles/spook/leptin

http://www.mindandmuscle.net/articles/spook/leptin_5


They go in concession, it's alot of reading/science, but a great place to learn, I hope all you will read these, they will help you understand the physiology of fat loss and nutrient partitioning to a much greater degree.

ENJOY!!!

[Tatyana]

There are also a few other related hormones that regulate fat besides leptin, and the obvious ghrelin.

Some are not that well elucidated, but include resistin, adiponectin and (oh I can't remember the name all that well), something like PPY-36.

Jeebus, I just found another.
ACRP30, a new hormone controlling fat and glucose metabolism

Tsu-Shuen Tsaoa, Harvey F. Lodisha, b, , and Joachim Fruebisc
a Whitehead Institute for Biomedical Research, Cambridge, MA 02142-1479, USA
b Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
c Genset Corporation, 10665 Sorrento Valley Rd., San Diego, CA 92121-1609, USA



Received 13 September 2001;
accepted 11 October 2001.
Available online 18 March 2002.

Abstract

Adipocyte complement-related protein of 30 kDa (ACRP30) is a secreted serum protein expressed exclusively in differentiated adipocytes. Recent studies have indicated that its expression and serum levels are reduced in humans and animals with obesity and insulin resistance. Metabolic studies have demonstrated a role for ACRP30 in the regulation of glucose and lipid homeostasis. This review will describe the current literature on the biochemistry of ACRP30 and its physiological functions. We will also discuss issues that are relevant to the directions of future research.



Author Keywords: ACRP30 (adipocyte complement-related protein of 30 kDa); AdipoQ; Adiponectin; Obesity; Diabetes; Insulin resistance; Lipid metabolism; Glucose metabolism

[natron]

a few others Tat?

fuck, there is alot! with new ones popping up quite frequently.

It does look like alot of these hormones are regulated by leptin though

[figurebre]

so, these articles are far above my head but I was thinking...
They found that the leptin levels were better after refeeds.
So, would carb or "calorie" cycling have a similar effect, i wonder?
just thinking outloud here.

[natron]

so, these articles are far above my head but I was thinking...
They found that the leptin levels were better after refeeds.
So, would carb or "calorie" cycling have a similar effect, i wonder?
just thinking outloud here.

This is what re-feed are all about Bre, not calorie cycling though, it has to be carb cycling.

@ 7-8% bodyfat I eat 2-3 boxes of kids cereals every 6-7 days, and kee p getting leaner. I've benn doing this for about 2-3 ears now, I love it. The leaner you get, the more often you need re-feeds.

I'll shoot you the approach I use, then I'll post it up in a seperate thread. Hope all is well, and if you dont mind ,keep you other thread here updated, if you can of course, for science!!!!

[natron]

Interseting little read regarding leptin

Neuroendocrinology. 2009 Nov 18. [Epub ahead of print]
Melanocortins Mimic the Effects of Leptin to Restore Reproductive Function in Lean Hypogonadotropic Ewes.

Backholer K, Bowden M, Gamber K, Bjørbæk C, Iqbal J, Clarke IJ.
Department of Physiology, Monash University, Monash, Vic., Australia.
Background/Aims: Leptin restores gonadotropic function in lean hypogonadotropic animals by an unknown mechanism. We aimed to test the hypothesis that restoration of gonadotropic function is a result of an upregulation of central acetylated melanocortin production. Methods and Results: Lean ovariectomised (OVX) ewes received intracerebroventricular (i.c.v.) infusions of leptin (or vehicle) for 3 days, which upregulated proopiomelanocortin (POMC) mRNA and restored pulsatile luteinizing hormone (LH) secretion. A melanocortin agonist (MTII), but not naloxone treatment, reinstated pulsatile LH secretion in lean OVX ewes. We treated (i.c.v.) lean OVX ewes with leptin (or vehicle) and measured peptide levels and post-translational modification in the arcuate nucleus (ARC). Levels of beta-endorphin (beta-END) were lower in lean animals, with no effect of leptin treatment. Desacetyl-alpha-MSH was the predominant form of alpha-melanocyte-stimulating hormone (alpha-MSH) in the ARC and levels were similar in all groups. In another group of lean and normal-weight OVX ewes, we measured the different forms of alpha-MSH in ARC, hypothalamus (ARC-removed) and the preoptic area (POA). Acetylated alpha-MSH levels were lower in lean animals in the terminal beds of the hypothalamus and POA but not the ARC. Conclusions: Leptin corrects the hypogonadotropic state in the lean condition by upregulation of POMC gene expression, and may increase transport and acetylation of melanocortins to target cells in the brain. Melanocortin treatment restores LH secretion in lean animals. Copyright © 2009 S. Karger AG, Basel.

PMID: 19923792 [PubMed - as supplied by publisher]

[natron]

Metabolism. 2009 Sep;58(9):1297-305. Epub 2009 Jun 18.
A herbal extract with acetyl-coenzyme A carboxylase inhibitory activity and its potential for treating metabolic syndrome.

Chen CH, Chang MY, Lin YS, Lin DG, Chen SW, Chao PM.
Food Industry Research Development Institute, Hsinchu 300, Taiwan.
Acetyl-coenzyme A carboxylase (ACC) plays a crucial role in fatty acid metabolism, and its inhibition is an effective approach for treating metabolic syndrome. Partially purified ACC from rat liver was used to screen herbs commonly used in Taiwanese folk medicine for ACC inhibitory effects. An ethanol extract of Polygonum hypoleucum Ohwi (EP), the Taiwan tuber fleece flower, was found to have the highest inhibitory activity (half-maximal inhibitory concentration = 30 microg/mL). We then tested the physiologic effects of EP using high-fat (HF) diet-fed C57BL/6J mice. After 4 weeks, body weight and levels of blood glucose, insulin, triacylglycerol, total cholesterol, and leptin were significantly reduced (P < .05) in mice fed a 3% EP-containing HF diet. The EP also improved the glucose tolerance and insulin sensitivity of HF diet-fed mice. In addition, EP at concentrations of 0.0725 and 0.145 mg/mL (2.5- and 5-fold higher than the half-maximal inhibitory concentration) was also effective in decreasing ACC and fatty acid synthase activity and the triacylglycerol content of HepG2 cells incubated in high-glucose (30 mmol/L) medium. These results show that EP, acting by inhibiting ACC activity, is effective in alleviating the symptoms associated with metabolic disease.

PMID: 19500808 [PubMed - indexed for MEDLINE]

[natron]

Clin Cancer Res. 2009 May 1;15(9):3068-75. Epub 2009 Apr 14.
Supplementation with branched-chain amino acids inhibits azoxymethane-induced colonic preneoplastic lesions in male C57BL/KsJ-db/db mice.

Shimizu M, Shirakami Y, Iwasa J, Shiraki M, Yasuda Y, Hata K, Hirose Y, Tsurumi H, Tanaka T, Moriwaki H.
Department of Medicine and Tumor Pathology, Gifu University Graduate School of Medicine, Japan. [email protected]
PURPOSE: Obesity and related metabolic abnormalities, including insulin resistance and activation of the insulin-like growth factor (IGF)/IGF-I receptor (IGF-IR) axis, are risk factors for colon cancer. Supplementation with branched-chain amino acids (BCAA) reduces the risk of liver cancer in cirrhotic patients who are obese, and this has been associated with an improvement of insulin resistance. The present study examined the effects of BCAA on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice that were obese and had hyperinsulinemia. EXPERIMENTAL DESIGN: Male db/db mice were given 4 weekly s.c. injections of AOM (15 mg/kg of body weight) and then they were fed a diet containing 3.0% BCAA or casein, a nitrogenc content-matched control diet, for 7 weeks. RESULTS: Feeding with BCAA caused a significant reduction in the number of total aberrant crypt foci and beta-catenin accumulated crypts, both of which are premalignant lesions of the colon, compared with the control diet-fed groups. BCAA supplementation caused a marked decrease in the expression of IGF-IR, the phosphorylated form of IGF-IR, phosphorylated glycogen synthase kinase 3beta, phosphorylated Akt, and cyclooxygenase-2 proteins on the colonic mucosa of AOM-treated mice. The serum levels of insulin, IGF-I, IGF-II, triglyceride, total cholesterol, and leptin were also decreased by supplementation with BCAA. CONCLUSION: BCAA supplementation in diet improves insulin resistance and inhibits the activation of the IGF/IGF-IR axis, thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model that was also associated with hyperlipidemia and hyperinsulinemia. BCAA, therefore, may be a useful chemoprevention modality for colon cancer in obese people.

PMID: 19366832 [PubMed - indexed for MEDLINE]

[natron]

anti histamines and the potential to alter serum leptin levels to control appetite

Effect of cyproheptadine on serum leptin levels

JournalAdvances in Therapy PublisherSpringer Healthcare Communications ISSN0741-238X (Print) 1865-8652 (Online) IssueVolume 22, Number 5 / September, 2005 DOI10.1007/BF02849860 Pages424-428 Subject CollectionMedicine SpringerLink DateTuesday, March 11, 2008 Add to marked items
Add to shopping cart
Add to saved items
Permissions & Reprints
Recommend this article

PDF (243.2 KB)Free Preview

Effect of cyproheptadine on serum leptin levels
Ömer Çalka1 , Ahmet Metin1, Haluk Dülger1 and Reha Erkoç1
(1) Dermatoloji AD, YYU Tip Fakultesi Arastirma Hastanesi, 65200 Van, Turkey Abstract Leptin is a 167 amino acid protein encoded by the obesity gene that is synthesized in adipose tissue and interacts with receptors in the hypothalamus linked to the regulation of appetite and metabolism. It is known to suppress appetite and increase energy expenditure. Cyproheptadine is a piperidine antihistamine that increases appetite through its antiserotonergic effect on 5-HT2 receptors in the brain. Although both leptin and cyproheptadine are effective in controlling appetite, their interaction has not been addressed in clinical studies. This study evaluated serum leptin concentrations in patients who received cyproheptadine to treat a variety of disorders. Sixteen patients aged 7 to 71 years (mean, 26.25 years) were given cyproheptadine 2 to 6 mg/day for a minimum of 7 days. Body weight was measured and blood samples were obtained at baseline and after 1 week of treatment. Serum leptin levels were determined by leptin radioimmunoassay. The mean body weight at baseline (52.59 kg) did not differ significantly from that at 1 week after treatment (52.84 kg; P > .05), but the mean leptin level after 1 week of treatment with cyproheptadine (3.14 ng/mL) was 14.2% higher than that at baseline (2.75 ng/mL; P < .05). This increase may suggest that both leptin and cyproheptadine may affect appetite via similar receptors and that cyproheptadine does not impair leptin activity through these receptors. Further study will be necessary to clarify this relationship.

[natron]

http://www.ebmonline.org/cgi/content/full/228/10/1106

[GirlyMuscle]

I just want to thank you Natron for the original post. I alwasy skip the scientific articles because I'm not a scientist and I can't make heads or tails of anything they say. Your explanation was very good for someone like me. Enough to explain the whys in a way I can understand.

Now...what's LeptiGen and what is it supposed to do?

[natron]

I just want to thank you Natron for the original post. I alwasy skip the scientific articles because I'm not a scientist and I can't make heads or tails of anything they say. Your explanation was very good for someone like me. Enough to explain the whys in a way I can understand.

Now...what's LeptiGen and what is it supposed to do?

LeptiGen is a product formulated by Avant Labs, they have a few versions dependant on where your at, a athlete in the middle of prep needs a different product than a typical fatty looking to lose weight, for example.

Basically, the product is designed to promote the FED state in order to keep hormones from regulating themselves and bringing weigh loss, or weight gain to a halt.