How Leptin, Ghrelin, and other Hormones can Thwart your best efforts to get “thin.”

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In 1950, researchers at Maine’s Jackson Labs produced a strain of Mice labeled OB/OB, or Obese/Obese, as both parents carried a recessive mutation that was expressed in Obesity. This recessive mutation was found to cause the mice to become three times as large as normal mice, and their appetites were ravenous. They were inactive and suffered from some chronic conditions including obesity, constant appetite, a diabetes-like syndrome of hyperglycemia, glucose intolerance, elevated plasma insulin, subfertility, impaired wound healing and an increase in hormone production from both pituitary and adrenal glands. They were found to have slowed metabolic processes and lower than normal body temperature. The obesity is characterized by an increase in both the number and the size of adipocytes (fat cells). The excess in weight and excess fat continued even after restricted diet that was sufficient for normal weight maintenance in normal mice.

Dr. Jeffery Friedman, a molecular geneticist at the Rockefeller University, became curious as to why the defect in just one gene (of the approximately 25,000 genes) would have such dramatic effects on the mice’s weight, appetite, and behavior. He began searching for the gene he suspected was causing this obesity in mice in the late 1980’s using a recently discovered methodology called positional cloning. Positional cloning has become the process of choice when searching to identify genetic mutations that underlay pathology using Mendelian inheritance. After eight years of searching, Friedman was able to identify and cloned the OB gene in mice. He found the corresponding gene in humans, and by 1995 had managed to purify the product expressed by the OB gene; a hormone he called Leptin.

Friedman discovered that through leptin, and the regulation of food intake and metabolism, fat functioned as an endocrine organ. Therefore obesity can be best understood as a problem of biology. Leptin is a 16-kDa polypeptide that is primarily produced in white adipose tissues and secreted into the blood stream. Like many hormones in the mammalian body, leptin acts to maintain homeostasis. How fat controls the physiology and metabolism is through secretion of leptin into the bloodstream where it acts on parts of the brain through influencing the neurotransmitters used to communicate, including melanocortin peptides that allow the brain to regulate food intake and energy expenditure. When fat is reduced, the levels of leptin in the bloodstream diminish, stimulating appetite and suppressing metabolism until the fat mass has been restored. Conversely, when fat mass increases, leptin levels also increase thus suppressing appetite until the weight is brought back to homeostatic level. This system maintains control of adipose mass and is extremely difficult to circumvent.

Because leptin modulates the amount of adipose tissue in the body, it acts on specific receptors in the hypothalamus to inhibit appetite through both counteractive and stimulatory mechanisms through interaction with other hormones such as ghrelin (that tells your body you are full), and neuropeptide Y as well as the effects of a cannabinoid neurotransmitter called anandamide which stimulates appetite. Leptin also promotes the synthesis of an appetite suppressant called α-melanocyte-stimulating hormone. When the fullness hormone ghrelin is suppressed, the stimulation of neuropeptide Y and anandamide, the result is an almost addictive desire to eat. Researchers are finding that as fat mass decreases, the level of plasma leptin falls, thus stimulating appetite until the fat mass is recovered. There is also a decrease in body temperature; energy expenditure (metabolism) is also suppressed.

Leptin also plays an important role in regulating and modulating the onset of puberty. For example, girls from undernourished societies and underweight women take longer to reach puberty than heavier girls. In fact, girls who are too thin often fail to ovulate during menstrual cycles. Reproductive growth and fat stores are therefore vital in the regulation of reproduction. In the athletic field, dancers and other energy-intense training young women sometimes cease menstruating due to a lack of adequate adipose tissue.

As it turns out, Leptin is so central to the treatment of obesity that it has begun to be developed as a therapy for some forms of obesity including life-threatening metabolic disorders such as lipodystrophy (a medical condition characterized by abnormal or degenerative conditions of the body’s adipose tissue), some forms of diabetes, and hypothalamic amenorrhea (caused when the hypothalamus gland slows or stops releasing gonadotropin-releasing hormone). Dr. Friedman’s landmark research has created a flood of research in laboratories around the globe, resulting in tens of thousands of research articles.

Made by the body’s fat cells, leptin is now understood to be the critical hormone of a very complex endocrine system that not only maintains the body’s weight; it exerts controlling effects on other hormones that control glucose metabolism and insulin sensitivity, and even immune function. In fact, the neuroendocrine system itself is greatly influenced by leptin. Dr. Friedman came to understand that the OB mutated mice completely lacked the gene for leptin; they ate until they became obese, simply because their brains went into a permanent starvation mode. And when given leptin supplements, these OB mice ate less. They lost weight and became more active. It was also found that they responded better to insulin, a significant factor in Type II Diabetes and Metabolic Syndrome. Mouse models are used to better understand disease states because the genetic, biological and behavior characteristics closely resemble those of humans, and many symptoms of human conditions can be replicated in mice. It should come as no surprise that in humans would leptin mutations who are also unable to produce leptin are massively obese and suffer from some chronic conditions that drastically improve with leptin therapy.

When our bodies are functioning properly, excess fat cells will produce leptin, which in turn triggers the hypothalamus to lower the appetite response. This allows the body to utilize the fat stores to feed us. Unfortunately, when someone suffers obesity, they will have too much leptin in the blood. This can result in leptin insensitivity and lead to leptin resistance. Because the person feels hungry despite not utilizing stored energy, they keep eating, and the fat cells produce more leptin to signal the hypothalamus to send the satiation signal, leading to increased leptin levels and more leptin insensitivity.

This does not mean that all persons suffering from obesity have similar mutations. In fact, some studies have shown that only a small subset of people with obesity was able to lose weight with leptin therapy. Most humans, like most mice, produce ample amounts of leptin, but their bodies simply were resistant. One possible means of reducing this leptin resistance is through combination therapy with other hormones, in articular, Amylin.

Amylin is a peptide hormone that is co-secreted along with insulin from the pancreatic β-cell and has been found to be deficient in patients with Type-II Diabetes. By combining leptin with amylin, at least in clinical studies with obese patients, a reduction of 13% bodyweight has resolved. If you are struggling with obesity or weight, these hormones can affect your overall health as well as your scale. Excess body fat causes problems with hormonal secretion, neurochemistry, and even immune function. While leptin has been called the starvation hormone, this is not accurate; a better term might be the satiation hormone as leptin inhibits hunger, regulates energy balance, and prevents the body from triggering hunger responses when energy is not needed.

Low levels of leptin are rare but do occur. There are a very few people who suffer from a genetic condition called congenital leptin deficiency. This condition prevents the body from producing leptin. Without leptin, the body is confused and thinks it has too little body fat, signaling the brain to consume resulting in an intense, uncontrolled hunger. This often manifests in childhood obesity and delayed puberty. The treatment for leptin deficiency is currently leptin injections. However, significant research is now taking place.

 

 

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