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Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism

Abstract: Leptin is secreted by adipose tissue and regulates energy homeostasis, neuroendocrine function, metabolism, immune function and other systems through its effects on the central nervous system and peripheral tissues. Leptin administration has been shown to restore metabolic and neuroendocrine abnormalities in individuals with leptin-deficient states, including hypothalamic amenorrhea and lipoatrophy. In contrast, obese individuals are resistant to leptin. Recombinant leptin is beneficial in patients with congenital leptin deficiency or generalized lipodystrophy. However, further research on molecular mediators of leptin resistance is needed for the development of targeted leptin sensitizing therapies for obesity and related metabolic diseases.


Alex’s Notes: Leptin is a hormone produced mainly by your white adipose tissue that plays an important role in regulating energy homeostasis and several metabolic processes. Let me start over.

Leptin is THE master regulator for energy homeostasis secreted primarily by white adipose tissue (WAT) in a direct proportion to the amount of body fat, thereby reflecting the status of long-term energy stores. Additionally, its levels can fluctuate in response to calorie intake with a marked decrease during starvation. Put another way, this is the hormone that causes bodybuilders to feel like death when they are becoming contest lean. It is why our metabolic rate slows during dieting. It is why your “mojo” disappears and why staying in fitness model shape (often below 8% body fat for men and perhaps 18% for women) is so difficult. For completeness, it is secreted in a pulsatile manner, with the lowest levels at mid-afternoon and the highest levels at midnight. Women also tend to have higher levels than men even after controlling for body fat, suggesting a role of sex hormones in its regulation, but also supporting the difficulties women have losing weight relative to men.

Leptin exerts its effects via leptin receptors (LepRs) within the CNS that active several signaling pathways upon binding. Many of these may sound familiar and include JAK2-STAT3, PI3K, MAPK, and AMPk. In a nutshell, leptin interacts with our brains to control food intake by activating anorexigenic neurons that work to reduce food intake and increase energy expenditure. Conversely, when leptin levels decline, orexigenic neurons are stimulated, thereby increasing food intake and decreasing energy expenditure. In this way, high leptin levels theoretically aid in weight loss while low leptin levels aid in weight gain. One of the orexigenic compounds expressed with low leptin levels is neuropeptide Y, which if you recall from a previous study in June has adipogenic and antilipolytic effects. On the flip-side, leptin acts synergistically with GLP-1 and CCK in the brain to promote satiety.

But it is not all about food intake. In rodents, leptin increases energy expenditure increased expression of uncoupling protein-1 in brown adipose tissue. Unfortunately, human adults don’t have significant brown fat to make this relevant, but it could play a role in developing children, especially infants, and help explain why they are so readily able to control food intake to match energy needs (if they eat too much they get hot). Interestingly, leptin also appears to interact with the cortical and hippocampal neurons of the brain as well. Leptin deficient rodents have decreased brain weight and volume, and brain imaging studies in humans with congenital leptin deficiency show structural and functional deficits.

Lessons from congenital leptin deficiency

Leptin’s role in energy homeostasis is most evident in those who have congenital leptin deficiency. They are hyperphagic and obese and unlike most people who blame genetics for their weight problems, they can literally blame genetics for being morbidly obese. Fortunately for them, leptin treatment fixes everything.

Leptin levels in adipose tissue and plasma fall rapidly during fasting. Circulating leptin levels decrease in overweight men after negative energy balance is achieved with exercise and calorie restriction, indicating that leptin levels reflect energy status.Low leptin levels during fasting trigger metabolic and hormonal responses in mice and humans consisting of hyperphagia, hypogonadotropic hypogonadism, and suppression of thyroid and growth hormone (GH) levels, which are prevented by physiologic doses of leptin.These hormone changes are similar to congenital leptin deficiency which results in hypogonadism and failure of pubertal development, and overall suggest a vital role of leptin in reproduction. Moreover, leptin administration to weight-reduced individuals reverses the declines in T3 and T4 levels and in energy expenditure.

Leptin deficiency also results in insulin resistance, diabetes, steatosis, and other features of metabolic syndrome, which are all fixed with leptin replacement therapy. It is likely these benefits on glucose and fat metabolism are mediated by leptin’s effect on the CNS and peripheral tissues via the previously mentioned signaling pathways (AMPk, PI3K, etc.). These work to reduce glucose production in the liver and promote uptake into skeletal muscle, as well as stimulate fatty acid oxidation. Interestingly, leptin also has an intimate relationship with insulin by inhibiting its gene expression and glucose-stimulated secretion. In turn, insulin stimulates leptin synthesis and secretion, thus establishing a relationship between fat cells and the pancreas. This is also a reason for carbohydrate-dominated re-feeds during times of extreme or prolonged dieting.

As far as exercise goes, it has recently been shown that skeletal muscle also possesses some leptin receptors. It is thought that leptin acts to directly increase skeletal muscle glucose uptake and fatty acid oxidation, and it is interesting to note that one week of bed rest induces skeletal muscle leptin resistance. Alternatively, sprints have been shown to enhance leptin signaling.

So why not give leptin to all obese people?

As critical as leptin is to energy homeostasis, the vast majority of obese people are insensitive to leptin treatment. Their over-nutrition and sedentary lifestyle creates “leptin resistance” if you will. In fact, leptin can be thought of as playing a more critical role in the maintenance of weight loss rather than the weight loss itself. In other words, elevated leptin may not do much but its decline with dieting and “leanness” stimulates a host of mechanisms that all work towards weight-regain and the prevention of further fat loss via hormonal down-regulation, increased appetite, and metabolic slowing.

Indeed, we have already established that leptin replacement dramatically reduces body fat and reverses hormonal and metabolic abnormalities in those with leptin deficiency. Along similar lines, those who diet down to levels that naturally suppress leptin production – such as women with hypothalamic amenorrhea – leptin replacement therapy restores normal menstrual cycles, corrects abnormalities in the gonadal, thyroid, and adrenal axes, and improves bone mineral density. To be honest, with all the drugs that professional bodybuilders and many fitness models take, leptin during times of dieting would probably be the most useful.

So there you have it, a very brief overview of the master regulator leptin. To summarize everything that is relevant, when eat in a caloric deficit and/or have low levels of body fat your natural production of leptin will fall, and this in turn will reduces thyroid and testosterone levels, make you hungry and insatiable, irritable, and slow your metabolic rate. In essence, leptin is the evolutionary hormone that kept us alive during times of starvation.


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