Leptin and Weight Loss:
The Hormonal Key to Fat Reduction and Heart Health
By Kimberly Pryor
Leptin is a relative newcomer on the hormonal playing field. It wasn’t discovered until 1994, but it’s one of the most interesting hormones for anyone trying to lose weight. Although it often takes back burner to insulin in discussions about weight loss, research is emerging that it is equally important in regulating proper body weight and that it may be the reason why people on diets experience “rebound” weight gain.
Leptin is synthesized and secreted primarily by adipocytes (fat cells). It is present in blood serum in direct proportion to the amount of adipose (fat) tissue and as fat cells become enlarged in obesity, they secrete more leptin. This important hormone communicates with the central nervous system to regulate energy intake and energy stores in the body so that the hypothalamus can efficiently maintain a stable body weight.
Leptin receptors are present in tissues throughout the body, suggesting that it can have direct effects on other aspects of health. Leptin helps regulate immunity1, maintain healthy blood pressure levels2, and support cognitive function3. In addition, women with premenstrual syndrome have been found to have overly high levels of this hormone4 as do individuals with hypothyroidism.5 High leptin levels correlate with left ventricular hypertrophy, a major risk factor for congestive heart failure6, and leptin levels are a significant predictor of fibrinogen7, a clotting factor and major risk factor for heart disease.
Clearly, leptin is of interest in a wide range of conditions, and may be one of the most important hormones in the human body.
At first glance, leptin can seem like a confusing and contradictory hormone. Leptin suppresses food intake8 and increases thermogenesis9 and metabolic rate.10 Evidence also exists that leptin can mimic some of insulin’s actions. Accordingly, leptin increases glucose uptake in skeletal muscle and brown adipose tissue in vivo11-12, and normalizes blood glucose levels in diabetic rats.13
Consequently, one would think that it would be desirable to increase leptin levels.
However, in most overweight people, leptin levels are actually excessively high due to leptin resistance, a process similar to the concept of insulin resistance.
To understand why this is so, we must look at the way a normal weight body is designed to communicate. The process begins when the brain notes the amount of leptin secreted by fat cells. If the brain determines these leptin levels are normal, it shuts off the signal to store extra calories as fat. The body no longer feels like eating because the brain, with the help of leptin, has given the full signal.
When our hunter/gatherer ancestors experienced decreased food supply, calories stored as fat were broken down and used as fuel. This caused leptin levels to decline and metabolism to decrease to adjust to the decreased food supply. When food supply once again increased, so too did leptin levels. Once the hunter/gatherer humans had replenished their reserves, leptin signaled our ancestors to stop eating.
In today’s society, however, food surrounds us and overeating is common. This disrupts the hormonal signals in our bodies. Eventually leptin receptors become desensitized to leptin’s effects. Once a person becomes leptin resistant, the body has a difficult time transporting leptin past the blood brain barrier to the hypothalamus where it is needed to send satiety signals. Even though blood levels of leptin may be excessively high, brain levels are insufficiently low, resulting in food cravings and weight gain. The brain believes the body is in a famished state and tells it to continue to store fat.
In addition, circadian changes of blood leptin level in non-obese people are more significant than these changes in obese people.14 Because leptin inhibits cortisol, if leptin is highest first thing in the morning (when it should be at its lowest levels), it may inhibit cortisol production at a time when cortisol is needed to feel awake and energized.15
Leptin levels tend to rise as we age, one possible reason why individuals under 30 have an easier time losing weight gained than people who are in their 40s and beyond. Furthermore, estrogen deficiency is related to a rise in leptin, offering a potential explanation for why women gain weight more easily after menopause.16
Leptin and Weight Gain
Leptin is a powerful appetite suppressant—we even have leptin receptors on our taste buds, which help to regulate cravings for sweet foods.17 Ironically, as previously stated, leptin levels are excessively high in obese people and this leptin resistance is associated with weight gain. When a person becomes leptin resistant, leptin receptors throughout the body, including those on the taste buds and in the brain, aren’t getting the message that food consumption should stop. Research indicates that lowering leptin levels in overweight people can restore this malfunctioning leptin system and trigger weight loss.
In one study, researchers investigated leptin changes in 26 obese adolescents (12 boys and 14 girls) during and after a 9-month weight-reduction program in a specialized institution with lifestyle education, moderate energy restriction and regular physical activity, followed by a 4-month period at home. After 9 months, the adolescents had lost 19 percent body weight and 41.3 percent fat mass. At the same time, plasma leptin concentration was 70 percent lower. After the subjects had returned home for four months, leptin rose to an intermediate level in the 10 adolescents who had regained some of the body weight they had lost.18
In another study of 23 obese patients (8 males, 15 females) who had undergone laparoscopic adjustable gastric banding surgery to achieve weight loss, their body mass index was reduced by 33 percent while the levels of circulating leptin declined by 52 percent. Leptin levels strongly and persistently correlated with body mass index (BMI) during the study and, compared to insulin, leptin showed the most significant and persistent correlation with BMI.19
Leptin research also has shed some light on why people who diet often gain back the unwanted pounds. Researchers studied 154 overweight Japanese men who were enrolled in a 24-month weight loss program. Rebound weight gain was defined as significant weight loss at 6 months but subsequent body weight regain during the next 18 months.
The results showed that 37 subjects maintained weight loss during 24 months, whereas 36 subjects had rebound weight gain. Subjects who maintained weight loss had at entry several things in common: significantly lower fat mass, lower leptin levels and lower plasma norepinephrine levels compared to those with rebound weight gain. In fact, body fat mass, leptin levels, and norepinephrine levels at the study’s start predicted the degree of change in body weight during the 24-month study period.
Subjects with rebound weight gain had a significantly higher polymorphism (or abnormality) in a certain gene that was linked to significantly higher levels of plasma leptin, norepinephrine, and body fat mass levels and a greater waist-to-hip ratio both at entry and throughout the study.20
Leptin and Cardiovascular Health
Leptin may govern other areas of our health. One of its most important responsibilities could be that of supporting the cardiovascular system. Studies have linked high leptin levels to an increased risk of cardiovascular disease and leptin receptors are expressed in coronary arteries21 and in the heart.6 In obese subjects, leptin levels are the most significant predictor of higher levels of fibrinogen, a clotting factor considered to be one of the most important risk factors for heart disease.7 In obese patients with left ventricular hypertrophy, a risk factor for congestive heart failure, the higher the leptin levels the greater the left ventricular mass.6
Another factor involved in leptin’s heart disease promoting role is its ability to upregulate endothelin-1 production. Endothelin-1 is one of several peptides derived from the vascular endothelium and is a potent vasoconstrictor. By constricting blood vessels, endothelin-1 could have a role to play in the development of cardiovascular disease, and by upregulating endothelin-1, leptin could be involved in obesity-related heart disease.22
High leptin levels also are associated with hypertension.23
Leptin-Controlling Lifestyle Factors
Sufficient sleep is one of the most important factors in controlling leptin. Like melatonin, leptin is secreted in the highest amounts at night, and in human subjects deprived of sleep the timing of the leptin secretion peak occurred earlier, disrupting hormonal profiles and encouraging weight gain.24
Avoiding sugar and bad fats and instituting a daily exercise regimen also can help to a certain extent. However, research has shown that when engaged in a weight loss program, obese subjects aren’t as efficient at reducing leptin levels as normal weight subjects. When morbidly obese and lean females went on a 24-hour fast, serum leptin levels decreased by only 20 percent in obese subjects compared to 62 percent in lean subjects, even though the obese subjects did lose some of their body mass index.25
While lifestyle factors are important in controlling leptin levels, to achieve weight loss, individuals may need to turn to leptin-lowering supplements. Scientists have explored the possibility that a number of nutritional supplements can reduce levels of this weight-controlling hormone.
As mentioned above, melatonin plays a key role in regulating leptin. Both of these hormones work together to regulate body mass and energy balance. In addition, melatonin receptors were recently found in adipocytes, where leptin is synthesized. Furthermore, pineal melatonin secretion declines with aging, whereas visceral fat, plasma insulin, and plasma leptin tend to increase.26
A number of studies show that melatonin supplementation can lower leptin levels and that the pineal gland helps control leptin release. In one study, giving melatonin to rats with pineal glands resulted in significant decreases in leptin levels compared to the control group. In rats without pineal glands—the gland where melatonin is synthesized—serum leptin levels were significantly elevated. Melatonin treatment of the rats without pineal glands resulted in suppressed leptin secretion.27
In another study, daily melatonin administration in middle-aged rats reduced body weight, intra-abdominal obesity, and plasma leptin and insulin levels to youthful levels, regardless of how much food the animals consumed. Compared to controls, 12 weeks’ of melatonin supplementation decreased body weight by 7 percent, intra-abdominal fat by 16 percent, plasma leptin by 33 percent, and plasma insulin by 25 percent. Melatonin-treated rats that were then crossed over to control treatment for a further 12 weeks gained body weight, whereas control rats crossed to melatonin treatment lost body weight. Food intake did not change in either group. Feed efficiency (grams of body weight change per gram of cumulative food intake), was negative in melatonin-treated rats and positive in control rats before crossover; this relationship was reversed after crossover.28
In a later study by some of the same researchers, melatonin reduced body weight and leptin levels in middle-aged rats fed a diet similar in high-fat content to the typical American diet.29
Beyond stimulating weight loss, melatonin helps reduce the free radical damage associated with nitric oxide, produced in fat cells when leptin levels are high. Nitric oxide causes oxidant damage and ultimately cell death and may be partly responsible for the increased heart disease rate associated with obesity.30
L-carnitine is another nutrient shown to exert some promising leptin-lowering effects. Overweight/obese premenopausal women consumed a hypocaloric diet (30 percent protein, 30 percent fat and 40 percent carbohydrates) in addition to increasing the number of steps per day. For ten weeks, 35 of the women received carnitine in a randomized, double-blind manner, while 35 women remained untreated.
After carnitine supplementation, leptin levels declined by nearly 6 percent. In addition, carnitine-treated subjects decreased total energy by 26.6 percent, energy from carbohydrates by 17.3 percent, body weight by 4.6 percent, body mass index by 4.5 percent, and waist circumference by 6.5 percent. Ten of 19 participants with insulin resistance became insulin sensitive and 7 of 8 participants with the metabolic syndrome no longer had the syndrome after the intervention.31
Lowering leptin levels also may account for conjugated linoleic acid’s (CLA) ability to cause weight loss. Researchers at Ohio State and Purdue Universities conducted a double-blind, eight-week study of 21 type-2 diabetics. One group of subjects consumed a CLA supplement daily, the other group consumed a safflower oil supplement as a control.
Diabetics who supplemented their diet with CLA had a lower body mass than subjects who did not include the fatty acid in their diet. In the group taking safflower supplements, weight remained the same. Higher CLA levels in the bloodstream were associated with lower levels of leptin. In the safflower group, leptin levels rose slightly.
In addition, the CLA-supplemented subjects had nearly five-fold lower blood sugar levels compared to patients taking the safflower oil.32
In animals, CLA also has exerted both weight-lowering and leptin-lowering properties. In one rodent study, compared to controls, CLA significantly reduced serum leptin concentration by 42 percent while also decreasing the weight of visceral adipose tissue. CLA supplementation produced a 5.2 percent decrease in body weight compared with the control even though food intake was similar in both groups.33
In vitro, CLA significantly reduced leptin secretion from cultured adipocytes (fat cells), and reduced leptin mRNA levels within the cells.34
Another natural substance with potent leptin-lowering properties is omega-3 fatty acids. In cultures where fish is eaten daily, blood leptin levels are low. Researchers compared two African tribes, both equal in their daily caloric consumption and lifestyles. The main difference between the two groups was that the 279 who dwelled near a lake derived approximately one quarter of their total calories from fish. The 329 members of the other group lived farther inland, and consumed the majority of their calories from fruits and vegetables.
The study comparing the two tribes found that men who consumed fish had 2.5 nanograms of leptin per milliliter of blood—less than one quarter of the leptin level of the non-fish-consuming males. Significantly lower leptin levels were also found in females who ate fish compared to their non-fish-consuming counterparts.
The researchers speculated that eating fish may alter the influence of leptin on body fat and help the body become more finely tuned to the signals leptin sends to the body.35
Leptin is emerging as a hormone that is integral to weight management. Studies suggest that the key to successfully and permanently lowering weight may be lowering levels of this hormone. A number of natural substances have been highlighted in this article. Melatonin, Carnitine, CLA, and omega-3 fatty acids all seem to play an important role in controlling leptin by restoring leptin sensitivity.
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