* * by]
* * This is far from the detailed review you will find in the original Leptin series featured in Mind and Muscle Magazine, but I will try to summarize what I feel is the important information concerning this cool new hormone. If you have already taken the time to read the complete series, I probably won’t present too much you don’t already know. If you haven’t read the series, I highly recommend you do. Either way, this should be a good read as a basic summary.
*
* * 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]
* * 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]
* * 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]
* * 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. 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]
* * 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.
Melanotan 2 users are familiar with the appetite reduction post injection.* Fasting suppresses thyroid function and melanocortins have a role in regulation.* What about when you "hit the wall" and dose MT-2?*
MT-II Reduced Both Visceral and Subcutaneous Adiposity
MC3R & MC4R lie downstream of leptin receptor activation which Melanotan 2 (a-MSH) evokes a leptin-like anorectic (loss of appetite) response that mediates body fat and weight loss
Discussion
Weight loss through chronic administration of the melanocortin
receptor agonist MT-II is readily achieved in rodents
(Obici et al., 2001; Pierroz et al., 2002; Choi et al., 2003a,b;
Seeley et al., 2005). The current findings support existing
data and extend the literature in many ways. The data corroborate
previous studies in that MT-II elicits weight loss
most effectively in DIO rodents (Hwa et al., 2001; Cettour-
Rose and Rohner-Jeanrenaud, 2002; Pierroz et al., 2002;
Seeley et al., 2005). In contrast, rodents raised on low-fat
diets are less sensitive to peripheral MT-II (Cettour-Rose and
Rohner-Jeanrenaud, 2002; Pierroz et al., 2002). One of the
primary mechanisms for MT-II-induced weight loss is reduced
food intake. A critical point in understanding the
mechanism for weight loss maintenance during chronic
MT-II delivery is that once a new adiposity level is reached
and plasma leptin has fallen, food intake increases to reflect
the reduced inhibitory signaling of leptin on CNS circuits
that regulate food intake. Specifically, AgRP neurons are
targets for leptin, and when leptin levels are low, the inhibitory
effect of leptin on AgRP is reduced, which allows AgRP
to be more effective in increasing intake. In the present
study, high-fat-fed rodents given MT-II reduced food intake
for a period of time shorter than the length of delivery by the
mini-pump. At the time-point during which food intake increases,
weight loss had already reached its peak; therefore,
the increase in food intake that followed, while the rodents
maintained a lowered body weight, is a behavioral response
that reflects a new lowered level of leptin signaling, rather
than a waning of the anorectic effect of MT-II. This effect of
MT-II and other peptides, such as amylin, on food intake has
been reported by others (Hamilton and Doods, 2002; Raposinho
et al., 2003; Seeley et al., 2005; Roth et al., 2006). To
summarize, MT-II reduces food intake until lowered leptin
levels are attained, and once a new body fat level is reached,
food intake returns to normal (Seeley et al., 2005). Likewise,
if adipose stores are low, as in the rodents on the low-fat
diets, MT-II is relatively ineffective in reducing food intake
and lowering body fat.
Melatonin plus physical exercise are highly neuroprotective.
Spain 2012
Alzheimer's disease (AD) is a devastating age-related neurodegenerative disease with no specific treatment at present. Several healthy lifestyle options and over-the-counter supplements that it has been suggested delay the onset of the disease are in an experimental phase, but it is unclear whether they will have any therapeutic value against AD. We assayed physical exercise and melatonin in aged from 6 to 12 months, therefore from moderate to advanced phases of AD pathology. Melatonin was effective against the immunosenescence and voluntary physical exercise protected against psychological symptoms of dementia such as anxiety. Both treatments protected against cognitive impairment, brain oxidative stress, and a decrease in mitochondrial DNA (mtDNA). Interestingly, only the combined treatment of physical exercise plus melatonin was effective against the decrease of mitochondrial complexes. Therefore, melatonin plus physical exercise may exert complementary or synergistic effect against a range of disturbances present in AD.
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